Bisphenol A (BPA)
Links Between BPA and Diabetes/Obesity
Over 600 peer-reviewed studies published since 2005 in scientific journals have examined the relationship between BPA (and other bisphenols) and diabetes or obesity.
Overall, the majority of human epidemiological studies have found that people with higher exposures to BPA have a higher risk of type 2 diabetes or obesity. This evidence includes long-term, longitudinal studies that follow people over time, as well as some experimental studies in humans, in which people were exposed to BPA in a lab and experienced diabetes-related effects. The evidence linking BPA to gestational diabetes is growing but preliminary, and there are very few studies on BPA and type 1 diabetes.
Exposure to BPA in the womb or during early life-- key periods of susceptibility-- appears to increase the risk of developing diabetes or obesity later in life.
Laboratory studies on animals or cells show that BPA exposures can cause biological effects related to diabetes/obesity, and have helped to identify the key periods of susceptibility and the mechanisms involved. These studies show that exposure to BPA during early development can lead to diabetes/obesity-related effects not only in first generation offspring, but also in later generations.
An expert panel of scientists has estimated that prenatal BPA exposure has a 20 - 69% probability of causing 42,400 cases of childhood obesity in the European Union, with associated lifetime costs of €1.54 billion (Legler et al. 2015).
Studies have also found links between BPA exposure and the risk of diabetes complications.
Yet the U.S. FDA still says that BPA is safe, despite "overwhelming evidence of harm." (vom Saal and Vandenberg 2020).
Reviews of BPA and Diabetes/Obesity
Type 1 Diabetes and Autoimmunity
A review of BPA and autoimmune diseases finds that "Data from animal models provided consistent evidence highlighting the role of BPA in the pathogenesis, exacerbation and perpetuation of various autoimmune phenomena including ... insulitis in type 1 diabetes mellitus." (Sharif et al. 2021).
Another review on autoimmunity finds that BPA has been found to affect the immune system, leading to the development of autoimmunity, and that BPA has been found to play a role in the pathogenesis of systemic and organ-specific autoimmune diseases, including type 1 diabetes (Lazurova et al. 2021).
Type 2 Diabetes and Obesity
A review of bisphenols (including BPA substitutes) and obesity finds that their effects on fat tissue may be involved in cardiovascular disease as well (Callaghan et al. 2021).
A review concludes that BPA exposure is a risk factor for the development of diabetes and obesity (Pérez-Bermejo et al. 2021).
A systematic review and meta-analysis of 10 human studies found that each 1-ng/mL increase in BPA level increased the risk of obesity by 11% (Wu et al. 2020).
A meta-analysis of studies involving over 32,000 people found that higher BPA levels were associated with an increased risk of overweight, obesity, and a higher waist circumference in adults (Ribeiro et al. 2020).
A meta-analysis of 16 studies found that BPA exposure is associated with a higher risk of type 2 diabetes in humans (Hwang et al. 2018).
A systematic review and meta-analysis of 33 large human studies concluded that, "there is evidence from the large body of cross-sectional studies that individuals with higher BPA concentrations are more likely to suffer from diabetes, general/abdominal obesity and hypertension than those with lower BPA concentrations.... Moreover, among the five prospective studies, 3 reported significant findings, relating BPA exposure to incident diabetes, incident coronary artery disease, and weight gain" (Rancière et al. 2015). (A review focusing just on hypertension finds that BPA has an adverse on blood pressure, depending gender, dose, and timing (Wehbe et al. 2020).)
Another review summarizes "both epidemiological evidence and in vivo experimental data that point to an association between BPA exposure and the induction of insulin resistance and/or disruption of pancreatic beta cell function and/or obesity" (Chevalier and Fénichel 2015). An additional review, of 13 studies on type 2 diabetes and BPA argues that, "chance is unlikely the plausible explanation for the observed association" between BPA exposure and type 2 diabetes (Sowlat et al. 2016).
A systematic review and two meta-analyses of 13 epidemiological studies on BPA and childhood obesity looked at associations in both directions, to see if BPA increased the risk of obesity, or if obesity affected levels of BPA. It found that the relatively high-exposed group had a significantly higher risk of childhood obesity than the relatively low-exposed group. However, the obese group showed no significant difference in the BPA concentration when compared to the normal group. This suggests that there is possible causality between BPA exposure and childhood obesity (Kim et al. 2019).
Another review finds that "Most data support the effects of bisphenol A ... on the development obesity and type 2 diabetes mellitus. These endocrine disrupting chemicals interfere with different cell signaling pathways involved in weight and glucose homeostasis." (Stojanoska et al. 2017). An additional review finds that "Most of the clinical observational studies in humans reveal a positive link between BPA exposure, evaluated by the measurement of urinary BPA levels, and the risk of developing type 2 diabetes mellitus. Clinical studies on humans and preclinical studies on in vivo, ex vivo, and in vitro models indicate that BPA, mostly at low doses, may have a role in increasing type 2 diabetes mellitus developmental risk, directly acting on pancreatic cells, in which BPA induces the impairment of insulin and glucagon secretion, triggers inhibition of cell growth and apoptosis, and acts on muscle, hepatic, and adipose cell function, triggering an insulin-resistant state." (Provvisiero et al. 2016).
A review finds that "Over the last decade, an enlarging body of evidence has provided a strong support for the role of BPA in the etiology of diabetes and other metabolic disorders... Exposure to EDCs [endocrine disrupting chemicals] during early life may result in permanent adverse consequences, which increases the risk of developing chronic diseases like diabetes in adult life. In addition to that, developmental abnormalities can be transmitted from one generation to the next, thus affecting future generations." (Tudurí et al. 2018).
According to a review on BPA and insulin resistance, "The hypothesis states that unnoticed and constant exposure to this environmental chemical might potentially lead to the formation of chronic low-level endocrine disruptive state that resembles gestational insulin resistance, which might contribute to the development of diabetes. The increasing body of evidence supports the major premises of this hypothesis, as exemplified by the numerous publications examining the association of BPA and insulin resistance, both epidemiological and mechanistic. However, to what extent BPA might contribute to the development of diabetes in the modern societies still remains unknown." (Pjanic 2017). Another systematic review and meta-analysis of BPA found an association between BPA and a higher BMI and insulin resistance and (as well as with polycystic ovary syndrome (PCOS), which is linked to type 2 diabetes and obesity (Hu et al. 2018). Workers exposed to BPA tend to have higher levels of exposure; this is a concern for metabolic disease as well (Caporossi and Papaleo 2017).
For a nice (and free full text) review of the evidence linking prenatal BPA exposure to diabetes and obesity, see Alonso-Magdalena et al. 2015.
A further review concludes that BPA should be considered an obesogen (Legeay and Faure 2017).
A systematic review and meta-analysis of 61 studies on early-life exposure to BPA and obesity-related outcomes in rodents finds that it may increase fat weight and lipid levels, especially in males, and at exposure levels below the U.S. "safe" dose (Wassenaar et al. 2017). However, another finds that, "Although vast experimental literature exists, there is limited epidemiological evidence to support the hypothesis for the obesogenic effect of BPA" (Hoepner 2019). Regarding the experimental literature, a review finds that when laboratory conditions are the same, obesity is a consistent finding in BPA studies (Rubin et al. 2019).
A review of epidemiological and laboratory studies on BPA and type 2 diabetes finds that BPA alters various aspects of beta cell metabolism; varying concentrations of BPA disrupt glucose homeostasis and pancreatic beta cell function. BPA also plays a role in the development of insulin resistance and has been linked to long-term adverse metabolic effects following fetal and perinatal exposure (Farrugia et al. 2021). Additional reviews also discuss links between BPA exposure and diabetes (e.g., Akash et al. 2020).
There are more reviews as well (e.g., Biemann et al. 2021).
So why is BPA still legal to use? It is beyond me. Ask the FDA. And in fact, a large study tried to address this issue with the FDA, called CLARITY-BPA. It ended up in a big mess with the various authors disagreeing with each other about the conclusions the others drew from the same data (Vandenberg et al. 2019). Meanwhile, the chemical regulators in Europe are looking closely at BPA and may be making some progress (e.g., determining that BPA is an endocrine disruptor: ANSES's Working Group on "Endocrine Disruptors," et al. 2018; Beausoleil et al. 2018a Beausoleil et al. 2018b).
Type 2 Diabetes, Insulin Resistance, and Body Weight
Experimental Studies in Humans
When researchers gave low, supposedly "safe" levels of BPA to adults, their insulin secretion was directly affected (Stahlhut et al. 2018). This article in Environmental Health News has a good description of the study: In a scientific first, researchers gave people BPA — and saw a link to precursor of type 2 diabetes.
A second study also found that giving BPA to adults (well, college students) resulted in immediate, measurable changes. They found lower levels of insulin, glucose, and c-peptide (a marker of beta cell function) (Hagobian et al. 2019).
Elderly adults who consumed two beverages out of cans containing BPA had significantly higher blood pressure two hours later, as compared to when they drank beverages out of glass (Bae and Hong, 2015). In a further randomized crossover dosing trial, this lab also found epigenetic changes two hours following BPA consumption that were linked to high blood pressure (Kim et al. 2020).
The procedures for another upcoming study have also been published. The purpose is to determine whether orally administered BPA for 4 days at the EPA's "safe" dose has an adverse effect on insulin resistance or liver glucose production (Hagobian et al. 2020).
Watch the webinar, "Getting a Clear View: Lessons from the CLARITY-BPA Study," featuring Dr. Laura Vandenberg of Univ. of Massachusetts (July 2019). Sponsored by the EDC Strategies Partnership and hosted by the Collaborative on Health and the Environment.
Longitudinal Studies in Humans
The strongest evidence for the ability for environmental exposures to contribute to the development of diabetes comes from longitudinal studies. These are studies that take place over a period of time, where the exposure is measured before the disease develops.
The first published longitudinal study of BPA and type 2 diabetes used data from the U.S. Nurses Health Studies 1 and 2. In the Nurses Health Study 1, which includes older women (average age 66), BPA levels were not associated with type 2 diabetes. However, in the Nurses Health Study 2, which includes middle-aged women (average age 46), BPA levels were associated with type 2 diabetes (after adjusting for body mass index (BMI)). Thus, BPA exposures may be associated with the risk of type 2 diabetes among middle-aged women, but not older women. These findings may be due to menopausal status (although chance cannot be ruled out). While the younger women had higher levels of BPA than the older women, these differences did not explain the findings. Because experimental data suggests that BPA interferes with the function of the insulin-producing pancreatic beta cells by activating estrogen receptors, the authors hypothesized that any associations between BPA and diabetes would be stronger in pre-menopausal women than post-menopausal women. Indeed, the association between BPA and diabetes shows a clear linear trend in pre-menopausal women, but there is no association in post-menopausal women. And, the association between BPA and diabetes was stronger in women who developed diabetes at a younger age (under 55). These interesting findings should be examined in other cohorts. Note that this paper also found similar results for phthalate exposure levels (Sun et al. 2014).
BPA Associated with Increased Risk of Type 2 Diabetes
Type 2 diabetes incidence increases as levels of BPA increase in premenopausal women (A), but not in postmenopausal women (B).
A similar study by many of the same authors, also based on the Nurses Health Studies, found that women (without diabetes) with the highest levels of BPA (and some phthalate) exposure gained more weight during the 10 year follow-up period than those with lower levels of exposure (Song et al. 2014).
A longitudinal study from France found a near doubling of the risk of type 2 diabetes from BPA and BPS exposure levels (Rancière et al. 2019). For an article describing this study, see Bisphenol Exposure and Type 2 Diabetes: New Evidence for a Potential Risk Factor, published in Environmental Health Perspectives (Seltenrich 2020).
In middle-aged and elderly East Asians, BPA levels were associated with fasting glucose levels, but only in people with genetic risk of diabetes (Bi et al. 2016). A longitudinal Chinese study found that BPA exposure levels were associated with increased fasting blood sugar levels and lower beta cell function in women, but not men (Wang et al. 2019). A longitudinal study of Chinese men found an increased risk of metabolic syndrome in those with higher BPA levels, but mainly in smokers (Wu et al. 2019).
In adults over age 40 in Shanghai, China, BPA levels were associated with a higher risk of developing obesity, over a 4 year period, especially in women, individuals who were younger than 60, those of normal weight, non-smokers, non-drinkers, and those without high blood pressure (Hao et al. 2018). A further study by these authors found that high BPA exposure, especially maintained a long time period apart, was associated with higher LDL cholesterol levels and lower HDL cholesterol levels among middle-aged and elderly adults (Wang et al. 2020). Another study from China found no association between BPA levels and type 2 diabetes, with 5 years of follow-up (Shu et al. 2018). Also in China, BPA levels were associated with lower HDL cholesterol levels over a 5 year period (Li et al. 2020).
In elderly Swedish adults, BPA levels were not associated with measures of obesity (fat mass and fat distribution) two years later. BPA levels, however, were associated with levels of the hormones adiponectin, leptin, and ghrelin, which are involved with hunger and satiety (Rönn et al. 2014).
A longitudinal study of the elderly in South Korea found BPA levels were associated with overweight in women, but not men (Lee et al. 2015).
Belgian adults who were obese had higher levels of BPA than those who were not. Over 3, 6, and 12 months of weight loss (via either dieting or bariatric surgery), levels of BPA did not change (Geens et al. 2015).
