Endocrine Disruption and Diabetes/Obesity
Numerous endocrine disrupting chemicals (EDCs) are linked to type 2 diabetes, type 1 diabetes, gestational diabetes, and obesity. Exposure during early development likely plays an important role. The health effects discussed on this page were almost all seen at very low doses, such as we encounter in the environment. For an excellent, free full text review of the role of EDCs in type 2 diabetes, see Sargis and Simmons, 2019.
And it's not only humans that are seeing the effects of these exposures; EDCs have been linked even to equine metabolic syndrome (in horses) (Durward-Akhurst et al. 2019) and may play a role in the increasing obesity rates seen in other animals as well (Klimentidis et al. 2014).
About The Endocrine System
The endocrine system of the body is made up of glands that secrete hormones. The pancreas, for example, is an endocrine organ that secretes the hormone insulin. The hormone/endocrine system is one system of communication within the body. Certain cells release hormones as a result of some signal (e.g., the beta cells in the pancreas release insulin when they sense that glucose levels in the blood are rising), and the hormone (in this case, insulin) travels through the blood to bind with hormone receptors (e.g., insulin receptors) on various cells. That triggers some effect, in this example, when insulin binds to a receptor, glucose can enter the cell. Almost all (or perhaps all) cells would have receptors for insulin, but only certain cells would have receptors for other hormones (e.g., estrogen or testosterone, etc.). The numbers and types of hormone receptors on cells change over time, and change depending on the concentration of the hormone in the blood, and on the stage of development of the organism.
Endocrine organs include, among others, the pancreas, thymus, thyroid gland, and adrenal gland. Endocrinologists treat diseases of the endocrine system, such as diabetes and thyroid disease. There are many hormones in humans, estradiol, estrogen, testosterone, androgen, insulin, glucagon, glucocorticoid, thyroid hormones, and more. Vitamin D is also considered to be a secosteroid, a type of steroid hormone.
Many hormones have diabetes-related effects, aside from insulin, including vitamin D, estrogen, testosterone, and more. Estrogen is often thought to be protective against type 2 diabetes, since premenopausal women (who produce more estrogen) have a lower type 2 risk than postmenopausal women, women taking estrogen also often have a lower risk, and women in general have a lower type 2 diabetes risk than men (De Paoli and Werstuck 2020). But the specific effects of hormone can depend on a lot of other things, including sex. For example, higher testosterone levels (due to genetics) increases the risk of type 2 diabetes in women, but reduces the risk in men (Ruth et al. 2020). Interestingly a double-blind, randomized, placebo-controlled trial of post-menopausal women (who have lower natural estrogen levels than pre-menopausal women) found that those who took estrogen and progestin produced less insulin and had higher glucose levels than women wo did not take these hormones (Depypere et al. 2020). This conflicts with the findings of earlier studies, and it is not clear why, but that does show that it may be complicated.
About Endocrine Disrupting Chemicals (EDCs)
Substances that can interfere with the endocrine (hormone) system are called "endocrine disruptors." These substances may act like hormones, binding with their receptors, or block the receptors, preventing hormones from binding with them, affecting the ability of cells to produce or secrete hormones hormones, and more (Hotchkiss et al. 2008). For example, an estrogenic chemical is one that acts like estrogen, and binds to estrogen receptors on cells, triggering a response that normally estrogen would trigger. An anti-androgen is a chemicals that can block androgen hormones from binding with their receptors, preventing the cells from responding to an androgen hormone. Some chemicals can affect the ability of beta cells to either produce or secrete the hormone insulin, sometime increasing and sometimes decreasing these processes.
A number of environmental chemicals (as well as other substances, such as some pharmaceutical drugs) are endocrine disruptors (Hotchkiss et al. 2008). Gore et al. (2006) list some common characteristics of how endocrine disruptors can act:
the timing of the dose is critical to the outcome of the exposure (since it depends on when receptors are present, and how many);
exposure during fetal, perinatal, or early post-natal periods may produce life-long effects (whereas adult exposures may have more transient effects);
effects may be seen with low level exposures (like those found in the environment, since hormones act at very low levels);
effects may not increase predictably as the dose increases (they exhibit complex dose response curves; when there are low levels of a hormone in the blood, they body will respond easily, while when there are high levels of a hormone in the blood, the number of receptors may actually start to decline and the body will not respond as much); and
the effects may sometimes be transmitted to subsequent generations (probably involving epigenetic mechanisms).
