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Phthalates

Phthalates and diabetes/obesity

Summary

Links Between Phthalates and Diabetes/Obesity

The Details

About Phthalates
Reviews of Phthalates and Diabetes/Obesity



Summary

Links Between Phthalates and Diabetes/Obesity

Over 300 peer-reviewed studies published since 2006 in scientific journals have examined the relationship between phthalates and diabetes or obesity.

The majority of human epidemiological studies have found that people with higher exposures to phthalates have a higher risk of type 2 diabetes or obesity. This evidence includes long-term, longitudinal studies that follow people over time. The evidence linking phthalates to type 1 or gestational diabetes is preliminary to non-existent.

Exposure to phthalates in the womb or during early life-- key periods of susceptibility-- may affect the risk of developing diabetes or obesity later in life.

Laboratory studies on animals or cells show that phthalates exposures can cause biological effects related to diabetes/obesity, and have helped to identify the key periods of susceptibility and the mechanisms involved.

Studies have also found links between phthalates exposure and the risk of diabetes complications.

An expert panel of scientists determined that in the European Union, phthalate exposure has a 40 - 69% probability of causing 53,900 cases of obesity in older women with €15.6 billion in associated costs. Phthalate exposure was also found to have a 40 - 69% probability of causing 20,500 new-onset cases of diabetes in older women with €607 million in associated costs (Legler et al. 2015). In China, exposure to phthalates is estimated to be associated with ~2.50 million cases of infertility, obesity, and diabetes in 2010, causing ~57.2 billion Chinese Yuan (equivalent to ~9 billion U.S. dollars) of health care costs in a year (Cao et al. 2019).


The Details

Reviews of Phthalates and Diabetes/Obesity

A review of the human evidence of six phthalates and their metabolic effects found that for DEHP, studies of insulin resistance and diabetes were consistent, with a dose-response effect. For DBP and DIBP exposure, there are strong positive associations with diabetes and insulin resistance as well. For other phthalates, the evidence was slim to unstudied. The authors conclude, "the available evidence does indicate an association between exposure to these phthalates and insulin resistance, but the small number of studies and the lack of coherence with diabetes decreases confidence." (Radke et al. 2019).

A review of phthalates in obesity concludes, "Many in vitro studies indicate that phthalates are likely obesogens, promoting obesity via several mechanisms, including activation of PPARs, antithyroid effects, and epigenetic modulation. The fetal period appears to be a critical window for exposure, and differential effects are observed depending on the dose of phthalates received and gender. Recent human studies have examined the possible effects of phthalate exposure on the development of obesity, although most of them are cross-sectional and short-term prospective studies. Although the random concentrations of phthalate metabolites have good reproducibility, large-scaled longitudinal study including measures at different life ages is needed to establish the impact of phthalate exposure on the obesity epidemic" (Kim and Park, 2014).

Another review finds that "Most data support the effects of ... some phthalates, such as di-2-ethyl-hexyl phthalate, diethyl phthalate, dibuthyl phthalate, dimethyl phthalate, dibenzyl phthalate, diisononyl phthalate and others 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).

A systematic review and meta-analysis of 8 studies found a positive association between exposure to phthalate metabolites and increased insulin resistance, even after adjusting the analysis for multiple other variables (Shoshtari-Yeganeh et al. 2019).

About Phthalates

Phthalates, chemicals often used as plasticizers, are present in a large variety of consumer products.

Type 2 Diabetes, Insulin Resistance, and Body Weight

Longitudinal Studies in Adults

How Are We Exposed to Phthalates?

cosmetics

Cosmetics are a major source phthalate expsosure, and thus women have higher exposure levels than men. DEHP is the most commonly used phthalate, used to make food packaging and medical devices (Feige et al. 2007). 

Blacks, Mexican Americans, and women living in poverty are exposed to the highest levels of phthalates in the U.S. (James-Todd et al. 2012).

Teenagers who use personal care products like make-up have higher levels of many phthalates (Berger et al. 2018), and have been able to reduce their phthalate levels by choosing phthalate-free products (Harley et al. 2016). Teens who ate a diet of fresh/unprocessed food also lowered their phthalate levels (Correia-Sá et al. 2018).
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 longitudinal study of phthalates and type 2 diabetes published 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), total phthalate levels were not associated with type 2 diabetes. However, in the Nurses Health Study 2, which includes middle-aged women (average age 46), total phthalate levels were associated with type 2 diabetes. Thus, phthalate 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. While the younger women had higher levels of phthalates than the older women, these differences did not explain the findings. Note that this paper also found similar results for BPA exposure levels (Sun et al. 2014).

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 some phthalate (and BPA) exposures gained more weight during the 10 year follow-up period than those with lower levels of exposures (Song et al. 2014). 

Among post-menopausal women in the U.S. Women's Health Initiative, levels of various phthalate metabolites were associated with obesity and weight gain over 3 years, but not over 6 years (Díaz Santana et al. 2019).

Elderly Korean adults with higher urinary phthalate metabolite levels (from DEHP) had increased insulin resistance, especially women and those with diabetes. A marker of oxidative stress was also higher in those with higher insulin resistance and phthalate levels (Kim et al. 2013). In elderly Swedish women (not men), the phthalate MiBP was related to increased abdominal body fat two years later (Lind et al. 2012).