Longitudinal Studies in Children
In Dutch children, total bisphenols and bisphenol A were associated with a decrease in BMI from 6 to 10 years (Silva et al. 2021).
BPA exposure levels in Korean pre-adolescent girls were associated with higher insulin and insulin resistance levels one year later (Lee et al. 2013).
In Mexican girls (but not boys), BPA levels during childhood (but not in utero) was associated with skinfold thickness (Yang et al. 2017).
Exposure During Development
Evidence is growing that exposure to pollution during critical developmental periods, such as in utero or during childhood, may have effects later in life.
Most of the longitudinal human studies on BPA thus far are related to growth and body weight outcomes (not diabetes), all at typical U.S. exposure levels.
Dutch infants born to women with higher amounts of BPA had smaller heads and grew slower in the womb than infants whose mothers had lower amounts of BPA. The results were more significant depending on how often the BPA was measured during the pregnancy; the more measurements, the more significant (many other BPA studies rely on one measurement of BPA, which is less accurate-- this study measured BPA multiple times). The study suggests that BPA exposure during pregnancy may impair fetal growth (Snijder et al. 2013). Prenatal BPA levels were also associated with higher blood pressure in Dutch boys, but lower blood pressure in girls (Sol et al. 2020a). Prenatal BPF levels, meanwhile, were associated with lower insulin levels in boys (Sol et al. 2020b). Another study, however, found no association between prenatal BPA levels and weight-related measures during childhood (Sol et al. 2020c).
A large European study found no association between prenatal or childhood BPA exposure levels and childhood BMI (Vrijheid et al. 2020).
The University of Michigan (go blue!) hospitals found that BPA exposure was associated with lower birth weight and taller height (Veiga-Lopez et al. 2015). (Note that lower birth weight is associated with an increased risk of type 2 diabetes as well as other outcomes). A meta-analysis of eight studies, however, found no association between prenatal BPA exposure levels and birth weight (Hu et al. 2018) Maternal (but not paternal) BPA levels before conception, however, were associated with lower birth weight, which is interesting, as exposures before conception are have not really been examined much yet (Mustieles et al. 2018). Prenatal exposure to BPA substitutes, BPF and BPS, are also associated with lower birth weight (Hu et al. 2019).
In Spain, prenatal BPA levels were associated with increased waist circumference and higher body mass index (BMI) in children at age 4, but not at earlier ages (Valvi et al. 2013). The same study, when including 27 different endocrine disrupting chemicals, found that in utero levels of various persistent organic pollutants were associated with overweight/higher BMI at age 7, while other chemical levels (BPA, arsenic, phthalates, flame retardants, lead, and cadmium) were not associated (Agay-Shay et al. 2015).
Early Life Exposure to BPA Causes Later Life Obesity in Rodents
Rodents exposed to BPA in the womb grow to be fat later in life. Does this happen in humans too? Scientists are trying to find out.
Source: Photo used with permission from Dr. Desai, from these studies:
Desai M, Jellyman J, Han G, Beall MH, Ross MG. Endocrine disruptor (Bisphenol A) increases proliferation and lipid storage of adipocyte progenitor cells. Reproductive Sciences 2013, 20(3), 200A; Abs F-032.
Jellyman JK, Oses C, Shelar P, Abinader R, Han G, Beall MH, Ross MG, Desai M. Maternal Bisphenol A Programs Offspring Adipose Tissue Inflammation via Adipogenic Angiotensinogen. Reproductive Sciences 2014, 21(3), 266A; Abs F-091.
Prenatal BPA exposures were associated with a lower BMI, less body fat, and less overweight/obesity in Californian girls at age 9, while current BPA levels were associated with higher BMI, obesity/overweight, waist circumference, and fat mass at that age (Harley et al. 2013). For an article describing this study, see Unclear relationship: Prenatal but not concurrent bisphenol A exposure linked to lower weight and less fat, published by Environmental Health Perspectives (Betts 2013).
In Cincinnati, Ohio, prenatal BPA exposure levels were not associated with BMI in early childhood. Children with the highest exposures, however, grew fastest between age 2 and 5 (Braun et al. 2014).
In Canada, first-trimester maternal levels of BPA were associated with adipnectin levels in male infants-- a hormone that influences a number of metabolic processes, such as blood glucose levels. These infants will be followed to see if there are any later-life effects (Ashley-Martin et al. 2014). Also in this cohort, gestational BPA levels were associated with small increases in girl's central adiposity during early childhood (Braun et al. 2019).
In Crete (Greece), while prenatal BPA levels were not consistently associated with excess weight, exposure levels in early childhood were. BPA exposure levels at age 4 were associated with a higher BMI, waist circumference and skinfold thickness (Vafeiadi et al. 2016). In Cyprus, cord blood levels of BPA were not associated with weight-related measures at birth (Dalkan et al. 2019).
In New York City, prenatal BPA levels were not associated with fat mass during childhood (age 4-9) (Buckley et al. 2016). However a different New York City study found that prenatal BPA levels were associated with fat mass during childhood, as well as percent body fat and waist circumference at age 7 (BPA levels during childhood were not associated with any of these outcomes) (Hoepner et al. 2016).
In Korea, maternal BPA levels were associated with epigenetic changes in the offspring at age 2 (but not later in childhood). These changes were in genes linked to obesity (Choi et al. 2020).
A Korean study found that maternal BPA levels were associated with higher diastolic blood pressure in children at age 4 (Bae et al. 2017). Another found that prenatal exposure to BPA was associated with lower growth in the womb, and higher growth during early childhood (Lee et al. 2018). In Japan, maternal BPA and various phthalate levels were associated with lower leptin and BPA with higher adiponectin levels in cord blood (Minatoya et al. 2018).
In China, breastmilk levels of BPA were associated with lower weight and length gain in infants (Jin et al. 2019). Also in China, prenatal exposure to BPA was associated with a higher waist circumference and the risk of central obesity in 7 year old girls (Guo et al. 2020). At age 2, Chinese girls (not boys) exposed to higher levels of BPA prenatally had higher systolic and diastolic blood pressure. In boys, medium maternal prenatal BPA level was associated with higher glucose levels. No associations were found between prenatal BPA and child BMI, skinfold thicknesses, cholesterol/triglycerides, or insulin. There were no associations between levels of BPA in the 2 year olds and any of these measurements, implying that prenatal exposure is more important (note that BPA was detectable in 98.2% of mothers prenatally and 99.4% of children at age 2 years (Ouyang et al. 2020).
Epigenetics may play a role in exposures during development; epigenetic changes in growth and metabolism-related genes in infants were associated with BPA and phthalate levels in cord blood (Montrose et al. 2018). In the U.S., cells obtained from amniocentesis showed that fetuses exposed to BPA in the womb had gene expression patterns related to obesity and liver problems (Bansal et al. 2019).
In the womb, sugar is transported from the maternal to the fetal blood via glucose transporters (GLUTs). A study found that while no differences in GLUTs were detected between placentae from normal weight vs overweight mothers, there were differences in response to BPA. The placental response to BPA in overweight mothers resulted in a reduction in GLUT levels. Given the importance of glucose as a major source of nutrients and energy for the fetus, a worsening of its transport across the placenta could be detrimental to the fetal growth and development (Ermini et al. 2021).
Thus the results vary by study, with some showing that BPA may increase the risk of obesity, and others showing that BPA may decrease the risk of obesity. In either case, BPA may be able to affect growth rates, and the details and effects remain to be determined-- these effects may depend on a variety of things, such as the population studied, other environmental exposures, timing of exposure, dose of exposure, socio-economic factors, nutrition, etc. Also, many of the animal studies that find that BPA exposure leads to a higher body weight (see below) do not find that increase in body weight until the exposed animals reach puberty (Betts 2013).
Cross-Sectional Studies in Adults
Cross-sectional studies are studies that measure exposure and disease at one point in time. These provide weaker evidence than longitudinal studies, since the disease may potentially affect the exposure, and not vice versa.
A number of cross-sectional human studies on BPA use the same dataset, the National Health and Nutrition Examination Survey (NHANES), which is the Center for Disease Control and Prevention’s biennial biomonitoring survey of a large sample of U.S. residents. Using NHANES data from 2003/04, Lang et al. (2008) found that higher BPA concentrations in urine were associated with diabetes and cardiovascular diagnoses, but not with other common diseases. Melzer et al. (2010) then analyzed NHANES data from a subsequent survey, from 2005/06, and found that in those years, BPA levels were lower than they had been in 2003/04. The association between heart disease and BPA remained significant in 2005/06. The association between BPA and diabetes was significant in pooled data (2003-06), but did not reach significance in 2005/06 alone.
Shankar and Teppala (2011) also analyzed NHANES data, and found that pooled data from 2003-08 show a positive association between BPA and diabetes. Silver et al. (2011) took a slightly different view of the 2003-08 NHANES data, defining diabetes by whether or not participants took a diabetes medication, or had high long-term blood glucose levels (instead of using self-reported diabetes, as in the previous analyses). These authors also found an overall positive association between BPA and diabetes in 2003-08 pooled data, although breaking down by year, the association was only significant in 2003/04, not 2005/06 or 2007/08. Curiously, average BPA levels in 2007/08 were up again slightly, after falling between 2003/04 and 2005/06.
Also using NHANES data, Beydoun et al. (2014) found that higher BPA levels were associated with higher insulin levels and increased beta cell function, as well as increased insulin resistance, especially in males.
How Are We Exposed to BPA?
Exposure to BPA is significant and continuous. It is found in plastics, can linings, dental sealants, toys, and other products, and can leach out of these products into our bodies-- especially when exposed to heat or acidity. It also can be absorbed through the skin by handling paper receipts and money. Worldwide, over 6 billion pounds of BPA are produced each year, and over 100 tons are released into the air annually (Vandenberg et al. 2009).
New sources of BPA exposure keep being discovered; wearing clothes is the latest discovery (Wang et al. 2019).
Avoiding BPA by buying BPA-free products may help reduce your exposure to BPA, but you may just end up being exposed to BPA replacement chemicals like BPS and BPF (Dodson et al. 2020).
In adults, BPA was associated with a higher BMI and waist circumference in both genders and in all ethnic groups (also NHANES data, from 2003-2008) (Shankar et al. 2012). Another study, based on NHANES data (from 2003-2008), found that BPA levels were associated with metabolic syndrome in adults (Teppala et al. 2012). Metabolic syndrome is a cluster of conditions associated with type 2 diabetes, sometimes preceding the disease. Some of the same authors also found (using the same data), that BPA was associated with pre-diabetes, defined as a somewhat high fasting blood glucose level or post-meal blood glucose level (not to the point of diabetes) (Sabanayagam et al. 2013). Another study, using NHANES data from 2003-2006, found that among adults, BPA levels were associated with both general obesity and central obesity (Carwile and Michels, 2011). A meta-analysis of data from six cross-sectional NHANES studies found no associations between BPA and levels of cholesterol or triglycerides (Dunder et al. 2019).
A Canadian study using a similarly designed dataset (the Canadian Health Measures Survey, a survey of the general population), found that BPA levels were associated with diabetes, glucose levels, and HbA1c levels (a measure of long-term blood glucose control) in adult men (but not women) (Tai and Chen 2016). A different study using the same dataset found that BPA levels were associated with obesity (as defined by BMI) (Do et al. 2017).
In American Indians of the South Dakota Cheyenne River Sioux tribe, BPA levels-- which were higher than in the average U.S. population-- were not associated with diabetes (Chang et al. 2019).
In Mexican women, BPA levels were associated with a higher risk of diabetes (Murphy et al. 2019).
Another study on BPA and diabetes analyzed a group of Chinese adults, whose average urinary BPA level was lower than in the U.S. Dividing participants into quartiles of BPA exposure, the data shows that risk of diabetes was higher in people in the second and fourth quartiles of exposure, but not the third. The overall trend was not significant (Ning et al. 2011). However, since BPA is an endocrine disruptor, a linear association would not necessarily be expected. Another study from China also found non-linear associations between type 2 diabetes and BPA, as well as with the sum of bisphenols. It also found that BPAF and BPS concentrations were positively associated with T2DM (Duan et al. 2018).
In Chinese adults over 40 living in Shanghai, BPA levels were associated with increased insulin resistance, general obesity, and abdominal obesity (Wang T et al. 2012). In Singapore, BPA levels were associated with BMI as well as oxidative stress (Liu et al. 2018). Also in China, those who lived in electronic waste recycling areas had higher levels of BPA in their bodies, as well as higher rates of abnormal fasting blood glucose levels, compared to those who did not live in these areas (Song et al. 2019).
In Taiwan, young adults with higher BPA exposure levels had higher BMI, blood pressure, and inflammation (Tsen et al. 2021).
In Korea, while the risk of diabetes was somewhat higher in adults with the highest levels of BPA, the results were not statistically significant (Kim and Park, 2013). In contrast, in Iran, the risk of diabetes was much higher in adults with the highest levels of BPA (Ahmadkhaniha et al. 2014). In Koran adults, those with higher BPA levels had a higher waist circumference and were more likely to be obese than those with lower levels. BPA levels were associated with BMI and body fat as well (Ko et al. 2014). In South Korean women of reproductive age, BPS levels were associated with higher insulin resistance (Lee et al. 2019). A Korean study also found associations between BPA and markers of inflammation, regardless of obesity or insulin resistance (Choi et al. 2017). In Korean adults, higher BPA levels were associated with greater abdominal obesity in women, especially in postmenopausal women (Lim et al. 2020). Also in Korean adults, higher BPA levels were associated with an increased risk of both diabetes and obesity (Lee et al. 2020). BPA concentrations were positively associated with obesity in nationwide representative samples of Korean adults (Moon et al. 2021).