Scientists have identified ten "Key Characteristics" that define endocrine disruptors-- meeting any one of these criteria would qualify a chemical as an endocrine disruptor (La Merrill et al. 2020). The key characteristics include:
Interacts with or activates hormone receptors
Antagonizes hormone receptors
Alters hormone receptor expression
Alters signal transduction in hormone-responsive cells
Induces epigenetic modifications in hormone-producing or hormone-responsive cells
Alters hormone synthesis
Alters hormone transport across cell membranes
Alters hormone distribution or circulating levels of hormones
Alters hormone metabolism or clearance
Alters fate of hormone-producing or hormone-responsive cells
A number of the chemicals considered here, including arsenic, some persistent organic pollutants (POPs) (including PCBs, dioxin, organotins, PBDE flame retardants, and PFASs), BPA, phthalates, some pesticides, probably heavy metals, and possibly nitrate, are considered endocrine disruptors. Please visit those pages for studies on these chemicals.
Most research on endocrine disruptors thus far has focused on the reproductive system, but the effects of these chemicals on other body systems are now under investigation. The immune system, the digestive system, the cardiovascular system, the central nervous system, metabolism, and fat (adipose) tissue are also targets of endocrine disrupting compounds (Hotchkiss et al. 2008).
Endocrine disruptors may interact with other mechanisms, such as epigenetics, oxidative stress, mitochondrial dysfunction, and more (Zhou et al. 2020).
While everyone is exposed to endocrine disrupting chemicals, some are more highly exposed than others. For example, ethnic and racial minorities tend to be exposed to higher levels of BPA, phthalates, parabens, and flame retardants than whites (James-Todd et al. 2016). In fact, there is substantial evidence that these disparities in exposure levels play a role in the disparities found in type 2 diabetes (Ruiz et al. 2018).
Early Life Exposures
Endocrine disruption is important especially during a fetus/infant/child's development, because hormones play a critical role in controlling how the body develops. Endocrine disrupting chemicals are linked to changes in metabolic processes even in umbilical cord blood, which could contribute to metabolic disorders like diabetes or obesity later in life (Remy et al. 2016). Endocrine disruptors can affect growth and metabolism even earlier as well, including in the womb (Street and Bernasconi 2020).
If you give animals hormones during development, it can affect their later risk of diabetes-related health effects. For example, researchers exposed pregnant ewes to androgen (testosterone), estrogen, and glucocorticoid hormones. The offspring of ewes exposed to androgens had altered development of their pancreas, leading to excess insulin secretion in adolescence (Ramaswamy et al. 2016). Gestational exposure to testosterone also causes insulin resistance in sheep (Puttabyatappa and Padmanabhan 2017; Puttabyatappa et al. 2018), as well as high cholesterol levels (Siemienowicz et al. 2019) and changes in fat tissue (Puttabyatappa et al. 2019). Scientists are working out the mechanisms by which this insulin resistance occurs (Guo et al. 2020). As adults, the female offspring of pregnant rats dosed with testosterone developed high glucose and insulin levels and insulin resistance (Ferreira et al. 2020).
Early life exposure to endocrine disruptors can also affect the health of future generations (see box).
Interestingly, since endocrine disruptors can affect the development (differentiation) of cells, they affect the activity of stem cells. Some authors argue that this has importance for the therapeutic uses of stem cells to treat diseases (Bateman et al. 2017).
Effects Can Be Passed Down Generations
The effects of endocrine disrupting chemicals are sometimes passed down from one generation to the next. Early life exposure to some chemicals cause obesity in animals, as well as in their offspring, and their offspring, and their offspring...
"Transgenerational effects of chemical exposure raise the stakes in the debate about whether and how endocrine disrupting chemicals should be regulated."