Longitudinal Studies in Children

In New York City children, certain phthalate exposures measured at age 6-8 were associated with a higher body mass index and waist circumference one year later (Teitelbaum et al. 2012). In Italian adolescents, changes in DEHP metabolite levels were associated with obesity and insulin resistance. Also, the more MEHP was metabolized, the greater the insulin resistance (Smerieri et al. 2015). In other words, the body's ability to metabolize phthalates may be important. This is similar to another study from Korea, which also found phthalate metabolite levels associated with obesity and insulin resistance in girls, although this time the MEHHP metabolite (Kim et al. 2018).

Also in Korea, various phthalate metabolites were associated with increased triglyceride and insulin resistance levels in children (Han et al. 2019).

In 2011, it was discovered that in Taiwan, DEHP phthalate had been added to food illegally as an emulsifier. A study of some children exposed to high levels of DEHP showed that these children had lower body weight, height, and growth hormones (Tsai et al. 2016). Thus high levels of exposure may impede growth, but low levels (more normally encountered) may promote growth.

European children with higher levels of MBP have lower systolic blood pressure (Warembourg et al. 2019).

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. Prenatal exposure to phthalates was associated with changes in BMI and head circumference during the first year of life in the Netherlands-- boys with lower phthalate exposures had a higher BMI than those more highly exposed, at 11 months of age (de Cock et al. 2014).

In Spain, prenatal phthalate exposure was associated with lower early weight gain in infancy and lower BMI at 4-7 years of age in boys, but with higher infant weight gain and childhood BMI in girls (Valvi et al. 2015). The same Spanish study, this time analyzing 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 (phthalates, flame retardants, arsenic, BPA, lead, and cadmium) were not associated (Agay-Shay et al. 2015).

In the U.S., levels of non-DEHP phthalates in the womb were associated with a lower BMI, smaller waist circumference, and lower fat mass in boys at age 5-7 (there was no association in girls, or with DEHP metabolite levels). This study was based on data from the Columbia Center for Children’s Environmental Health (CCCEH) study of African-American and Dominican women in New York City (Maresca et al. 2016). These authors also found epigenetic changes in the placenta that were associated with phthalate levels and may explain mechanisms behind associations (Adibi et al. 2017). Also in New York City, data from the The Mount Sinai Children’s Environmental Health Study showed that pre-natal phthalate levels were not associated with body fat in children at age 4-9, although high DEHP levels were associated with slightly lower fat mass at that age (Buckley et al. 2016a). For an article on this study, see Phthalates and Childhood Body Fat: Study Finds No Evidence of Obesogenicity, published in Environmental Health Perspectives (Nicole 2016).

A U.S. study, of data from 3 different cohorts, found that maternal levels of the phthalate metabolite MCPP was associated with overweight/obesity in children at 4-7 years of age. DEPH levels were associated with lower BMI in girls as well (Buckley et al. 2016b). Another study of three U.S. sites found that phthalate levels at age 6-8 were associated with gains in BMI and waist circumference at age 7-13. The associations were only found for low molecular weight phthalates (Deierlein et al. 2016). A study from Ohio, found that early life exposure was generally not associated with signs of obesity (Shoaff et al. 2017).

The U.S. Center of Health Assessment of Mothers and Children of Salinas (CHAMACOS) is a longitudinal birth cohort study examining the impact of pesticide and other environmental exposures on the health and development of Mexican-American children living in the Salinas Valley, an agricultural region in California. In this cohort, in utero exposure to some phthalates was associated with an increased risk of obesity or overweight at age 12 (Harley et al. 2017). Examined in more detail, the authors find different childhood BMI development patterns in relation to phthalate exposure levels, including a non-linear association between prenatal monoethyl phthalate urinary concentrations and BMI in children, which varies by sex (Heggeseth et al. 2019). In newborns, prenatal phthalate exposure levels were associated with epigenetic changes in genetic regions related to inflammation and endocrine function (as well as cancer and male fertility) (Solomon et al. 2017). Exposure to phthalates in pregnant women is associated with oxidative stress in these mothers (Holland et al. 2016), and with markers of oxidative stress and metabolic dysfunction in their children (Tran et al. 2017).

In Canada, first-trimester maternal levels of phthalates were associated with higher leptin levels in male infants-- leptin is a hormone that controls the amount of fat stored in the body. These babies will be followed to see if there are any later-life health effects associated with early phthalate exposure (Ashley-Martin et al. 2014).

In Greece, prenatal phthalate exposure was not consistently associated with child weight-related measures. Exposure during childhood, however, was. Phthalate metabolite levels were associated with lower BMI in boys and higher BMI in girls; DEHP was associated with a lower waist circumference in boys and higher in girls; phthalate metabolite concentrations at age 4 were negatively associated with blood pressure; and MiBP was associated with higher total cholesterol levels (Vafeiadi et al. 2018).

The Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study of pregnant women and their offspring in Mexico City has looked at phthalate exposures in the womb and later metabolism in the children, finding that early life exposure (from prenatal through puberty) to various phthalates were associated with aspects of metabolism in 8-14 year old children. The associations varied by sex, age, and stage of puberty. For example, exposure to MEP in the womb was associated with lower insulin secretion in boys at puberty and higher leptin levels in girls (Watkins et al. 2016). Exposure to MBzP in the womb was associated with a lower BMI in childhood, and childhood exposure to MEHP was associated with a lower waist circumference in childhood (Yang et al. 2017). Additional phthalates were associated with higher growth and BMI by age 14, in ways that varied by sex and by exposure timing (Yang et al. 2018). Early gestation MBP, MIBP, and MBzP were associated with higher BMI and other weight-related measures in girls, whereas second trimester and adolescent MBzP were associated with weight-related measures in boys in opposite directions (Bowman et al. 2019). Various phthalates levels (at puberty, but not in utero) were associated with lower cholesterol levels in these children (Perng et al. 2017).