In Thailand, BPA levels were highest in adults with diabetes than in those without diabetes, with a stronger association in men than women. Impaired fasting glucose levels were not associated with BPA (Aekplakorn et al. 2015). However a different study of Thai adults found the opposite-- that impaired fasting glucose was associated with BPA, but not type 2 diabetes (Chailurkit et al. 2017).
In India, levels of BPA were significantly higher in people with type 2 diabetes compared to controls, and positively associated with poorer blood glucose control, insulin resistance, and inflammation (Soundararajan et al. 2019). Also in India, BPA levels were higher in people with diabetes in comparison to those without diabetes. In people with diabetes, levels of BPA were linked to higher BMI, waist circumference, and leptin levels, and with lower adiponectin levels (Jain et al. 2020). In Pakistan, BPA levels were higher in those with diabetes or obesity, and associated with higher blood glucose levels (HbA1c), higher insulin resistance, and markers of inflammation, oxidative stress, dyslipidemia, and impaired liver/kidney function (Haq et al. 2020).
A study from Samoa found no significant associations between daily BPA intake and BMI or waist circumference in mothers or children, but unlike most studies, these researchers estimated BPA exposure via diet and did not measure levels in the body directly (Heinsberg et al. 2020).
In Italian adults, BPA levels were associated with higher waist circumference, triglycerides, inflammation, glucose levels, and visceral adiposity (Savastano et al. 2015).
A small pilot study from Cyprus found that while total BPA levels were not associated with diabetes, monochlorinated BPA levels were strongly associated with diabetes. Monochlorinated BPA is formed when chlorine-containing chemicals come in contact with BPA (Andra et al. 2015). Expanding their analysis to a larger group, and this time looking at obesity, these same authors found that an association between BMI and monochlorinated BPA that was relatively weak (Andra and Makris 2015). A study from Spain found higher levels of BPA in those with diabetes, although the difference was not statistically significant (Pastor-Belda et al. 2016).
In Serbia, BPA levels in women with PCOS was associated with increased metabolic risk including an increased risk of obesity, higher insulin levels, and increased insulin resistance (Milanović et al. 2020).
In Lebanon, BPA exposure levels were associated with type 2 diabetes and metabolic syndrome (Mouneimne et al. 2017). In Saudi Arabia, numerous phenols (including BPA, BPF, parabens, etc.) had a higher risk of type 2 diabetes (Li et al. 2018).
Cross-Sectional Studies in Children
A study published in the prestigious Journal of the American Medical Association, based on NHANES data (from 2003-2008), found that Caucasian children (not Blacks or Hispanics) with higher levels of BPA had higher rates of obesity (Trasande et al. 2012). Another study of children using NHANES data (also from 2003-2008) similarly found that those with higher levels of BPA were more likely to be obese, especially non-Hispanic whites (Bhandari et al. 2013). And, a study using NHANES data from 2003-2010 found that BPA was associated with a higher risk of obesity as well as an abnormal waist circumference-to-height ratio in children. The study did not find associations between BPA and insulin or glucose levels (Eng et al. 2013). The children in all of these studies were ages 6-18. Another study using NHANES data (from 2003-2006, in children 8-19), found that BPA levels were associated with higher lean body mass index in boys, and higher fat mass in girls (Li et al. 2017). Another NHANES study (2013-14) found that levels of both BPA and the substitute chemical BPF (but not BPS) were positively associated with higher risk of obesity in children and adolescents, primarily in boys (Liu et al. 2019). Whereas an NHANES analysis of the years 2013-16 finds associations between BPS and BPF and obesity, but not BPA, in youth age 6-19 (Jacobson et al. 2019). Further analysis suggest that in NHANES, children with higher BPA levels had elevated odds of obesity during 2003 to 2008, whereas these associations were inconsistent during 2009 to 2014 (Okubo et al. 2019). It is not clear why.
Can We Reduce Our BPA Exposures?
There is evidence that we can. One 3-week intervention trial successfully reduced BPA levels in women via BPA-free cosmetics and food/water containers. Whether this will lead to a reduction in diabetes or other health outcomes is not known, however (Hagobian et al. 2017).
However, a study of teenagers, found that they were not able to reduce their BPA levels via diet, over a week (Galloway et al. 2018).
A Canadian study found no association between BPA levels and diabetes or blood glucose levels in children (but as mentioned above, there was an association in adult men) (Tai and Chen 2016). A Danish found even opposite associations-- that normal-weight teens and children with higher BPA levels had lower insulin levels, lower insulin resistance, lower leptin, triglyceride, and total cholesterol levels, and lower fat mass, compared with those with lower BPA levels (Carlsson et al. 2018).
Higher BPA levels have been linked to higher body mass index (BMI) in Chinese schoolchildren in Shanghai, aged 8-15 (Wang HX et al. 2012). Another study of Shanghai schoolchildren found that girls aged 9-12 with the highest BPA levels (equivalent to average levels in the U.S.) had twice the risk of excess body weight (over 90th percentile) as those with the lowest exposure levels (Li et al. 2013). Also in Chinese children, higher BPA levels were associated with lower height at puberty (Wang et al. 2018). In Italian children, BPA levels were associated with BMI as well (D'Aniello et al. 2015). However, in children from India, BPA was not associated with obesity (Xue et al. 2015).
A study of U.S. children (using NHANES data from 2003-2010) found that BPA levels were associated with an increased weight-to-height ratio (WHR), a measure of central obesity. WHR is thought to be a better indicator of cardiovascular risk than BMI (Wells et al. 2014).
A small study of overweight or obese Ohio children aged 3-8 found that BPA levels were associated with higher insulin resistance and other metabolic differences (Khalil et al. 2014). A study of obese Italian children found that BPA levels were directly associated with insulin resistance, no matter the BMI. In addition, laboratory experiments showed that BPA does indeed have these effects on children's fat cells (Menale et al. 2017).
In Spanish children, higher BPA levels were associated with higher BMI, increased odds of overweight/obesity, and a greater risk of abdominal obesity (Mustieles et al. 2019). Also in Spanish children, dietary exposure to phytoestrogens (found in plants like soy) and BPA were related to the risk of obesity (as was lack of exercise) (Heras-González et al. 2019).
In Iranian children and adolescents, higher BPA levels were associated with higher BMI, waist circumference, risk of obesity, systolic and diastolic blood pressure, and fasting blood sugar (Amin et al. 2018).
In Turkey, obese children with metabolic syndrome had significantly higher urinary BPA levels than obese children without metabolic syndrome, and both obese groups had considerably elevated levels of urinary BPA than those without obesity (Aktağ et al. 2021).
In North Indian children and adolescents, BPA exposure levels were higher in those who were obese (Malik et al. 2021).
Another phenol, 4-tert-octylphenol, was associated with lower measures of insulin, insulin resistance, β-cell function, and body mass index, and with higher levels of HDL cholesterol in youth from Taiwan (Lin et al. 2018).
Laboratory Studies: Diabetes/Obesity
Laboratory studies are often used to determine the mechanisms through which environmental chemicals act.
Mice exposed to low doses of BPA for 4 weeks developed high blood glucose levels, had lower levels insulin, and had reduced beta cell function (soy counteracted some of these effects) (Veissi et al. 2018).
A single injection of BPA increases insulin levels and decreases blood glucose levels in adult mice. Over a 4 day exposure period, BPA increased insulin levels and insulin resistance in mice, and decreased glucose tolerance-- at doses well below the supposed "safe" level designated by the U.S. EPA (Ropero et al. 2008; Alonso-Magdalena et al. 2006). After an 8 day exposure, adult mice developed insulin resistance and showed disrupted insulin signaling in numerous body tissues (Batista et al. 2012). You might ask how a chemical found to lower blood glucose levels in mice is suspected to contribute to the development of diabetes-- a disease defined by high blood sugar levels-- and that would be a good question. The scientists who conducted this research point out that excess insulin in the blood can itself cause insulin resistance as well as beta cell dysfunction, eventually leading to type 2 diabetes (Nadal et al. 2009). In addition, while the immediate effects of one injection was a lowering of blood glucose, the chronic effects of BPA exposure over a few days time -- including the decrease in glucose tolerance -- caused BPA-exposed mice to have higher blood glucose levels than the unexposed mice after a glucose tolerance test (Alonso-Magdalena et al. 2006). You might just say that these studies show that BPA can mess with blood glucose and insulin levels. And, mice exposed to low levels of BPA for a longer time period-- 8 months-- developed high blood sugar as well as high cholesterol levels (Marmugi et al. 2014). Other authors found that after just 4 weeks of BPA exposure, mice developed high blood sugar (and higher body weight) as well (Moghaddam et al. 2015). Others have also found that BPA causes higher fasting blood sugar, as well as glucose and insulin intolerance in rats (Mullainadhan et al. 2017). After long-term (21 week) exposure, exposure to BPS induced a significant body mass gain in rats, and both BPA and BPS altered cholesterol levels and led to the development of glucose intolerance (Azevedo et al. 2019). Mice exposed to BPA for 2 months had increased triglycerides and total cholesterol levels, and lower HDL cholesterol levels (Trusca et al. 2019). Other studies have also found that BPA exposures increases insulin resistance and messes up glucose metabolism in rodents (Haq et al. 2020).
Scientists Recommend That Patients Are Told How to Reduce Exposure
"Surprisingly, the medical community still gives insufficient attention to the role that endocrine disruptors might have in the emerging pandemic of obesity and type 2 diabetes mellitus. The work by Trasande and collaborators should act as a wake-up call.
I would recommend counselling of patients and their families by pediatricians, obstetricians, endocrinologists and general practitioners to decrease levels of exposure to endocrine disruptors particularly during important periods of development such as pregnancy, infancy and puberty."
- Dr. Nadal, Fat from plastics? Linking bisphenol A exposure and obesity, 2013.
Epigenetics may be involved in the effects of BPA. In rats, BPA exposure led to disturbed fasting blood glucose and glucose tolerance, causing epigenetic changes in genes involved in glucose levels (Rahmani et al. 2020).
BPA exposure may accelerate beta-cell failure in post-menopausal female mice (Oliveira et al. 2020). In older hens, BPA at the " no observable adverse effect level" (NOAEL) accelerated the process of fat formation (Li et al. 2020).
In adult mice, chronic long term exposure to BPA, TBT, and DES altered the hypothalamic circuits that control food intake and energy metabolism (Marraudino et al. 2021).
There also may be interactions with diet. Mice exposed to low doses of BPA for 30 days showed increased body weight and fat mass when fed a normal diet, but not a high-fat diet (Yang et al. 2016). Not all studies have found harmful metabolic effects of BPA, well, as least one didn't (Ding et al. 2016). In mice exposed to BPA and fed a high-fat diet, females had increased body mass, insulin level, and impaired glucose tolerance, while male mice only had impaired glucose tolerance. No change was found in mice fed a standard diet and exposed to BPA (Ma et al. 2021).
In mice, exposure to low and high doses of BPA around the time of puberty increased fat mass later in life (Yang et al. 2021).
In adult male zebrafish, exposure to BPA (and the flame retardant TBBPA) at concentrations commonly found in the environment led to obesity, increased appetite, and fat accumulation in the liver (Tian et al. 2021).
Rabbits exposed to BPA developed insulin resistance, fatty liver, hardening of the arteries, and heart problems (Fang et al. 2015).
BPA is considered an environmental estrogen, because it can act similarly to the hormone estrogen. The mechanism whereby BPA promoted insulin secretion has been shown to involve estrogen receptors (Adachi et al. 2005; Soriano et al. 2012). BPA can promote insulin secretion and also insulin resistance via its estrogenic effects (Alonso-Magdalena et al. 2006), as well as fatty liver (Lv et al. 2017). In fat cells, BPA as well as other estrogenic chemicals disrupt metabolism, at the dose encountered in people today (Tsou et al. 2017).
BPA may have other effects related to diabetes as well. Adult male mice exposed to the supposed "safe" dose of BPA for 2 weeks had impaired glucose sensing in their liver. Glucose sensing is important because it is the way the body tells what the blood sugar level is, and how to react. Glucose sensing is impaired in people with type 2 diabetes, and we don't know why (Perreault et al. 2013).
BPA even affects fruit flies. These effects, involving the gut as well as metabolism-related tissues, involved epigenetic mechanisms, and were enhanced with a high-sugar diet (Branco and Lemos, 2014). And worms. Even the metabolism of worms are affected by BPA (García-Espiñeira et al. 2018). And fish. Fish metabolism is also affected by BPA (Guan et al. 2018), including insulin resistance (Mukherjee et al. 2020). The toxic effects of BPA on zebrafish depend on the dose: low doses induce fat deposition, while high doses cause adverse effects on inflammation and antioxidants (Sun et al. 2019). In carp, BPA exposure increased total cholesterol, LDL cholesterol, and HDL cholesterol levels, and induced oxidative stress and inflammation (Gu et al. 2021).