In Korea, DEHP levels in newborns were associated with a higher body mass increase in the first three months after birth (Kim et al. 2016). In Japan, maternal phthalate levels were associated with cord blood leptin and adiponectin (a hormone that helps regulate glucose levels) as well as birth size (Minatoya et al. 2017). Another study from the same authors found maternal phthalate levels were associated with lower leptin levels in cord blood (Minatoya et al. 2018).

Epigenetics may also 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 of Michigan babies (Montrose et al. 2018).

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.

U.S. adult women with higher levels of several phthalates had a higher risk of diabetes. Women with the highest levels of some phthalates had twice the risk of diabetes as those with the lowest levels (James-Todd et al. 2012). In an expansion of this study, some of the same researchers found that phthalate levels were associated with higher fasting blood glucose levels, fasting insulin levels, and increased insulin resistance. These associations were strongest in Mexican Americans and non-Hispanic blacks, suggesting that these groups may be more vulnerable to phthalate exposures relating to diabetes (Huang et al. 2014). They also found that phthalate levels were associated with metabolic syndrome (the specific phthalate that was associated with metabolic syndrome varied, depending on sex and menopausal status) (James-Todd et al. 2016).

In Swedish elderly people, three of four types of phthalate metabolites were associated with an increased prevalence of type 2 diabetes. The phthalate metabolites linked to diabetes included MMP, MiBP, and MEP, which are breakdown products of phthalates found in body care products. MiBP was related to poor insulin secretion, while MMP and MEP were related to insulin resistance. The phthalate metabolite MEHP, which is a breakdown product of the plasticizer DEHP, was not associated with diabetes (Lind et al. 2012). Phthalates activate certain hormone receptors called PPARs. PPARs are known to influence blood glucose levels, via insulin resistance, insulin secretion, and fat formation. Interestingly, pharmaceutical drugs that have the opposite effect on PPARs are used to treat type 2 diabetes, by decreasing insulin resistance (Lind et al. 2012). Another study of the elderly, this time in men from Australia, also found phthalate levels to be associated with obesity (Bai et al. 2015). And in Chinese elderly people with diabetes, phthalate levels were associated with higher levels of insulin resistance (Dong et al. 2018).

Phthalates have also been associated with diabetes in Mexican women. That study found that levels of three types of DEHP metabolites were higher in adult women with diabetes than those without diabetes. The results suggest that phthalate exposures may play a role in diabetes development (Svensson et al. 2011). In elderly Swedes, various phthalates were associated with fasting blood glucose levels, as well as cholesterol and blood pressure (Olsén et al. 2012). In obese Belgian adults, phthalate levels were linked to insulin resistance (Dirinck et al. 2015). While in Turkish adults, phthalate levels were strongly associated with BMI (Oktar et al. 2017). And in U.S. adults, certain phthalates were linked to high blood pressure, a component of metabolic syndrome (Shiue 2014a; Shiue 2014b).

In the U.S., levels of several phthalate metabolites were associated with increased insulin resistance and abdominal obesity in men (Stahlhut et al. 2007). In another U.S. study, of people aged 6-80, various phthalate metabolites were associated with higher body mass index (BMI) and waist circumference in men aged 20-59. Effects in women were not as consistent. In some ages, exposures was associated with lower BMI (Hatch et al. 2008; Hatch et al. 2010). In a third U.S. study, a number of phthalates were associated with obesity in men and women, with differences depending on the type of phthalate, age, and sex (Buser et al. 2014). In a fourth U.S. study, certain phthalate metabolites were associated with an increased risk of overweight/obesity and BMI in black children, but not children of other ethnic groups (Trasande et al. 2013b). And a fifth study found that phthalate metabolite levels in U.S. women were associated with BMI, waist circumference, and cholesterol levels. The associations varied by metabolite. Women who had slower conversion of MEHP to its metabolite had both higher BMI and waist circumference (Yaghiyan et al. 2015). Compared to other phthalates and other chemicals, mono carboxyoctyl phthalate (MCOP), was one of the most important chemicals associated with obesity (Zhang et al. 2018). Thus the relationship between phthalates and obesity may depend on gender, age, race, type of phthalate, and metabolic rate of processing phthalates in the body. And some argue that according to their model, increased food intake can lead to both higher weight and higher phthalate levels, which might help explain some associations (Campbell et al. 2018). The relationship between DEHP and insulin resistance also appears to be affected by the levels of beta-carotene (an antioxidant) in blood; thus diet is also important and may help protect against the effects of phthalates (Li et al. 2019). 

Canadian teens and adults without diabetes with higher phthalate levels had higher blood glucose levels, insulin levels, and insulin resistance (Dales et al. 2018).

In Slovakian hairdressers exposed to high occupational levels of phthalates, various phthalate levels were associated with BMI and fat mass (Kolena et al. 2017). Another study of Slovakians occupationally exposed to phthalates found that MEHP was associated with a lower BMI and other variables in females, but not in males (Petrovičová et al. 2016). In the Czech Republic, phthalate levels were higher in people with type 2 diabetes (but not associated with blood pressure or lipid/cholesterol levels) (Piecha et al. 2016). In Serbia, phthalate levels in men were associated with a variety of metabolic markers, including lower HDL levels (the "good" cholesterol), higher BMI, and higher triglycerides (Milošević et al. 2017).

In Australian men, phthalate levels were associated with type 2 diabetes, high blood pressure, cardiovascular disease, and inflammation (Bai et al. 2017).

In Taiwanese military personnel, higher daily intake of dimethyl phthalate (DMP) was associated with higher insulin resistance and metabolic syndrome. Higher daily intake of benzyl butyl phthalate (BBzP) was associated with an increased risk of abdominal obesity (Ko et al. 2019). Also in Taiwan, in both adults and children, phthalate levels were associated with various measures of growth hormones (Huang et al. 2017).

In China, numerous phthalate metabolites were associated with diabetes in males, as well as with high cholesterol levels in both sexes (Dong et al. 2017a). Another study from China (Shanghai), found that numerous phthalates were associated with obesity, especially central obesity, especially in women, and especially in women under 45 (Dong et al. 2017b). Exposure to phthalates was positively associated with type 2 diabetes, fasting glucose, and long-term blood glucose (HbA1c) levels in an additional Chinese study, and the associations differed based on sex, BMI, and age (Duan et al. 2019). Also in China, phthalate levels were associated with high blood pressure and higher total cholesterol levels (Zhang et al. 2018). 

In Korea, MEHHP phthalate levels were positively associated with metabolic syndrome (Shim et al. 2019).

In Saudi Arabia, phthalate levels were higher in people with diabetes than in those without diabetes (Li et al. 2019).

Cross-Sectional Studies in Children

In U.S. adolescents, DEHP phthalate metabolite levels were associated with increased insulin resistance (Trasande et al. 2013a). DEHP is being replaced with DINP and DIDP. It turns out that metabolites of those replacements are also associated with insulin resistance in U.S. adolescents (they also confirmed the previous association with DEHP metabolites) (Attina and Trasande 2015). Some of the same authors also report that higher molecular weight phthalates (a category that includes DEHP, DINP, and DIDP) are associated with insulin resistance in Mexican American and Hispanic 10-13 year olds (Kataria et al. 2017). Also in U.S. adolescents, the phthalate metabolite MnBP and was associated with metabolic syndrome; some other associations varied by sex (Gaston and Tulve 2018).

In Chinese schoolchildren, levels of certain phthalates were associated with increased BMI or waist circumference (Wang et al. 2013). Another Chinese study found that levels of certain phthalates were associated with higher BMI and fat distribution in boys over 10, but lower fat distribution in girls under 10 (Zhang et al. 2014). A third found that phthalates were associated with various growth hormone levels in young Chinese children (Wu et al. 2017). A fourth found various associations between various phthalates and different measures of obesity/weight (Wu et al. 2018). A fifth found an association between MnBP levels and overweight/obesity (Xia et al. 2018). 

In Korean girls, certain phthalates were associated with obesity (Choi et al. 2014), and phthalate levels were associated with higher LDL cholesterol levels in children and adolescents (Hyun Kim et al. 2018).

In Taiwanese children, levels of certain phthalates were associated with a higher BMI in boys, and others with a lower BMI in girls (Lien et al. 2018). In Taiwanese adolescents, phthalate levels were associated with abdominal obesity (Hou et al. 2015). Another study of Taiwanese adolescents and young adults found that phthalate levels were associated with insulin resistance (and lower testosterone levels) in the young adults, but not in the adolescents (Chen et al. 2017). A Thai study did not find an association between metabolic markers and MBP or MMP phthalates in obese children/teens (Saengkaew et al. 2017). 

In Iranian children and teens, almost all phthalates measured showed associations with BMI and waist circumference (Amin et al. 2018a), as well as cardiovascular risk factor and obesity (Amin et al. 2018b). Also in Iranian children and teens, phthalate levels were associated with metabolic problems no matter what their weight (Mansouri et al. 2019).

In Denmark, phthalate levels in normal-weight teens and children were not associated with various measures of diabetes or metabolism (Carlsson et al. 2018).

Birth Weight

Maternal exposure to phthalate metabolites has been associated with birth weight in infants. (Low/high birth weight is also associated with type 2 or 1 diabetes; see the Gestation and Birth page). Prenatal phthalate metabolite levels are associated with low birth weight in Chinese newborns (Song et al 2018Zhang et al. 2009). In mothers from Greenland, Poland, and Ukraine, the metabolite MEHHP was associated with lower birth weight, but that the metabolite MOiNP was associated with higher birth weight (Lenters et al. 2016). In a small study from the Netherlands, higher maternal levels of the metabolite MECPP were associated with lower birth weight in boys, but MEHHP was associated with higher birth weight in boys (de Cock et al. 2016).

Interestingly, the father's exposure to phthalates before conception might also be important for offspring health. Paternal preconception levels of DEHP were associated with lower birth weight in offspring conceived by IVF (Messerlain et al. 2017). Very few studies have looked at paternal exposures, so this will be an important area to pursue.

Laboratory Studies: Diabetes/Obesity

In animals, rats given the phthalate DEHP developed symptoms of diabetes, including higher blood sugar and lower insulin levels. The changes reversed when the exposure was removed (Gayathri et al. 2004). A study at the cellular level shows the direct adverse effect of DEHP on the gene expression relating to insulin and glucose, suggesting that DEHP exposure may have a negative influence on insulin signaling (how the body responds to insulin) (Rajesh and Balasubramanian, 2014). Short term treatment of rats with a number of different phthalates found that some of the phthalates (DEHP, MEHP, and MBeP) caused high blood glucose levels (Kwack et al. 2010). Rats treated with DEP had higher blood glucose levels than controls as well (Pereria and Rao, 2006). Mice genetically prone to heart disease developed high blood sugar and glucose intolerance when exposed to phthalates, although the symptoms resolved 4-12 weeks after exposure ended (Zhou et al. 2015).