Exposure During Development
Most of the animal research on BPA has involved exposing pregnant animals to the chemical, then looking for effects on the offspring.
One of the first studies on this topic found that when pregnant mice were exposed to low and high doses of BPA, the exposed male offspring, at 6 months of age, had increased insulin resistance, reduced glucose tolerance, and altered insulin secretion. The offspring exposed to the lower doses of BPA in utero had higher birth weights than the controls, while the offspring exposed to the higher doses in utero had lower birth weights. The results suggest that BPA could contribute to the development of diabetes, and predispose male offspring to type 2 diabetes in adulthood (Alonso-Magdalena et al. 2010). The researchers at this laboratory have also treated mice with BPA during pregnancy, and then fed the offspring either a normal or high-fat diet (controls in both diet groups were not exposed to BPA). The BPA group fed a normal diet caught up in weight to the unexposed high-fat diet before age 28 weeks. Both BPA-exposed groups and the high-fat diet group developed high fasting blood sugar, glucose intolerance, disrupted insulin release from beta cells, high triglycerides, and other effects as well, all of which resemble type 2 diabetes and obesity in humans (García-Arevalo et al. 2014).
BPA Exposure During Development Leads to Glucose Intolerance and Insulin Resistance in Adulthood in Mice
These graphs show how exposure to BPA during development affects health outcomes in male mice in adulthood. On the left, insulin resistance is higher in mice exposed to the lower dose of BPA. On the right, glucose intolerance was higher in mice exposed to both doses of BPA.
Source: Alonso-Magdalena et al. 2010, EHP.
A number of other researchers have pursued this topic further. When researchers exposed mother rats to BPA during pregnancy and lactation, their offspring weighed more and had glucose intolerance as adults. If the offspring were fed a high-fat diet, these effects were accelerated and exacerbated: they were obese and developed severe metabolic syndrome. Interestingly, these effects showed up at the lowest dose of BPA, but not the higher doses (Wei et al. 2011). Male offspring rats exposed to BPA while in the womb and through lactation had higher blood glucose levels and insulin resistance. These effects showed up earlier in life in the rats that received a higher dose, and later in life in the lower dosed rats (Song et al. 2014). Female offspring rats exposed to BPA during development also show higher glucose levels, as well as higher triglycerides and total cholesterol levels (as do their mothers, who were exposed while pregnant) (Moustafa and Ahmed 2016).
When pregnant and lactating mice were exposed to high and low doses of BPA (both relevant for human exposure), the male offspring exposed to the higher BPA dose developed glucose intolerance as adults, and the female offspring exposed to the higher BPA dose were heavier, ate more food, and had more fat than the unexposed offspring, although only when they ate a high-fat diet as adults (Mackay et al. 2013). Additional studies also show that BPA may be able to affect food intake, which could have obesity-related effects (Marraudino et al. 2019). The offspring of BPA-exposed pregnant and lactating rats had higher fasting blood glucose levels and insulin levels, as well as higher body weight at birth and after weaning (Liu et al. 2012).
Rat offspring whose mothers were exposed to BPA during pregnancy and lactation developed impaired glucose tolerance (only males), and higher glucose-stimulated insulin secretion (Galyon et al. 2017). Also in rats, developmental exposure to BPA resulted in significantly increased body weight and adipose tissue, abnormal serum lipids, and lower adiponectin levels in both female and male offspring (Gao et al. 2016). And another found that fat cells held more fat in offspring (Desai et al. 2018).
Rats exposed to BPA during development showed higher body weight throughout life, an effect that was somewhat lessened in the animals fed a soy-based diet (Patisaul et al. 2014). Other studies have also found that rats exposed to low doses of BPA during development show a variety of metabolic disruption effects, including changed glucose metabolism (Tremblay-Franco et al. 2015) and increased body weight later in life (in females) (Hass et al. 2016). Some studies have found that BPA exposure during development can also lead to lower body weight and food intake later in life (Suglia et al. 2016), while others show that BPA exposure during development can cause higher body weight and food intake later in life (Stoker et al. 2019). Perhaps the different results are due to different doses or the timing of exposure. Age and sex can also influence the specific metabolic effects of BPA during development in rats (Nguyen et al. 2020).
BPA intake 8 times lower than the European Food Safety Authority's (EFSA's) current tolerable daily intake (TDI) during gestation and early development causes increased insulin secretion in rat offspring up to one year after exposure (Manukyan et al. 2019).
Miyawaki et al. et al. (2007) found that mice exposed to BPA in the womb and afterwards developed obesity as well as lipid abnormalities. Rubin et al. (2001) found that mother rats exposed to low doses of BPA had heavier offspring, even after the exposure ended. The weight gain persisted longer in females, and, interestingly, was higher at lower doses. Exposure to BPA in utero and in early life can not only affect the body weight of animals, but affect fat cells as well (Rubin and Soto 2009).
Juvenile male mice exposed to BPA for 12 weeks developed glucose intolerance and insulin resistance, in combination with a high fat diet. The BPA made the problems worse than the diet alone (Moon et al. 2015). Rats exposed to BPA only while in the womb showed lower levels of adiponectin and other hormones, and higher levels of leptin and insulin as fetuses (Ahmed 2016). Developmental exposure to BPA also affected leptin sensitivity in mice offspring in adulthood (MacKay et al. 2017), as well as the expression of genes in the liver, including those involved in glucose and lipid metabolism (Ilagan et al. 2017). Developmental exposure to low doses of BPA increased triglyceride levels in males and increased fat cell density in females, as well as affected gene expression (Lejonklou et al. 2017). In offspring rats, Low-dose developmental BPA exposure led to altered desaturation activity, whatever that is, and altered fatty acid composition, both related to insulin resistance (Dunder et al. 2018).
In the liver of female (not male) rat fetuses, in utero exposure to very low doses of BPA causes significant changes in the proteins involved in cholesterol and fatty acid synthesis (Tonini et al. 2021).
An extensive study designed to test how BPA can program metabolism in early life -- at levels relevant to human exposures -- exposed mice during gestation and lactation to 8 different low doses of BPA, and followed offspring for 20 weeks after weaning, with no further exposure (until mouse adulthood). The effects varied depending on sex: adult male offspring showed dose-dependent increases of body and liver weights, no effects on fat pad weights and a dose-dependent decrease in glucagon levels. Adult female offspring showed a dose-dependent decrease in body weight, liver, muscle and fat pad weights, fat cell size, lipids (fats, e.g., cholesterol levels), leptin and adiponectin levels. Physical activity was decreased in exposed males and slightly increased in exposed females. These results suggest that BPA cannot be categorically labeled an obesogen-- males showed higher body weight from exposure while females showed lower-- but that BPA does have the ability to alter metabolism later in life, following early life exposure, and that the specific effects vary by sex (van Esterik et al. 2014). The mechanisms did not appear to involve DNA methylation, an epigenetic change (van Esterik et al. 2015). Other studies, however, do find that prenatal exposure to BPA induces epigenetic changes in the fatty tissue of mice, that may be linked to later life obesity (Taylor et al. 2018). Examination of both human and laboratory evidence showed that epigenetic changes control the impact of prenatal BPA exposure on body weight in offspring by triggering fat cell development (Junge et al. 2018). Epigenetic changes in the liver caused by BPA may also be important. In rats, early-life BPA exposure causes metabolic dysfunction in adulthood and causes epigenetic changes in the developing liver which persists long after the initial exposure. Many of the affected genes remain silent until their impact on metabolism is revealed by a later life exposure to a Western-style diet (Treviño et al. 2020).
Certain subgroups may be more susceptible to BPA. Male mice that are light at weaning, but then experience rapid catch-up growth immediately after weaning, are more vulnerable to the metabolic effects of very low levels of BPA (Taylor et al. 2018).
We know that maternal BPA exposure disrupts metabolism, but what about paternal exposure? In a mouse study, when males were exposed to BPA after puberty, their offspring had normal body weight, body composition, and glucose tolerance. However, when fathers were exposed to BPA during gestation and lactation, their female offspring had impaired glucose tolerance (Rashid et al. 2020).
Additional studies also detail how exposure to BPA during development affects metabolism (e.g., Esteban et al. 2019; Long et al. 2020; Marchlewicz et al. 2021; Martínez et al. 2020; Neier et al. 2019), including effects on the gut microbiome (Diamante et al. 2020).
Studies in Sheep and Cows
Sheep have also been exposed to BPA during pregnancy, and their offspring also show metabolic changes that can lead to insulin resistance, although the outcomes depended on the genetic strain of sheep (Veiga-Lopez et al. 2016). Curiously, these authors also found that BPA exposure prevented the adverse effects of postnatal obesity in inducing high blood pressure. BPA also partially reversed the effects of overfeeding. Note that BPA did, however, affect many genes related to obesity, blood pressure, and heart disease (Koneva et al. 2017). They also found that BPA enhances the development of fat cells in female offspring (Pu et al. 2017). BPA exposure during development also affected the growth of sheep, in the womb and post-natally: males grew slower during the early postnatal period and caught up later, while females had the opposite growth trend (Vyas et al. 2019).
In general, exposing sheep to BPA (and other steroid chemicals) prenatally can lead to insulin resistance, higher weight and higher blood pressure (Cardoso and Padmanabhan 2018). These authors are now figuring out how prenatal BPA exposure causes insulin resistance in sheep; oxidative stress may be one mechanism involved (Puttabyatappa et al. 2019). Impaired skeletal muscle development may be another mechanism. Gestational exposure to both BPA and BPS impaired skeletal muscle development in sheep. However, these exposures did not alter fetal muscle tissue responsiveness to insulin, suggesting that the insulin resistance in skeletal muscle caused by BPA may not occur until later in life (Jing et al. 2019). Prenatal BPA-treatment induces changes in gene expression in the fat tissue of adult sheep. These changes may contribute to the metabolic disorders seen in prenatal BPA-treated female sheep (Dou et al. 2020).
Cow embryos exposed to low levels of BPA showed metabolic effects, even as embryos (Choi et al. 2016).
More Information on BPA
Factsheet on BPA from the National Institute of Environmental Health Sciences (NIEHS)/National Toxicology Program (NTP)
What Does BPA free Mean? A Thorough Guide to BPA and Your Health, by the Health Insurance Fund of Australia (2018)
BPA Affects the Development of the Pancreas
When pregnant mice were exposed to BPA, their fetuses showed altered pancreatic development. These changes may have implications for both the structure and function of the pancreas in later life (Whitehead et al. 2016).
When pregnant mice were exposed to BPA, it affected the development of the pancreas. For the first month of life, the exposed animals had higher beta cell mass, but at 4 months, beta cell mass was equal or lower than the unexposed controls. The exposed mice also had altered fasting glucose levels (García-Arévalo et al. 2016). In mice, in utero exposure to BPA caused higher blood glucose, insulin, and cholesterol levels as well as changes to the pancreatic tissue and body weight (Bano et al. 2019). BPA affects beta cell development via the estrogen receptor β (ERβ) (Boronat-Belda et al. 2020).
In zebrafish, embryonic exposure to low levels of both BPA and BPS impaired the normal expression of pancreatic-associated genes, and caused higher glucose levels (Gyimah et al. 2021).
In fact, some authors point out that developmental exposure to BPA affects not only the pancreas but also the other organs that also derive from the endoderm, including the thyroid, liver, gut, prostate and lung (Porreca et al. 2017).
Another phenol, octylphenol, when given during development, has adverse effects on fat metabolism in pregnant rats (Kim et al. 2015). In tadpoles, octylphenol exposure influenced gene expression levels related to fat digestion and absorption, and altered the structure and composition of the gut microbiome (Liu et al. 2020).
Exposure to nonylphenol during development leads to higher fasting blood glucose levels in male offspring rats, and increased body weight as well (Yang et al. 2017). Rats exposed to nonylphenol and given a high-sucrose/high-fat diet gained more weight and had glucose intolerance, higher fasting blood glucose levels, lower levels of insulin and leptin, and fewer/smaller islets (Yu et al. 2018). In zebrafish, exposure to nonylphenol affected the expression of genes associated with fatty liver, metabolism, immune response, and oxidative stress (Huff et al. 2019).
Are Bisphenol-based BPA Substitutes Safe?
No. BPS and BPAF, for example, are associated with an increased risk of type 2 diabetes in humans (Duan et al. 2018). According to a review, BPA substitutes appear to affect human health, especially in relation to obesity (Andújar et al. 2019). In fact, BPS appears to be even worse than BPA regarding obesity-related health effects (e.g., Martínez et al. 2020; reviewed by Thoene et al. 2020).
A cross-sectional study of youth using NHANES data in the years from 2013-2016, as BPA was replaced by BPS and BPF, found that BPA, BPS, and BPF were detected in 97.5%, 87.8%, and 55.2% of samples, respectively. BPS levels were associated with an increased prevalence of general and abdominal obesity. BPF detection (vs not detected) was associated with an increased prevalence of abdominal obesity and BMI. On the other hand, BPA and total bisphenols were not statistically significantly associated with general obesity, abdominal obesity, or any body mass- related measure (Jacobson et al. 2019).