Female obesity-resistant mice exposed to DEHP for 10 weeks gained weight, had increased fat mass, and had impaired insulin tolerance. It appears that DEHP affects the function of fatty tissue, but perhaps not whole-body glucose metabolism, because things like glucose tolerance, glucose levels, and insulin levels were not affected (Klöting et al. 2015). Male mice given DEHP for 5 weeks gained weight and also developed hypothyroidism (Lv et al. 2016). Adolescent rats exposed to DEHP developed higher fasting glucose levels, higher insulin levels, and insulin resistance (Xu et al. 2018). These authors also found that DEHP exposed rats had increased body weight, more fat cells, inflammation, and higher cholesterol levels (Zhou et al. 2018). DEHP also increases blood pressure in mice (Deng et al. 2019).

Adult rats given DEHP for a month developed high blood sugar, insulin resistance, and other changes associated with diabetes. Those given DEHP plus the antioxidant vitamins E and C, however, did not develop these symptoms of diabetes (Rajesh et al. 2013; Srinivasan et al. 2011). These vitamins essentially prevented diabetes in phthalate-exposed mice-- a sign of how nutrition and chemical exposures may interact to affect disease risk.

Rats exposed to DEHP had increased body weight, as well as higher lipid, insulin, and leptin levels (Jia et al. 2016). Other researchers have also found that DEHP leads to increased body weight in rats (Zhang et al. 2019). The insulin resistance caused by DEHP is due to mechanisms involving PPARγ (Zhang et al. 2017). MEHP also appears to act on fat cells via mechanisms related to PPARγ (Chiang et al. 2017).

The phthalate BBP also disrupts metabolism and increases fat cell development (Yin et al. 2016). BPP has been shown to increase adipogeneis via epigenetic mechanisms (Zhang and Choudhury, 2017).

Low-dose exposure to the phthalate DBP leads to higher glucose levels, weight gain, and higher BMI in rats (Majeed et al. 2017). In mice, DBP exposure causes insulin resistance and impairs insulin secretion (Deng et al. 2018).
 
The phthalate MEHP was found to promote the formation of fat cells (DEHP is converted to the metabolite MEHP when ingested) (Feige et al. 2007). The phthalate DCHP has also been shown to promote the formation of fat cells through mechanisms involving the hormone glucocorticoid (Sargis et al. 2010). Disturbed glucocorticoid action is associated with a number of conditions, including type 2 diabetes, obesity, and autoimmune disease (Odermatt et al. 2006). 

Desvergne et al. (2009) discuss potential mechanisms of phthalate action on obesity, via what they call "metabolic disruptors," a subset of endocrine disrupting chemicals (such as phthalates) that can alter metabolism. MEHP promotes fat formation through metabolic disruption and by affecting gene expression (Feige et al. 2007 Ellero-Simatos et al. 2011). Metabolic disruptors also may affect things like fat storage in the liver; phthalates have been found to increase fat content of the liver and liver inflammation, for example (Chen et al. 2016; Zhang et al. 2017).

Phthalates are present in house dust (along with other chemicals). Samples of house dust were found to cause metabolic effects such as triglyceride accumulation and fat cell promotion. One of the most potent of these chemicals was dibutyl phthalate (Kassotis et al. 2017).

Fish also show higher levels of glucose, triglycerides, food intake, and body weight when exposed to phthalates (Yuan et al. 2017). The phthalate DiDP increased total cholesterol and triglyceride levels in fish (Cocci et al. 2019). Exposure to the phthalates DEHP, DEP and DBP enhanced fat accumulation in the small freshwater crustacean Daphnia magna as well (Seyoum and Pradhan, 2019).

And, even fruit flies develop diabetes-like conditions when eating food contaminated with phthalates (DEHP), at levels comparable to human exposures (Cao et al. 2016); these fruit flies show that phthalates disrupt metabolism by controlling genes involved in glucose and lipid metabolism (Williams et al. 2016). 

Scientists are now figuring out the mechanisms by which phthalates affect metabolism (e.g., Qi et al. 2019) and blood pressure (Deng et al. 2019Xie et al. 2019).

Exposure During Development

A systematic review of 31 studies found that early life exposure of rodents to DEHP was significantly associated with increased fat weight, and non-significantly associated with increased body weight (Wassenaar and Legler, 2017).

When pregnant and lactating rats were given DEHP, their offspring developed abnormal beta cells, and alternations of the genes controlling beta cell function at the time of weaning. In adulthood, the female offspring had high blood glucose, impaired glucose tolerance and impaired insulin secretion. The adult males had increased insulin secretion. These results suggest that developmental exposure to phthalates can lead to beta cell dysfunction and glucose abnormalities, and is a potential risk factor for diabetes development (Lin et al. 2011). 

When pregnant rats were exposed to DEHP, their offspring developed higher blood glucose, impaired glucose tolerance, and impaired insulin secretion/beta cell dysfunction later in life. They also showed epigenetic effects that changed the expression of genes relating to beta cell development and function (Rajesh and Balasubramanian, 2015). Male rats exposed to DEHP in the womb were smaller at birth but then caught up to controls and grew fatter as adults, and ended up with glucose intolerance as well (Strakovsky et al. 2015). Male offspring exposed to DEHP in the womb/early life had lower insulin levels than controls (Yang et al. 2018). Rats exposed to DEHP and DBP in the womb/early life had higher fasting glucose levels, and those exposed to DEHP also had lower insulin secretion (Venturelli et al. 2019). Studies with zebrafish also show that phthalates can affect beta cell development (Sant et al. 2016), and reduce the area of beta cells in the pancreas (Jacobs et al. 2018).