BPA-free products often still leach estrogenic chemicals (Bittner et al. 2014). Some BPA substitutes, like BPS, have also been shown to disrupt hormones (Viñas and Watson, 2013; Rochester and Bolden, 2015; Usman et al. 2019) as well as affect obesity, diabetes, and metabolic function (reviewed by Pelch et al 2019), in cells (Berni et al. 2019; Boucher et al. 2016a; Boucher et al. 2016b; Héliès-Toussaint et al. 2014), and in lab animals (Brulport et al. 2020; da Silva et al. 2019; Qiu et al. 2019; Rezg et al. 2018a; Rezg et al. 2018b; Wang et al. 2019; Wang et al. 2018; Xiao et al. 2020; Zhao et al. 2018a). BPF, for example, increases glucose and insulin levels in lab animals (Zhao et al. 2018b). BPS, however, is more likely than BPF to be an obesogen (Drobna et al. 2019), although BPF-exposed adolescent rats showed significantly increased body growth and abdominal fat than unexposed rats (Wagner et al. 2021). Like BPA, BPS and BPF also affect the immune system (Dong et al. 2018; Lee et al. 2017; Qui et al. 2018; Zhao et al. 2018) and the cardiovascular system (Pal et al. 2017; Zhang et al. 2020). BPS causes high blood sugar in rats (Mandrah et al. 2020). BPS and BPF rapidly increased insulin release from beta cells, similar to BPA (Marroqui et al. 2020).
Developmental exposure is still a problem as well (Ivry Del Moral et al. 2016; Meng et al. 2019a; Pu et al. 2017). For example, perinatal exposure to BPS may increase the risk of obesity because it interferes with cholesterol and glucose metabolism in mice offspring (Meng et al. 2019b). In male mice, prenatal BPS exposure increased fat cell size in fatty tissue and the susceptibility to high-fat diet-induced formation of fat cells in adulthood (Ahn et al. 2020). Maternal exposure to BPS also affected the gut microbiota of offspring mice as adults (Gomez et al. 2020).
While one study of US adults did not find an association between BPS or BPF and obesity (while BPA was associated), this study did not consider exposure during development (Liu et al. 2017). In lab animals, early life exposure to BPS and BPAF have even worse glucose-related effects than BPA and BPF (Meng et al. 2018). BPAP, another substitute, can affect blood glucose levels of laboratory animals, even at low doses (Xiao et al. 2018). In fat cells, BPAF causes inflammation and affects metabolism (Chernis et al. 2019). In fat cells, BPB, BPE, BPF, BPS, and 4-CP all affected fat accumulation and leptin levels to the same extent and potencies as BPA (Ramskov Tetzlaff et al. 2019). Other studies also find that BPS has similar effects on fat cells as BPA (e.g., Peshdary et al. 2020).
Some studies find that BPS has different effects of BPA... for example in mice, chronic exposure to environmentally relevant concentrations of BPS exerted an unexpected hypoglycemic effect under various dietary conditions, due to lower insulin resistance and disrupted thyroid hormone levels (Guo et al. 2021).
A computerized screening tool identified numerous bisphenols (especially BTUM, BPPH, and Pergafast 201) that may be able to target diabetes-related proteins (as well as proteins related to other diseases), implying they may play a role in diabetes (Montes-Grajales et al. 2021).
According to Dr. Frederick vom Saal, a BPA researcher from the University of Missouri, "The BPS that replaced BPA is, if anything, worse because it is very environmentally persistent." Collaborative on Health and the Environment call, Dec. 2014. A study that compared them directly found that BPS is a more potent promoter of fat cell development than BPA (Ahmed and Atlas 2016). In fact, low doses of BPA, BPS, and BPF all affect fat cell development (Verbanck et al. 2017). Another bisphenol, BPAF and its metabolite BPAF-G, induced fat accumulation and increased the expression of key markers in mouse pre-fat cells (Skledar et al. 2019).
In liver cells, four bisphenols (BPA, BPAF, BPF, and BPS) can disrupt glucose metabolism, but they appear to act through different mechanisms (Yue et al. 2019). A study of fat cells found that while BPA was more potent than BPS in its disturbance of cholesterol metabolism, their effects were similar, and both BPA and BPS exposure could lead to insulin resistance (Zeng et al. 2020). In human fat-derived stem cells, BPF and BPS both produced a linear dose-response increase in various obesogenic effects (Reina-Pérez et al. 2021). In human stem cells, low, environmentally relevant levels of BPA and BPAF increased fat formation and lipid production, whereas higher levels of BPA and BPAF decreased fat formation. All doses of tetramethyl bisphenol F (TMBPF), a food contact coating, reduced fat and lipid production, likely at least partially just killing them (Cohen et al. 2021). In fat cells, not only BPA but also four of its substitutes disrupted crucial metabolic functions and insulin signaling under low, environmentally relevant concentrations (Schaffert et al. 2021).
Researchers find that, "Because BPA substitutes such as BPS and BPF have similar structures to BPA, they appear to have similar metabolism, potencies, and action to BPA. In addition, they may pose similar potential health hazards as BPA." (Moon 2019). A data mining approach has examined health problems linked to BPS and found many, including obesity, metabolic disruption, and endocrine disruption, and identified some of potential mechanisms involved (Carvaillo et al. 2019). A review found that BPA replacement chemicals can affect the immune system, metabolic system, gut microbiome, and more, in many different species, including humans (McDonough et al. 2021).
When Is Exposure Most Harmful?
Some researchers have tried to determine the "critical windows of exposure" for BPA in relation to how it can cause glucose intolerance in animals. That is, when is an animal most susceptible to the glucose intolerance effects of BPA? These scientists exposed pregnant and lactating mice to different amounts of BPA at different times during and/or after pregnancy, and studied the effects on the offspring, later in life. Overall, they found that the effects of BPA exposure depends on the gender of the offspring, the dose, as well as the timing. The effects caused by fetal exposure were most severe, as compared to effects caused by later exposures (Liu et al. 2013). Even exposure only via breastmilk still has both short and long-term effects on the offspring, however (Santos-Silva et al. 2018).
A different study aimed to identify what dose and what timing were most important for BPA expsoure. It found that "both perinatal exposure alone and perinatal plus peripubertal exposure to environmentally relevant levels of BPA resulted in lasting effects on body weight and body composition. The effects were dose specific and sex specific and were influenced by the precise window of BPA exposure. The addition of peripubertal BPA exposure following the initial perinatal exposure exacerbated adverse effects in the females but appeared to reduce differences in body weight and body composition between control and BPA exposed males." Thus the effects varied by dose, sex, and timing (Rubin et al. 2017).
What Happens When Fathers Are Exposed?
An interesting study exposed only the father rats to BPA, not the mothers, and looked for effects in both the fathers and offspring. The offspring did not show metabolic effects, but the fathers did. The father rats, who were exposed to the supposedly "safe" dose of BPA over a number of weeks, showed disrupted blood glucose control and pancreatic function (but not body weight). A high fat diet worsened these effects (Ding et al. 2014).
How Can Early Life Exposure Lead to Effects Later in Life?
Some studies have tried to determine the specific mechanisms by which fetal and early-life BPA exposure can induce insulin resistance and diabetes later in life. For example, Ma et al. (2013) found that at 21 weeks of age, rats exposed to BPA (while in the womb and nursing) had higher insulin resistance and insulin levels than unexposed controls (just as other studies have found). None of these effects were apparent earlier in life, at 3 weeks of age. However, the researchers did find abnormal epigenetic changes that were not apparent in the controls, which suggests that these changes may play a role in later development of insulin resistance. And again, these rats were exposed to the U.S. EPA's supposed "safe" dose of BPA. Additional studies are now identifying the specific epigenetic changes that may explain BPA's effects on metabolism (Anderson et al. 2017).
Another study looked at metabolic changes in mice exposed to BPA early in life at 2 days and 3 weeks of age. Their tissues showed differences even at this early age, including in levels of glucose, that suggested BPA induced changes in whole body metabolism (Cabaton et al. 2013).
A review finds that BPA induces epigenetic changes in a variety of genes linked to effects on glucose metabolism (Rahmani et al. 2018).
Alarmingly, the epigenetic effects of BPA have been shown to sometimes pass from one generation to the next, across multiple generations (Singh and Li, 2012).
One study of developmental exposure to mixtures of chemicals tested a mixture of BPA and two types of phthalates (DEHP and DBP), both found in plastics. Pregnant rats were exposed to this mixture, and outcomes evaluated in their offspring, for 3 generations. The third generation offspring (the exposed mothers' great-grandchildren), had higher rates of obesity (in addition to many other health issues). The mechanism involved not changes to DNA, but epigenetic changes that were passed down from one generation to the next (Manikkam et al. 2013). You can listen to a recording of a call with one of the authors of this study, Transgenerational Effects of Prenatal Exposure to Environmental Obesogens in Rodents, sponsored by the Collaborative on Health and the Environment (2013).
When mother mice were exposed to low levels of BPA when pregnant, their male offspring had lower insulin secretion, lower beta cell mass, more islet inflammation, and more beta cell death. These changes persisted into the 2nd generation! (Bansal et al. 2017). Further research by the same authors shows that the changes also persisted into the 3rd generation, although not as severely. Interestingly, in all generations, immune cells had infiltrated the pancreas (which could be relevant for type 1 diabetes) (Bansal et al. 2018).
When pregnant and lactating rodents were exposed just to BPA, their grandchildren had impaired glucose tolerance and insulin resistance-- even though those grandchildren were not directly exposed to BPA. These effects were passed down via the sperm (Li et al. 2014). The same authors confirmed that the effects were passed through the male line, and found that the effects of BPA also included beta cell dysfunction (in addition to glucose intolerance). Epigenetic mechanisms probably are involved (Mao et al. 2015). And an additional study in mice has also found that BPA exposure in the womb led to higher body fat and disturbed glucose levels in male children and grandchildren (but not female offspring) (Susiarjo et al. 2015).
In one study, pregnant mice (the F0 generation) were exposed to BPS. Both F1 and F2 male offspring (i.e., children and grandchildren) developed intestinal inflammation in adulthood; this phenomenon disappeared in the F3 generation (great grandchildren). F1 males also had a significant decrease of blood cholesterol. F3 males had lower fat weight but higher blood glucose and cholesterol levels (Brulport et al. 2021).
BPA also has transgenerational effects, passed through the male line, that impede development of the heart and increase heart failure for a few generations, in addition to affecting insulin signaling in zebrafish (Lombó et al. 2015). A study of trout show that BPA in eggs affects both growth and the liver/cholesterol in two generations (Sadoul et al. 2017).
BPS also produces transgenerational effects in animals. Developmental BPS exposure caused obesogenic effects in multiple generations of mice, with the F2 generation being the most impacted (Brulport et al. 2020). BPS promotes fat storage and fat accumulation in four generations of worms (Zhou et al. 2021).
Nonylphenol and a high-fat diet synergistically accelerated the synthesis of fatty acids in the liver of male offspring rats, which induced abnormal metabolism and effects on the liver. All of these effects were passed on to the second generation as well (Zhang et al. 2021).
BPA Increases Islet Inflammation in Two Generations of Mice
These are pancreatic islets in mice. Both low (LowerB) and high (UpperB) BPA exposure levels increased islet inflammation across two generations in mice (A-H are from the first generation, and I-P are the second generation). The CD3 rows show T cells, and the F4/80 rows show macrophages.
Does "The Dose Make the Poison?"
Researchers exposed pregnant mice to BPA at a range of different levels, ranging from 10 times lower than the EPA's "safe" dose to 10 times above the EPA's predicted "No Adverse Effect Level (NOAEL)." They found that at doses below the NOAEL, there were significant effects in the adult male offspring (just as other studies have found), including lower glucose tolerance, increased insulin levels and insulin resistance, higher food intake, higher body weight, more abdominal fat, and more. For most of these effects, the dose-response curve was non-linear. At the highest dose studied, there were no significant effects (Angle et al. 2013). This is a very interesting study, not only because it finds significant effects at low doses, but also because the effects at low doses are worse than at high doses. That may be in part due to the way the body reacts to hormones (and BPA is a hormonally active endocrine disruptor); when the body encounters high levels of a hormone, it reduces its cellular receptors to that hormone. The authors conclude that "the dose does not make the poison," that is, that very high doses do not necessarily have a greater effect than very low doses (Angle et al. 2013).
As an example, a laboratory study that used doses of BPA below the NOAEL level found that this prenatal BPA exposure led to tens to thousands of changes in the fat, liver, and other tissues of male offspring in mice, with effects on lipid and glucose metabolism (Shu et al. 2018).
Other authors explain that BPA (and BPS) have mechanisms of action that explain why they are very potent at very low doses (Nadal et al. 2018).
A Closer Look at Body Weight
Exposure to BPA in utero and in early life may affect the body weight of animals, depending on dose and gender (Rubin and Soto 2009). One study, for example, found that exposure to a low dose of BPA during gestation and lactation increased the body weight of rats. The effects varied by age, gender, and diet (Somm et al. 2009). Another study found that exposure to BPA during gestation and lactation led to increased body weight and height after weaning in mice (as compared to controls), but that these difference disappeared by adulthood (Ryan et al. 2010). And yet another study found that early life BPA exposure was not associated with changed body weight in exposed mice, although body fat and weight were lower than controls in female mice of certain ages (Anderson et al. 2013). Juvenile rats exposed to BPA did not have different body weights later in life than unexposed rats, although the exposed rats did develop more fat in their liver than the unexposed rats (Rönn et al. 2013).