Female mice that were exposed to phthalates had higher body weight, more fatty tissue, and higher food intake than unexposed mice. Their offspring, only exposed during fetal development and while nursing, also exhibited similar metabolic changes, including higher body weight and more fatty tissue (Schmidt et al. 2012). For an article describing this study, see Long-term outcomes after phthalate exposure: food intake, weight gain, fat storage, and fertility in mice, published in Environmental Heath Perspectives (Holtcamp 2012). Another study also found that mice exposed to DEHP in the womb had higher food intake (Hayashi et al.2012).

Mice exposed to the phthalate MEHP in the womb had higher blood glucose levels, gained more weight, and had higher cholesterol levels later in life than unexposed mice (Hao et al. 2012). A similar study by the same authors found that another phthalate, DEHP, had the same effects (Hao et al. 2013). Male rats exposed to DEHP in the womb had fatty tissue inflammation as well as an increased immune response. DEHP may affect the development of pre-fat cells into fat cells, without affecting overall body weight (Campioli et al. 2014). Rats exposed in the womb to the phthalate DiBP had lower leptin and insulin levels later in life than controls, suggesting metabolic dysfunction (Boberg et al. 2008).

Mice exposed to DEHP in the womb had more obesity, higher blood pressure, and increased cholesterol levels (Lee et al. 2016). Other authors found that mice exposed to DEHP in the womb had higher glucose, insulin, leptin, and lipid levels, and more visceral fat (Gu et al. 2016). Developmental exposure to DEHP combined with a high fat diet in adulthood led to changes in metabolism in male offspring, and changes in the immune system in female offspring (Bastos Sales et al. 2018). Rat offspring exposed to DEHP had high blood glucose and insulin levels, impaired glucose and insulin tolerance, and reduced levels of insulin receptors (Rajagopal et al. 2018). Researchers are now figuring out the mechanisms by which phthalates have these types of effects (Hunt et al. 2017).

Rats exposed to low levels of DEHP only from nursing from their exposed mothers were found to have higher blood sugar and changes in insulin signaling later in life (Mangala Priya et al. 2014). Similarly, rats exposure to DEHP only in the womb were found to have higher blood sugar and insulin levels, and changes in insulin signalling later in life (Rajesh and Balasubramanian, 2014). Meanwhile, male rats exposed to DEHP only through their mother's milk had lower body weight but higher glucose levels (Parsanathan et al. 2018).

When pregnant mice were treated with the phthalate BBP, their offspring exercised less through early adulthood than untreated controls. Their body weight did not differ, however (Schmitt et al. 2016). In wild-type mice, in utero exposure to DEHP decreased glucose and leptin levels in offspring during the neonatal and weaning periods, which results in increased food consumption after weaning (Hayashi et al. 2019).

Even fruit flies show effects from phthalate exposure. Long-term, high-dose DEHP exposure resulted in significant body weight change; dosing the father or mother resulted in increased or decreased body weight of the offspring respectively (Chen et al. 2019). 

Additional laboratory studies also find that early life exposure to phthalates affects body size, weight, and other metabolic outcomes later in life (Moody et al. 2018Rajagopal et al. 2019).

In rats, exposure to phthalates during development negatively impacts the development of the small intestine (Setti Ahmed et al. 2018). In mice, phthalates damaged the small intestine (Yu et al. 2018). Exposure to MEHP during puberty, in combination with a high-fat diet, caused greater fat mass, higher total, HDL and LDL cholesterol, fat cell dysfunction, and a shift in gut microbiota composition in mice (Wang et al. 2018). The effects of phthalates on the gut are even seen in zebrafish (Buerger et al. 2019). Changes in the intestine or gut are linked to diabetes (see the Diet and the Gut page). 

Laboratory studies have established that epigenetic modifications caused by developmental exposure to environmental chemicals can induce alterations in gene expression that may persist throughout life. In the case of phthalates, some of these effects can be transferred from one generation to following generations (Singh and Li, 2012).

Transgenerational Effects

Another study of developmental exposure to mixtures of chemicals is even more alarming. It 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).

Chemical Mixtures

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 the phthalate DBP caused changes related to metabolic disorders in developing embryos of zebrafish (Dong et al. 2018). Exposure during development to a mixture of phthalates, triclosan, and perfluorinated compounds (based on the levels of these compounds found in pregnant Swedish women) affected metabolic rate, increased the number of fat cells and fatty tissue young zebrafish fed a calorie-rich diet (Mentor et al. 2019).

Exposing placental cells to a mixture of phthalates at levels that humans are exposed to during pregnancy affected the PPARγ receptors, in an opposite manner in males vs females (Adibi et al. 2017). Developmental exposure of mice to a mixture of phthalates that humans are exposed to led to lower body weight in pups (Kougias et al. 2018). Developmental exposure to DINP led to increased body weight in mouse offspring, yet adding DEHP or DBP to the mixture did not increase the effect (Neier et al. 2018). Similarly, in female mice, developmental exposure to DEHP led to increased body fat, and developmental exposure to DINP led to impaired glucose tolerance. However, developmental exposure to mixtures of phthalates had few metabolic effects and were not associated with larger effects than single exposures (Neier et al. 2019). Thus the effects of phthalates mixtures may be complex.

In Vitro Studies of Cells

An in vitro (test tube) study of mixtures of phthalates, BPA, and organotins increased the development of fat cells from stem cells-- the effects of phthalates and organotins were more significant than of BPA (Biemann et al. 2014). The phthalate MEHP disturbs the energy metabolism of fat cells as well (Chiang et al. 2016). A different lab showed that adult fat cells treated with MEHP led to inflammation and metabolic changes in the cells (Manteiga and Lee, 2017). MEHP disturbs energy metabolism in fat cells, increasing glucose uptake (Hsu et al. 2019). A number of phthalates that are approved for use in food contact materials, at low levels of exposure, increased fat accumulation in fat cells (Pomatto et al. 2018).

An interesting study found that BPA was more potent than phthalates in reducing beta cell function. Both BPA and the phthalate metabolites MiBP, MnBP, and MEHP reduced beta cell viability after 72 hours of exposure, with BPA most potent. Both BPA and the phthalate metabolites MEHP and MnBP increased insulin secretion after 2 hours of simultaneous exposure to the chemicals and glucose, with BPA again the most potent, followed by MEHP and MnBP. However, neither BPA nor the phthalates affected susceptibility to beta cell death. And, unlike other studies, low level exposures did not show effects (Weldingh et al. 2017).

Phthalates alone can reduce insulin secretion from beta cells, and induce beta cell death. Phthalates can kill beta cells by increasing oxidative stress, and decreasing the ability of beta cells to protect themselves from this stress (Sun et al. 2015). It seems to me that this would be relevant for both type 1 and type 2 diabetes (as well as any other type, for that matter). At low doses, phthalate metabolites can also increase proliferation and insulin content of human beta cells (Güven et al. 2016). While this may sound positive, increasing insulin secretion can end up wearing out beta cells and leading to insulin resistance in the long run. The mechanisms by which phthalates decrease the viability beta cells are still being worked out, but appear to involve oxidative stress (She et al. 2017). DEHP can kill beta cells in part via oxidative stress, and taurine, an amino acid, helps reverse this DEHP-induced oxidative stress (Li et al. 2019). 

In bone marrow cells, DEHP and MEHP increased development of fat cells, and decreased development of bone cells. This finding may help explain why phthalate exposure is linked not only to obesity, but also lower bone mineral density (Chiu et al. 2018).

Muscle cells are also affected by DEHP and MEHP in relation to insulin signalling (which plays a role in insulin resistance) (Viswanathan et al. 2017). In liver cells, DEHP exerted toxic metabolic effects and increased insulin resistance through interfering with glucose metabolism. Cells already insulin resistant were more susceptible than normal liver cells (Ding et al. 2019).

Curcumin appears to counteract the effects of phthalates on fat cells (Sakuma et al. 2017).

Phthalate Alternatives

In 2002, an alternative chemical to phthalates was introduced to the market, known as DINCH (cyclohexane-1,2-dicarboxylic acid diisononyl ester). One of its metabolites, MINCH, has been found to facilitate the development of pre-fat cells into fat cells (Campioli et al. 2015). In rats, prenatal exposure to DINCH causes high blood glucose levels and impairs the liver as well (Campioli et al. 2017). Another phthalate replacement, diethylene glycol dibenzoate (DGB), also exhibits obesogenic properties in the lab (Santangeli et al. 2018). This pattern seems to be typical-- replacement chemicals may not be an improvement over the old chemicals. Meanwhile, the company that produces this chemical is publishing its own articles trying to refute these findings (Langsch et al. 2018). Also typical.

In newborn mice, the phthalate DINP, an alternative chemical to DEHP, along with DEHP, caused changes total fatty acid composition in blood, heart, and fatty tissues, although each chemical had different specific effects (Huang et al. 2019). DINP also promoted fat cell development (Zhang et al. 2019).

Another alternative chemical, acetyltriethyl citrate (ATEC), a DEHP substitute, is used as a plasticizer in cosmetics and nail products. Mice exposed to DEHP or ATEC for 5 days had increased blood glucose levels, and a week after the exposure was removed, glucose levels returned to normal in DEHP-treated mice, but remained high in ATEC-treated mice (Lee et al. 2019). Thus the substitute may be even worse than the original. Wonderful.

Type 1 Diabetes and Autoimmunity

Phthalate Levels Are Associated With Low Vitamin D Levels

vitamin D and chemicals

In U.S. pregnant women, higher levels of both phthalates and BPA were associated with an increased risk of vitamin D deficiency. In these graphs you can see as chemical levels increase, vitamin D levels decrease. 
The first human study of phthalates and type 1 diabetes found higher levels of DiBP phthalate metabolites in children with new-onset type 1 diabetes (although not statistically significantly higher) (Castro-Correia et al. 2018).

In non-obese diabetic (NOD) mice, an animal model of type 1 diabetes, BPA, but not a mixture of BPA and phthalates, or phthalates alone, accelerated diabetes development. Phthalates in fact seemed to dampen some of the diabetes-related effects of BPA (Bodin et al. 2015).