In alligators, BPA exposed babies grew more quickly in early life but more slowly thereafter. They were fatter than unexposed controls at 5 weeks but then leaner at 21 weeks of age (Cruze et al. 2015).
Thus you can see that different studies have found different things. These differences may be due to a variety of factors, including the species studied, gender, the amount of BPA used, the timing/duration of exposure, diet/nutrition, etc. According to a review of the evidence, vom Saal et al. (2012) argue that these differences may also be explained by laboratory practices, e.g., measuring body weight instead of the more accurate body fat, making sure control animals are not inadvertently exposed to BPA or other estrogenic chemicals (e.g., via water bottles or cages), or feeding rodents soy-based chow that does not contain variable amounts of plant-based estrogens.
Economic and Social Costs of BPA
"BPA exposure was estimated to be associated with 12,404 cases of childhood obesity in 2008. Removing BPA from food uses might prevent 6,236 cases of childhood obesity per year."
- Dr. Trasande, Further limiting bisphenol A in food uses could provide health and economic benefits, 2014.
Another factor is exercise-- interestingly, female mice exposed to BPA during development participated in less physical activity than controls. They also had altered metabolism of carbohydrates and fats (Johnson et al. 2015). BPA may also affect appetite. Early life exposure to BPA increased appetite peptide and reduced satiety peptide expression in a study of the stem cells of newborn rats (Desai et al. 2018).
And, losing weight may affect BPA excretion. One study found that BPA excretion increases as bariatric surgery patients lose weight. They conclude that Heavier patients with insulin resistance may store more BPA in fat tissue and therefore excrete less BPA (Dambkowski et al. 2018).
Chemicals in Combination
What are the effects of mixtures of chemicals? Very few studies have been done on chemicals in combination with one another, although that is how humans are exposed. One study exposed mice -- starting from before conception -- throughout life to very low doses (at levels thought to be "safe") of a combination of chemicals commonly found in food, including phthalates, BPA, dioxin, and PCBs, and fed them a high-fat diet. As adults, compared to unexposed controls, pollutant-exposed females developed impaired glucose tolerance, and males showed liver and cholesterol effects, as well as epigenetic changes (Naville et al. 2013). The same authors subsequently fed mice a high-fat, high-sugar diet, both with and without this same low-dose mixture of chemicals. This time, the chemical-exposed females showed improvement in glucose tolerance, inflammation, and insulin resistance at 7 weeks of age, but then worsening of these factors at 12 weeks of age. Thus the chemicals cause at first an apparent improvement, then a worsening as aging takes place (as compared to the mice fed the same diet but without chemicals) (Naville et al. 2015).
Another study of mixtures by the same authors shows that mice with lifelong exposure to low levels of this BPA, phthalates, dioxin and PCB mixture caused changes to metabolism (e.g., high triglycerides), which were slightly different than the effects of a high-fat, high-sugar diet (Labaronne et al. 2017). This exposure not only resulted in significant changes in triglyceride levels, but also on the expression levels of a variety of genes, including those relating to metabolism, especially under a standard diet. Depending on nutritional conditions and on the metabolic tissue considered, the impact of pollutants mimicked or opposed the effects of the high-fat high-sugar diet (Naville et al. 2019).
A mixture of BPA and phthalates caused changes associated with metabolic disorders in the developing embryos of zebrafish (Dong et al. 2018). In rodents, a mixture of BPA and phthalates acted synergistically together in females and additively in males in the metabolic system (Tassinari et al. 2021). A mixture of DEHP, DBP and BPA was linked to markers of type 2 diabetes in rats, and probiotics reduced these effects (Baralić et al. 2021).
Exposure to either BPA, arsenic or their combination, induced metabolic disruption in male mice offspring, and the combined exposure exacerbated the metabolic changes induced by either BPA or arsenic alone. The combined exposure influenced both glucose tolerance and insulin tolerance, and affected the expression of genes involved in lipid and glucose metabolism (Wang et al. 2018).
Interestingly, mixtures of other endocrine disrupting chemicals can actually affect the levels of BPA. Single doses of triclosan, parabens, phthalates, or other phenols (and a combination of all of them) raised BPA (and estrogen) levels in mice, perhaps because they interfere with enzymes that metabolize estrogen (Pollock et al. 2018). For an article about this study, see Compound Interest: Assessing the Effects of Chemical Mixtures, published in Environmental Health Perspectives (Konkel 2017).
Additional factors can also interact with BPA to influence health effects. In rats, for example, if the parents are obese, the offspring exposed to BPA have increased cholesterol and triglyceride levels, along with higher birth weight and rapid weight gain, and the female offspring have increased insulin resistance (Dabeer et al. 2019). Also in rats, single and combined exposures to fructose and BPA had a variety of effects, including insulin resistance, which were worse with combined exposures (Lin et al. 2019).
Chemicals that can interact with BPA -- both beneficially and adversely -- are critical to the health effects of BPA (reviewed by Sonavane and Gassman, 2019). Which brings us to our next topic:
Things That Can Help Prevent the Effects of BPA
Cashiers tend to have high BPA levels because they handle a lot of paper receipts. Among cashiers, higher BPA levels were associated with higher fasting insulin levels and increased insulin resistance. If cashiers handle receipts with their bare hands, their BPA levels can double BPA at post-shift compared to those at pre-shift. If they wear gloves, however, their BPA levels do not change pre- to post-shift (Lee et al. 2018).
Italian researchers found that BPA plays potential role in non-alcoholic fatty liver disease (NAFLD), and also found a treatment (vitamins D and E, etc.) that helps improve it (including insulin resistance) (Federico et al. 2020).
Procyanidin A2, a chemical found in some plant foods (like avocado, cinnamon, cranberry) can help prevent the effects of BPA in mice. For example, it can prevent the death of insulin-producing cells that BPA causes, and also reduces high blood sugar caused by BPA (Ahangarpour et al. 2016).
In rats, maternal exposure to BPA induced pancreatic impairments in the offspring, which included disrupted insulin secretion, glucose intolerance, and impaired structure of beta cells. However, maternal folate supplementation counteracted the pancreatic effects of BPA (Mao et al. 2017).
In pregnant mice, vitamin B6 supplementation counteracted the gestational glucose intolerance caused by BPA (Susiarjo et al. 2017).
Dr. Nicole Acevedo and Dr. Beverly Rubin. Dr. Rubin, of Tufts University, studies the effects of BPA exposure during early life development on later life diseases, including obesity, and found that early life exposure to BPA increases the risk of later obesity in rodents.
Perinatal exposure to BPA led to weight gain, lipid accumulation, high levels of blood lipids, and deterioration of intestinal microbiota in female offspring rats. Supplementation with resveratrol butyrate esters reduced the weight gain and lipid accumulation caused by BPA, optimized the levels of blood lipids, and improved the gut microbiota (Shih et al. 2021).
Rats exposed to BPA in the womb developed obesity and adiposity, high blood sugar and insulin levels, insulin resistance, high triglycerides, and higher glucagon and free fatty acid levels. These effects were improved by Magnesium lithospermate B (MLB), an active compound of Salvia miltiorrhiza (danshen/red sage) (Huang et al. 2021).
Crocin, a component of saffron, protected the liver from BPA-induced toxicity in rats, and reduced triglyceride levels (although BPA also caused higher glucose levels, among other things) (Vahdati Hassani et al. 2017).
In rats, BPA increased blood pressure, total cholesterol, LDL cholesterol, body fat, leptin, adiponectin, insulin, and blood glucose levels. Grape seed extract, resveratrol, or vitamin E restored these detrimental effects of BPA in some cases (Rameshrad et al. 2019). Resveratrol also protected offspring rats from the developmental effects of BPA that lead to high blood pressure (Hsu et al. 2019). Resveratrol butyrate esters (RBE) are derivatives of resveratrol (RSV) and butyric acid and exhibit biological activity similar to that of RSV but with higher bioavailability. RBE can suppress BPA-induced obesity in female offspring rats, and has excellent modulatory activity on intestinal microbiota (Shih et al. 2021).
In rats, probiotics almost completely eliminated the toxicity of a mixture of phthalates and BPA (Baralić et al. 2020).
Antioxidants may be able to counteract the oxidative effects of BPA (Amjad et al. 2020).
In mice, Korean red ginseng inhibited BPA-induced changes in lipid metabolism (Park et al. 2020).
In cells, BPA, BPS, and BPF increased fat accumulation and Nakai extract suppressed these effects (Choi et al. 2020).
In Vitro Studies on Cells
Pancreatic Beta Cells
Beta cells are the cells in the pancreas that produce insulin. Studies show that BPA affects the production and activity of insulin by pancreatic beta cells. These effects have been seen in studies using human beta cells as well as mouse beta cells, at levels comparable to those humans encounter. The effects of BPA were similar in mouse and human beta cells, and were significant even at very small doses, the doses that we are exposed to in the environment, and are likely applicable to humans (Soriano et al. 2012). In rat beta cells, low levels of BPA (and other estrogenic chemicals) affect insulin secretion and disrupt beta cell function (Song et al. 2012). A study that compared BPA to other chemicals found that only BPA affected insulin secretion in mouse beta cells (Makaji et al. 2011).
A study that aimed to determine the mechanisms by which BPA affects beta cells found that BPA suppressed cell viability and disturbed insulin secretion. Eventually, the beta cells died. The authors found that BPA affected the mitochondria in the cells, leading to these effects (Lin et al. 2013), they are also working further to delineate the exact mechanisms involved (Wei et al. 2017). BPA has also been found to damage DNA in pancreatic beta cells, in conjunction with oxidative stress (Xin et al. 2014). It also may affect beta cells by affecting ion channels (Soriano et al. 2016). For example, BPA affects calcium ion channels in beta cells, interestingly in a non-monotonic manner (Villar-Pazos et al. 2017). In fact, BPA -- at doses that humans are exposed to -- affects the genes that control sodium (as well as calcium) ion channels, which in turn control insulin secretion. The mechanisms involves estrogen receptors as well (Martinez-Pinna et al. 2019).
Low dose exposure to BPA damaged beta cells, eventually leading to their death. BPA in combination with the stress of high glucose levels led to a reduced ability of beta cells to respond to damage (Carchia et al. 2015).
An interesting study found that BPA was more potent than phthalates in reducing beta cell function. Both BPA and the phthalate metabolites reduced beta cell viability after 72 hours of exposure, with BPA the most potent. Both BPA and the phthalate metabolites increased insulin secretion after 2 hours of simultaneous exposure to the chemicals and glucose, with BPA again the most potent. However, neither BPA nor phthalates affected susceptibility to beta cell death. And, unlike other studies, low level exposures did not show effects (Weldingh et al. 2017).
Exposure to MBP, a major metabolite of BPA, significantly reduced beta cell viability, caused insulin secretion dysfunction, and induced beta cell death (Huang et al. 2021).
Long-term, high dose exposure to BPA, as well as another phenol chemical, nonylphenol, promotes insulin secretion from the pancreatic islets in rats. Nonylphenol is used in some personal care products, pesticides, detergents, and paints (Adachi et al. 2005). (Nonylphenol also promotes obesity in mice (Hao et al. 2012).)
BPA has also been found to affect another hormone (besides insulin) that is released from beta cells (the hormone is human islet amyloid polypeptide, if you really want to know). Aggregation and misfolding of this hormone can lead to beta cell death, and indeed, BPA was found to exacerbate its aggregation in beta cells (Gong et al. 2013).
Additional studies also show that BPA can affect beta cells (Chen et al. 2018).
Beta cells are not the only types of cells affected by BPA. Using pre-fat cells from people with a normal body mass index (BMI), researchers found that exposing these cells to BPA induced them to turn into (differentiate) fat cells and accumulate fat (Boucher et al. 2014). A different lab also found that BPA enhanced the ability of human pre-fat cells to differentiate into fat cells, at levels that humans are exposed to (Ohlstein et al. 2014). Another study also found that BPA promoted adipogenesis in pre-fat cells (but not stem cells). These authors also found that a related compound, bisphenol A diglycidyl ether (BADGE), a BPA derivative, induced adipogenesis in both pre-fat cells and stem cells, at levels comparative to those found in humans (Chamorro-García et al. 2012). In human fat cells, low doses of BPA cause inflammation and inhibits glucose utilization, which lead to impaired fat cell function (Valentino et al. 2013). This lab also found that pre-fat cells cultured with low doses of BPA for 3 weeks showed increased pre-fat cell proliferation. Mature fat cells held more fat, had impaired insulin signalling, and reduced glucose utilization (Ariemma et al. 2016). Low levels of BPA can induce stem cells to develop into fat cells (Dong et al. 2018). Meanwhile, fat cells exposed to low levels of BPA can develop inflammation which can lead to insulin resistance even without excess fat (De Filippis et al. 2018).
BPA and the Metabolic Syndrome
Listen to Dr. Mina Desai and Dr. Michael Ross of UCLA discuss Maternal BPA Programs Offspring Metabolic Syndrome, sponsored by the Collaborative on Health and the Environment (2014).
In children's fat cells, BPA promotes inflammation and the expression of genes linked to lipid metabolism, and decreases the expression of a gene linked to insulin production (Menale et al. 2015). In children's fat cells, even at the lowest exposure level, BPA activated an enzyme that promotes conversion of pre-fat cells to fat cells (adipogenesis), and also affected gene expression (Wang et al. 2013). In women's mammary fat cells, BPA caused inflammation (Cimmino et al. 2019).