Laboratory studies do show that phthalates can affect the immune system, e.g., the secretion of inflammatory immune cells (Hansen et al. 2015). In a series of three studies, researchers examined the effects of phthalates on autoimmunity in mice. They found that after exposure to phthalates, different types of mice developed autoantibodies. But, only the autoimmune-prone mice went on to develop disease. They conclude that phthalates seem to be harmful only to susceptible strains of mice, while other strains are protected (Lim and Ghosh 2003; Lim and Ghosh 2004; Lim and Ghosh 2005). A study mentioned above found that male rats exposed to DEHP in the womb had an increased immune response, as well as chronic, low-grade systemic inflammation (Campioli et al. 2014). In fact, phtalate exposure in the womb caused epigenetic changes in adult male offspring in an area of genes that control the immune response (Martinez-Arguelles and Papadopoulos, 2015).

In rats, the phthalates DBP and DIMP aggravate autoimmune thyroid disease (Duan et al. 2019Duan et al. 2018).

In U.S. adults, phthalate levels are also linked to lower vitamin D levels (Johns et al. 2016), which may play a role in diabetes development (see the Vitamin D Deficiency page). These authors also found that phthalates were associated with vitamin D deficiency in pregnant U.S. women (Johns et al. 2017). In infants, phthalate levels were linked to change in the gut microbiota, which may affect the immune system later in life (Yang et al. 2019); these changes are also linked to type 1 diabetes, as described on the Diet and the Gut page. 

Gestational Diabetes

In Canada, there was no association between first trimester levels of phthalates and gestational diabetes (although the sutdy did find an association with arsenic) (Shapiro et al. 2015). U.S. women with higher MBP and MIBP phthalate levels in their urine during early pregnancy actually had lower blood glucose levels when screened for gestational diabetes (Robledo et al. 2015). Similarly, Mexican women with gestational diabetes had lower levels of MEHP than those without diabetes (Martínez-Ibarra et al. 2019).

However, in Boston women, exposure to MEP, a metabolite of the parent compound DEP, is associated with excessive gestational weight gain and impaired glucose tolerance during pregnancy. But higher DEHP was associated with a lower risk of impaired glucose tolerance (James-Todd et al. 2016). These authors also found that certain phthalates were associated with higher early gestational weight gain (Bellavia et al. 2017). They also found that among women at a fertility clinic, the phthalate metabolites MEP and MiBP were associated with higher pregnancy glucose levels (James-Todd et al. 2018), but that although higher MEP was associated with higher glucose levels in mothers, phthalate levels were not related to higher birth weight (Noor et al. 2019).

Another U.S. study found MnBP/MIBP levels in women with gestational diabetes (Adibi et al. 2017). In women without gestational diabetes, some phthalate levels were associated with higher post-meal glucose levels (Fisher et al. 2018). Also in the U.S., women with higher MEP levels had a higher risk of gestational diabetes. Additional phthalate metabolites were linked to a higher risk of glucose intolerance, with possible stronger associations in Asian Americans (Shaffer et al. 2019).

In fact a study from China did find that the associations depended on the type of phthalate. They found that first-trimester levels of MMP, MEP, MBP, MBzP and MEHHP were associated with higher fasting blood glucose levels in the third trimester, while MEHP and MEOHP levels were associated with lower glucose levels (Zhang et al. 2017). These results are different than the others' results, so more work to figure out what is going on is necessary.

In Mexican women, increased levels of the phthalate metabolite MCPP during pregnancy were associated with higher weight gain, and the phthalate metabolite MBzP with lower weight gain, in the decade following pregnancy (Rodríguez-Carmona et al. 2018).

In pregnant California farmworkers, higher phthalate levels were linked with markers of inflammation and cholesterol metabolism (Zhou et al. 2018). In Europe, higher phthalate levels have been associated with lower blood pressure in pregnant women (Warembourg et al. 2018).

Diabetes Management and Complications

A U.S. cross-sectional study found that phthalate levels were associated with retinopathy in people with type 2 diabetes (Mamtani et al. 2016). A study from China found that phthalates were associated with oxidative stress and inflammation in people with type 2 diabetes. These factors play a role in the development of complications from diabetes (Duan et al. 2017). In Italian people with type 2 diabetes, phthalate levels were associated with worse albuminuria, a kidney complication of diabetes, as well as with cardiovascular events (Mengozzi et al. 2018). Additional studies have also found associations between markers of kidney dysfunction and phthalate levels (Chen et al. 2019Kang et al. 2019; Lim and Yoon, 2019).

Phthalate levels have also been associated with the risk of heart disease (Su et al. 2019Wiberg et al. 2014), and other factors related to cardiovascular health-- even in adolescents (Su et al. 2019). Phthalate levels are also associated with high cholesterol and high blood pressure (Olsén et al. 2012), including higher blood pressure during pregnancy (Werner et al. 2015). Phthalates, as well as phthalate replacement chemicals, were associated with higher blood pressure in U.S. children as well (Trasande and Attina 2015; Trasande et al. 2013). (Those studies were not done in people with diabetes). A review finds that phthalate exposure may be associated with high blood pressure in adults (Lu et al. 2018).

In animals, phthalate exposure accelerates atherosclerosis and interferes with cholesterol levels as well (Zhao et al. 2016). Phthalates also affect heart rate variability and other factors linked to cardiovascular problems (Amara et al. 2019Jaimes et al. 2017). Phthalate exposure is linked to the development of non-alcoholic fatty liver disease (NAFLD) in laboratory studies as well (Bai et al. 2019Huff et al. 2018). Developmental exposure to phthalates also increases blood pressure in rat offspring (Mariana et al. 2018).

References

To download or see a list of all the references cited on this page, see the collection Phthalates and diabetes/obesity in PubMed.