Ben-Jonathan et al. (2009) reviews earlier studies of BPA's effects on fat cells. For example, BPA has been found to affect the transport of glucose in the fat cells of mice, which could have implications for the development of diabetes (Sakurai et al. 2004). BPA increases the deposition of lipids in fat cells, which could increase the likelihood of metabolic syndrome (Wada et al. 2007). BPA also promotes the development of fat cells (Masuno et al. 2002) and is linked to increased oxidative stress in fat cells in humans (Artacho-Cordón et al. 2019). BPA makes stem cells increase triglyceride levels and may support fat cell differentiation (Salehpour et al. 2020).
Scientists are now working to identify the mechanisms by which BPA can affect fat cell development (Boucher et al. 2014; Lee and Park 2019; Longo et al. 2020; Xie et al. 2016). For example, BPA can promote the development of fat cells from rodent pre-fat cells even under less-than-ideal conditions (Atlas et al. 2014). BPA can also likely affect fat cell health, via additional mechanisms (Ampem et al. 2019). And BPA can have other effects on fat cells as well (Szkudelska et al. 2021). Like BPA, BPS and BPF also increase the differentiation of fat cells from pre-fat cells (Choi et al. 2021).
BPA is also capable of acting like other hormones besides estrogen, by binding with various other hormone receptors (just like it binds with estrogen receptors) (MacKay and Abizaid 2018). For example, it can promote the formation of fat cells by activating glucocorticoid hormone receptors, which play a role in glucose metabolism (Sargis et al. 2010). In addition, exposure of human tissues to low doses of BPA inhibits the release of a hormone (adiponectin) that increases insulin sensitivity and reduces tissue inflammation. Any factor that inhibits this hormone's release could lead to insulin resistance (Hugo et al. 2008). BPA also has other effects on fat cells that may lead to insulin resistance (Dai et al. 2016).
Some compounds that are related to BPA and used as flame retardants can activate PPARγ (peroxisome proliferator-activated gamma receptor), which play a role in glucose metabolism as well as fat storage. In one study, BPA, however, did not activate PPARγ receptors Riu et al. 2011), but in another, it did (Biasiotto et al. 2016). For an article on the Riu study on halogenated BPA flame reatardants, see Warm reception? Halogenated BPA flame retardants and PPARγ activation, published by Environmental Health Perspectives (Barrett 2011). A study of zebrafish found that developmental exposure to these compounds promotes fat accumulation in larvae and weight gain in the juvenile fish (Riu et al. 2014).
BPA can affect liver cells; one study found it interfered with glucose metabolism processes (Olsvik et al. 2017); another found low levels of BPA increase cholesterol levels in liver cells (Li et al. 2019). Another phenol, 4-hexylphenol, also increases fat formation in liver cells, and increases differentiation of fat cells as well (Sun et al. 2020).
In skeletal muscle cells (which are involved in insulin resistance), BPA affects mitochondrial function and insulin resistance (Ahmed et al. 2019). BPS and BPF can also alter skeletal muscle cell proliferation and differentiation and lead to effects tied to insulin resistance (Jing et al. 2020).
In human placental cells, BADGE and its derivatives can affect triglyceride levels (Marqueño et al. 2018). Also in placental cells, BPA can increase oxidative stress and inflammation (Arita et al. 2019). In human embryonic stem cells, BPA and six of its replacements (BPS, BPF, BPZ, BPB, BPE, and BPAF) disrupt early embryonic development and lipid metabolism (Liang et al. 2020).
BPA and other bisphenols (BPF and chlorinated BPA, ClBPA), have been found in the brain tissue of human cadavers, showing they may be able to cross the blood-brain barrier. Brain levels of these bisphenols were associated with obesity in this study (Charisiadis et al. 2018).
And, as discussed in the type 1 diabetes section below, BPA can affect immune cells as well. In human macrophages, both BPS and BPA can activate PPARγ receptors (Gao et al. 2019).
BPA and BPS Metabolites
BPA is often thought to break down to harmless metabolites in the body. However, a study shows that these metabolites may not be harmless at all. Pre-fat cells treated with the metabolite BPA-Glucuronide (BPA-G) showed increased fat cell formation (Boucher et al. 2015). For an article describing this study, see Unexpected activity: Evidence for Obesogenicity of a BPA Metabolite, published by Environmental Health Perspectives (Nicole, 2015).
Residue of BPS, an alternative to BPA, is detected in drinking water supplies, suggesting that BPS can be chlorinated. One study identified the byproducts of the reaction of BPS with chlorine and the effects of the main byproducts on PPARγ, which is linked to obesity. The byproducts had a 2- to 4-fold enhancement in their activities on PPARγ in comparison with BPS itself (Zheng et al. 2018).
Type 1 Diabetes and Autoimmunity
The first human study published on type 1 diabetes and BPA was conducted in Turkey, and found that BPA levels were slightly higher in the children with type 1 diabetes compared to controls, although the difference was not statistically significant (İnce et al. 2018). A second study from Thailand found that children and adolescents with type 1 diabetes had significantly higher levels of BPA compared to children without diabetes (Tosirisuk et al. 2021).
Routes of BPA Exposure
Listen to Dr. Frederick vom Saal discuss BPA and Health: New Research Focuses on Routes of Exposure, sponsored by the Collaborative on Health and the Environment.
Dr. vom Saal discusses how BPA is absorbed through the skin from receipts and other thermal paper, especially after the use of hand sanitizers (see Hormann et al. 2014).
Also listen to Science Friday, Hand Sanitizer May Increase BPA Absorption (Oct. 2014).
Two studies have found that BPA exposure accelerates insulitis and diabetes development in non-obese diabetic (NOD) mice, an animal model of type 1 diabetes (Bodin et al. 2013 and Bodin et al. 2014). The first study found that long-term exposure to BPA at relatively high levels accelerated insulitis in NOD mice. The second found that exposing mothers to BPA caused their female offspring to have more severe and higher incidence of insulitis. The authors write, "In conclusion, transmaternal BPA exposure, in utero and through lactation, accelerated the spontaneous diabetes development in NOD mice. This acceleration appeared to be related to early life modulatory effects on the immune system, resulting in adverse effects later in life." (Bodin et al. 2014). The same authors found that a mixture of BPA and phthalates did not increase the effects, if anything, some of the effects of BPA were decreased (Bodin et al. 2015).
Other authors have found that BPA exposure accelerated type 1 diabetes in adult female NOD mice, but delayed it in males, and that immunomodulation was the primary mechanism (Xu et al. 2019a). These authors also found that timing was a major factor, and that the gut microbiota were also involved. Specifically, exposure to BPA increased type 1 diabetes risk in juvenile females, in conjunction with more inflammatory gut microbiota. Adult females had a trend of increased type 1 diabetes and a general increase in immune responses. However, female offspring had a reduced type 1 development and a microbiota shift towards anti-inflammation. Meanwhile in male offspring, BPA had minimal effects on immunity and type 1 (Xu et al. 2019b).
Another study, using different rodents with chemical-induced type 1, found that BPA increased diabetes incidence. The effects depended on dose, and were actually greater at lower doses in the early stages of disease, and both lower and higher doses affected disease development later on (Cetkovic-Cvrlje et al. 2017). In another study of mice with chemical-induced type 1, BPA and octylphenol helped beta cell survival, but then resulted in impaired regulation of glucose levels as well as insulin resistance (Ahn et al. 2018). An earlier study by these authors showed that BPA and octylphenol helped increase insulin secretion in these mice (Kang et al. 2014).
To examine the impact of diet in BPS-treated mice in relation to hyperglycemia, development of type 1 diabetes, immunomodulation, and behavioral changes, adult male and female non-obese diabetic excluded flora (NODEF) mice were exposed to environmentally relevant doses of BPS and fed either a soy-based diet, a phytoestrogen-free diet, or a Western diet. BPS-exposed NODEF mice had sex and diet-related changes in hyperglycemia, behaviors, and immune endpoints. For example, BPS-exposed male mice fed a soy-based diet had high blood glucose levels and impaired glucose tolerance (McDonough et al. 2021).
BPA has been shown to affect the immune system of rodents in ways that may be significant for autoimmune diseases (e.g., Özaydın et al. 2018). In genetically susceptible mice, BPA enhances the production of autoantibodies. The authors conclude that BPA may be a factor in the increased incidence of autoimmune disease in humans. Both estradiol, a natural estrogen, and the estrogenic pharmaceutical diethylstilbestrol (DES) showed the same autoimmune-enhancing effects as BPA (Yurino et al. 2004). Laboratory studies also show that BPA can affect the immune system of animals (e.g., Qiu et al. 2016). Because BPA exposure can influence the immune system, BPA is considered to be an immunotoxicant (described on the autoimmunity page (Dietert and Dietert 2007) and a risk factor for autoimmune diseases (Jochmanová et al. 2015). BPA has been associated with thyroid autoimmunity in humans, for example (Chailurkit et al. 2016).
Exposure to BPA during development may affect the risk of various immune-related diseases (Xu et al. 2016). In animals, developmental exposure to BPA causes immune system changes in offspring that are linked to autoimmune diseases, including decreasing regulatory T cells and causing inflammation (Gao et al. 2020).
In offspring mice, BPA, BPS or BPF exposure to mothers via skin led to adverse effects on immune response in the intestine and the body that was dependent on the specific bisphenol, the dose, and the offspring's sex. The effects included changes in gut microbiota, impaired intestinal immune response, intestinal inflammation, and effects on regulatory T cells; all these effects are linked to autoimmune diseases, including type 1 diabetes (Malaisé et al. 2021).
BPA also affects adult rodents' response to infection, and patterns of immune system cells called cytokines. Rodents exposed to BPA in utero showed an increased immune response as adults, with higher levels of certain cytokines. BPA's ability to disturb cytokine production in animals could influence inflammation; cytokines are discussed further on the inflammation page. In fact, BPA, BPS, and BPAF all affect cytokine production and are immunotoxic to macrophages: BPS was the least toxic, while BPAF was the most toxic, and BPA in the middle (Chen et al. 2018). The effects of BPA on the immune system of rodents depend on the timing of the exposure as well as gender (Richter et al. 2007). Additional studies of BPA also show that developmental exposure affects the immune system (Koike et al. 2018). Oxidative stress is another mechanism likely involved in the effects of BPA on the immune system. Zebrafish embryos, a model used to screen for toxicity in the lab, show a higher immune response when exposed to BPA (and nonylphenol), involving altered immune gene expression and oxidative stress (Xu et al. 2013). Studies of other autoimmune diseases, e.g., SLE (lupus), show that BPA can induce immune signalling that may potentiate these diseases (Panchanathan et al. 2015). Another study found that the structural alterations in DNA produced by BPA may be a factor responsible for the induction of anti-DNA autoantibodies in lupus (Alhomaidan et al. 2019). Gestational exposure to BPA can promote the development of the autoimmune disease MS in animals as well (Rogers et al. 2017). BPA can also trigger neurological autoantibodies (Kharrazian and Vojdani, 2017).
Numerous types of immune cells have been found to be affected by BPA, including T cells, regulatory T cells, B cells, dendritic cells, and macrophages (reviewed in Rogers et al. 2013; also see Huang et al. 2019). In fact, "virtually all the major cells of the immune system" are affected by BPA, and these pathways may be one way that autoimmune diseases are promoted by BPA (Kharrazian 2014). Many of these cells are involved in inflammation and human disease, including autoimmune disease such as type 1 diabetes. BPA has been found to specifically augment the Th1 immune response, which is linked to autoimmunity (Goto et al. 2007), additionally in experiments when exposure occurs during development (Yoshino et al. 2004). Developmental exposure to BPA also affects levels of Th17 cells, also linked to autoimmunity (Luo et al. 2016). However, another study found that BPA did not activate dendritic cells (as estrogen does), so that mechanism is probably not involved (Chakhtoura et al. 2017). Also, a more detailed study measured hundreds of immune cell outcomes following developmental BPA exposure in rats, and found changes in a few dozen of them. Most of these changes were somewhat sporadic, moderate in magnitude, were not necessarily consistent over time. The authors conclude that BPA exposure may not alter immune competence in adults (Li et al. 2018a; Li et al. 2018b).
At low doses, exposure to BPA and BPF during development induced intestinal and systemic immune responses linked to autoimmunity and inflammation in offspring mice (Malaisé et al. 2020). All of these changes are linked to type 1 diabetes.
In mice, BPA activates the immune system, and these effects can be passed down through multiple generations (Sowers et al. 2019).
A review of BPA and autoimmunity concludes that, "Although research at present does not directly link BPA exposure to the development of autoimmune diseases, a large body of evidence supports the pro-inflammatory effects of BPA on the immune system. Further studies are required to elucidate the role of BPA in autoimmune pathogenesis, however caution should be taken in the use of BPA containing products by those affected or genetically susceptible to developing autoimmune diseases" (Aljadeff et al. 2018).
BPA exposure can also cause insulin immunoreactive cells in the islets, and (as also described above) affect beta cell function (Ozaydin et al. 2018).
In adult male NOD mice, BPS exposure plus a soy-based diet led to increased insulin resistance and variable blood glucose levels, while adult females had lower blood glucose levels and delayed diabetes development. The effects could partly be explained by the diet (Xu et al. 2019c). Note that one characteristic of NOD mice is that many things can delay development of diabetes in these mice-- things that do not delay diabetes in humans-- so findings of diabetes delay in NOD mice is not necessarily applicable to humans (see the Of Mice, Dogs, and Men page for more information on this issue).
BPA, Viruses, and the Gut
Does BPA interact with viruses?
In humans, exposure to BPA has been associated with higher levels of cytomegalovirus antibodies in adults, a sign of altered immune system function. In youth, BPA exposure was associated with lower cytomegalovirus antibody levels. It is unclear what could account for these differences. The authors of this study suggest that perhaps the consequences of BPA exposure may vary depending on the timing, quantity, and duration of exposure. Perhaps short exposures stimulate the immune system, and longer exposures result in immune dysfunction (Clayton et al. 2011).
Some Anecdotal Evidence
According to an article in the St. Louis Post-Dispatch, Dr. Nathan Ravi developed type 1 diabetes after working with BPA as a chemical engineer. Two of his colleagues at the plant also developed type 1.
See: Doctor with diabetes speaks out about chemicals in plastics, St. Louis Post-Dispatch, April 7, 2016, by Harry Jackson Jr.
In rats, early life exposure to BPA made them more susceptible to intestinal infection than those unexposed, and impaired their ability to respond to food antigens (Ménard et al. 2014). Intestinal infections and food antigens are both linked to type 1 diabetes (see the diet and the gut page). Laboratory evidence also indicates that BPA detrimentally alters gut microbiota (Javurek et al. 2016, Koestel et al. 2017; Lai et al. 2016). In mice, BPA not only affected gut microbiota, but also increased intestinal permeability (Feng et al. 2019; Feng et al. 2020; Wang et al. 2021). In rats, BPA affected gut microbiota, caused intestinal dysfunction, and higher blood glucose levels (Ambreen et al. 2019). (Changes in gut microbiota and intestinal permeability are linked to diabetes development.) Developmental exposure of mice to BPA causes gut permeability, and weakens protective gut immune function, increasing susceptibility to inflammation (Malaisé et al. 2018), as well as more widespread inflammation (Reddivari et al. 2017). The effects that BPA has on the gut precede its effects on obesity (Malaisé et al. 2017). And, BPA causes intestinal cells to absorb more cholesterol (Feng et al. 2017) and has other detrimental effects directly on the intestine (Gonkowski 2020).
Adult exposure to BPA affected the diversity and composition of the gut microbiota in male mice and reduced the tight junctions in the colon, resulting in dysfunction of the gut barrier (Ni et al. 2021). BPA can not only induce intestinal cell barrier dysfunction, it also reduces the viability of intestinal mucus secreting cells, also affecting the intestinal mucus barrier (Zhao et al. 2019).
Developmental exposure to BPA as well as BPA substitutes alters the microbial structure and function of zebrafish (Catron et al. 2018).
A study of a mouse model of multiple sclerosis (MS), another autoimmune disease, found that BPA exposure in combination with a virus had numerous effects on these mice, including an acceleration of symptoms, increased inflammation, and changes in immune-related gene expression (Brinkmeyer-Langford et al. 2014). A mouse study of immune responses to food found that BPA, BPS and BPF impaired tolerance to food and caused inflammation (Malaisé et al. 2020).
BPA and Vitamin D Levels
Does BPA influence vitamin D levels? One cross-sectional study of U.S. adults found that women with higher BPA levels have lower vitamin D levels (Johns et al. 2016). These authors also found that BPA levels were associated with an increased risk of vitamin D deficiency in pregnant women (Johns et al. 2017). In rats, early life exposure to BPA increased urinary excretion of vitamin D and decreased its concentration in blood, especially in females (Kim et al. 2019). Giving mother mice vitamin D supplements reduces BPA-induced effects on the immune system in offspring (Wang et al. 2020). Low vitamin D levels are linked to diabetes development (see the vitamin D deficiency page). I expect these findings will encourage additional research on the topic.
Gestational Diabetes and Diabetes Following Pregnancy
When pregnant mice were exposed to low and high doses of BPA, their insulin resistance increased, and glucose tolerance decreased during the pregnancy (especially those exposed to the lower doses). Four months after the birth, they had increased insulin resistance and also weighed more than the untreated control mice (without differences in food intake). Interestingly, the effects were not apparent three months after the birth, but reappeared at four months. The results suggest that BPA could contribute to the development of gestational diabetes (Alonso-Magdalena et al. 2010). Another study by the same authors found that mother mice treated with low doses of BPA during pregnancy developed glucose intolerance, increased body weight, and insulin resistance, decreased insulin secretion, reduced beta cell mass, and increased beta cell death, several months after delivery (Alonso-Magdalena et al. 2015). These factors are important for a mother's development of diabetes following pregnancy (mothers commonly develop type 2 following gestational diabetes; I developed type 1 following gestational diabetes-- it does happen!)
In a prospective study from China, women with higher BPA levels had higher fasting glucose, fasting insulin, and insulin resistance in mid-pregnancy. They also had a higher risk of gestational diabetes, although that finding was not statistically significant (Yang et al. 2020).
Some human studies have not found links between BPA and gestational diabetes, however. One study done in Oklahoma did not find an association between pregnant women's BPA levels and gestational diabetes or fasting blood glucose levels (Robledo et al. 2013). Another study from Canada also did not find an association between BPA and gestational diabetes (although it did find an association between arsenic and gestational diabetes) (Shapiro et al. 2015). And in fact in China, higher levels of BPA were associated with a reduced risk of gestational diabetes (Wang et al. 2017). Similarly in Mexico, women with gestational diabetes had lower levels of BPA than those without diabetes (Martínez-Ibarra et al. 2019).
A study from the Boston area, however, found that BPA levels during the second trimester (but not the first) were associated with glucose levels in women from a fertility clinic (Chiu et al. 2017). Another study from the Boston area found that higher BPA levels were associated with higher glucose levels in overweight and obese women, but not in the overall population (Bellavia et al. 2018).
A longitudinal study from China found that BPA substitutes might increase the risk of gestational diabetes. BPF was associated with an increased risk of gestational diabetes in normal weight women. In overweight women, BPA had a non-linear association with fasting glucose levels. Women carrying a female fetus had higher fasting glucose levels associated with BPS levels as well (Zhang et al. 2019).
In Europe, higher BPA levels were associated with lower blood pressure in pregnant women (Warembourg et al. 2018). In pregnant women from the Netherlands, higher bisphenol levels in early pregnancy were associated with lower weight gain during later pregnancy (Philips et al. 2020a) and higher weight gain after pregnancy (Philips et al. 2020b). In Mexican women, BPA levels during pregnancy is associated with lower weight at delivery, but then a slower rate of weight loss through the first postpartum year (Perng et al. 2020).
BPA exposure during pregnancy is associated with inflammation and oxidative stress in mothers (Ferguson et al. 2016); perhaps these mechanisms could help explain the health effects of BPA on both mother and child. A review suggests that weight gain, insulin resistance and pancreatic beta-cell dysfunction in pregnancy may also play a role in BPA and gestational diabetes (Filardi et al. 2020).
Diabetes Management and Complications
People with type 2 diabetes who had higher levels of BPA in their bodies had a 7-fold (!) higher risk of developing chronic kidney disease than those with lower levels. That number is from a study of Chinese adults who were followed for 6 years (Hu et al. 2015). This finding deserves some attention!
Kidney dialysis machines are a source of BPA exposure (Bacle et al. 2019). People with diabetes undergoing dialysis have measurably higher BPA levels in their blood after a single dialysis session that before the session (those with diabetes also had higher BPA levels than those without diabetes) (Neri 2016; Turgut et al. 2016). Certain dialysis membranes expose patients to higher levels of BPA than others (Bosch-Panadero et al. 2016), and certain dialysis membranes release more BPA than others (Shen et al. 2019). Hemodiafiltration may be able to reduce the levels of BPA in people undergoing dialysis (Mas et al. 2018; Quiroga et al. 2017).
In a meta-analysis of data from two European cohort studies, in people with type 2 diabetes, the occurrence of heart attacks was significantly associated with BPA. Exposure to chlorinated derivatives of BPA, by-products of water chlorination, was very strongly associated with heart attacks in one of the studies but not in the other (whether these results may be explained by different water chlorination processes in France and Germany, resulting in different chlorinated BPA exposure levels, requires further investigation) (Hu et al. 2019).
BPA elimination is impaired in individuals with diabetes, obesity, or fatty liver, as shown in studies with human and mouse liver samples. The liver metabolizes BPA and leads to its elimination from the body (Yalcin et al. 2016).
In people with type 2 diabetes, BPA exposure may affect the development and normal function of cardiac cells (Liu et al. 2020).
In People Without Diabetes
Melzer et al. (2010) and Lang et al. (2008) and Cai et al. (2020) have found that BPA is associated with heart/cardiovascular disease in the general U.S. population. In fact, numerous human studies have shown that higher BPA concentrations in humans are associated with various types of cardiovascular diseases, including angina, hypertension, heart attack, and coronary and peripheral arterial disease (e.g., Aekplorn et al 2015; Han and Hong 2016, and reviewed in Gao and Wang 2014 and Fu et al. 2020). In Chinese adults, BPA is also associated with albuminuria (protein in the urine), a common complication of diabetes (Li et al. 2012). In Ohio children, BPA levels were associated with higher blood pressure and other adverse liver and metabolic changes (Khalil et al. 2014). In European children, prenatal BPA exposure is associated with higher diastolic blood pressure (Warembourg et al. 2019). In U.S. and Korean adults, BPA exposure was associated with hypertension (high blood pressure) as well (Bae et al. 2012; Shankar and Teppela, 2012), as was both BPA and BPS in Chinese adults (Jiang et al. 2019). And in those with hypertension, BPA is associated with the development of kidney disease (Hu et al. 2016). In animals, BPA exposure affects the heart muscle (Sivashanmugam et al. 2017), and exposure during development affects the development of the kidneys (Nuñez et al. 2018).
Higher nonylphenol exposure is associated with lower kidney function in humans (Chen et al. 2021).
The risk of suspected NAFLD is increased in adolescents with higher levels of BPA exposure, particularly in those of Hispanic ethnicity (Verstraete et al. 2018). In the general U.S. adult population, BPA is associated with an increased risk of NAFLD (Kim et al. 2019). BPF is also linked to an increased risk of NAFLD in humans, and can cause related changes in laboratory studies (Wang et al. 2020).
BPA is also linked to obstructive sleep apnea, common in people with diabetes, obesity, or metabolic syndrome. People with severe sleep apnea were found to have higher levels of BPA (and lower levels of vitamin D) (Erden et al. 2014).
Laboratory Studies: Complications
In animals, mice chronically exposed to BPA and a high-fat, high-cholesterol diet showed accelerated atherosclerosis as compared to control mice who ate the same diet but were not exposed to BPA. The exposed mice also had higher levels of non-HDL cholesterol than controls (Kim et al. 2014). Animal studies show that BPA causes atherosclerosis and high blood pressure in rodents (reviewed in Gao and Wang 2014, or specific studies such as Saura et al. 2014). In mice, BPA exposure during development also exacerbates atherosclerosis during adulthood (Sui et al. 2018).
Adult exposure to BPA causes fatty liver in lab animals (Sun et al. 2020; Yang et al. 2017); early-life exposure to BPA also enhances non-alcoholic fatty liver disease (NAFLD) in animals (Lin et al. 2019; Shimpi et al. 2017), especially in combination with a high fat diet (Wei et al. 2014; Strakovsky et al. 2015). Post-weaning exposure also causes NAFLD in mice (Lin et al. 2017). Fetal exposure also affects fetal development of the liver in mice (DeBenedictis et al. 2016). BPA's effects on the liver appear to involve mitochondrial dysfunction in liver cells (Khan et al. 2016) and oxidative stress (Vahdati Hassani et al. 2018). Nonylphenol also causes fatty liver disease in rats (Yu et al. 2017). And in pigs, low doses of BPA cause liver changes that are associated with diabetes and obesity in humans (Thoene et al. 2017). BPF and BPAF also affect the liver in animal studies (Meng et al. 2019), as does BPS (Qin et al. 2020).
After 12 weeks of a high-fat diet, male mice were exposed daily to BPA along with a high-fat diet for 3 weeks. BPA amplified diet-induced alteration of key factors involved in glucose and lipid metabolism, liver triglycerides accumulation, increasing the risk of fatty liver disease (Pirozzi et al. 2020).
BPA exposure from birth through young adulthood affects heart function and blood pressure in mice, with females at greater risk (Belcher et al. 2015). It affects heart function in sheep as well (MohanKumar et al. 2017). Exposure to BPA during development affects fatty acid levels in mice (Veiga-Lopez et al. 2015). BPA also has detrimental effects on the heart (Brown et al. 2018; Gear et al. 2017; Ljunggren et al. 2016), and makes it harder for animals to recover from a heart attack (Patel et al. 2015).
BPA can also cause "brain insulin resistance" in mice, which is a condition linked to Alzheimer's disease (people with type 2 diabetes have twice the risk of developing Alzheimer's than those without diabetes) (Fang et al. 2015; Wang et al. 2017).
Laboratory studies show that BPA may also contribute to kidney disease (Bosch-Panadero et al. 2018). In rats with diabetes, continuous BPA exposure worsened kidney impairment, and caused heart problems as well (Wu et al. 2021).