Mixtures of Chemicals
While this webpage focuses on chemicals individually, we are all exposed to hundreds of endocrine disrupting compounds at the same time. What are the effects? We have no idea. One study studied exposure to low doses of 27 chemicals, similar to those found in humans. They found a variety of effects, including effects on weight and metabolism (Hadrup et al. 2016). We need more studies that address chemical mixtures or new methods to address this problem, and some are beginning to show up (e.g., see Lee and Jacobs 2015; Watt et al. 2016). One finds, for example, that a mixture of endocrine disrupting chemicals has numerous metabolic effects on mice (Le Magueresse-Battistoni et al. 2017).
Interestingly, mixtures of other endocrine disrupting chemicals can actually affect the levels of other endocrine disrupting chemicals. 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).
Reviews of Endocrine Disrupting Chemicals and Diabetes/Obesity
The effects of endocrine disruptors on all endocrine glands, including the pancreas, and all relevant systems, including the immune system, are important areas to research. Suvorov and Takser (2008) point out that "the role of environmental contaminants in increasingly prevalent endocrine disorders such as childhood obesity and diabetes mellitus is an important research avenue."
The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals (EDCs) devotes a section to diabetes and obesity. Their summary points (Gore et al. 2015):
"Disruption of glucose and lipid homeostasis is a risk factor for metabolic disorders including obesity and diabetes mellitus.
BPA, phthalates, tributyltin, arsenic, PBDEs, perfluorooctanoic acid, dioxin, PCBs, and DDTs are known to have effects on cellular and animal models.
In animal models, prenatal and perinatal exposures to some EDCs disrupt the homeostatic control of adipogenesis and/or energy balance, and induce obesity. A growing number of EDCs alter insulin production, secretion, and/or function, increasing the susceptibility for type 2 diabetes mellitus (T2D). Some animal models suggest that EDCs have direct adverse effects on the cardiovascular system.
A number of cross-sectional epidemiological studies associate EDC levels with obesity, diabetes mellitus, and cardiovascular diseases in humans. There are important prospective studies associating exposure to persistent organic pollutants and T2D.
Obesogenic and diabetogenic effects are induced in a nonmonotonic dose-dependent manner. Exposures to different levels produce diverse phenotypes.
The molecular mechanisms involved are still largely unknown, but alteration of gene expression after binding to the aryl hydrocarbon receptor, PPAR, and ERs seems to play a role.
The interaction between EDC exposure and single nucleotide polymorphisms associated with obesity, T2D, and cardiovascular diseases is a key issue for future studies."
The Endocrine Society's Statement concludes, "...there is sufficient evidence to conclude that some EDCs act as obesogens and others act as diabetogens." Also, "...animal studies indicate that some EDCs directly target beta and alpha cells in the pancreas, adipocytes, and liver cells and provoke insulin resistance together with hyperinsulinemia."
They also call for more research on EDCs and type 1 diabetes: "Studies relating EDCs and other contaminants to T1D are beginning to emerge, although they are still very preliminary... this is an important area that deserves further research and more studies in humans" (Gore et al. 2015).
In 2018-9 the journal Frontiers in Endocrinology published a group of articles as a Research Topic on Endocrine Disruptors and Metabolism, which covers the role of EDCs in everything from obesity to type 2 to type 1 diabetes (full disclosure: I wrote the article on type 1, Howard 2018).
A review of the evidence on endocrine disrupting chemicals and obesity notes that:
Endocrine disruptors are ubiquitous in the environment-- we are all exposed;
They have been shown to affect energy and metabolism;
They have been shown to affect body weight, fat content, fat cell development, glucose levels, obesity, insulin resistance, food intake, and more;
Their effects are most profound when exposure occurs during fetal development;
Their epigenetic effects may be significant for future generations;
Genes, poor diet, and sedentary behavior cannot fully explain obesity;
And finally, the evidence "provides a plausible basis for hypothesizing that endocrine disruptors are responsible for the rapid increase in obesity at the end of the last millennium." (Schneider et. al. 2014).
Among the various health effects of endocrine disruptors, diabetes and obesity are some of the best supported by evidence. For example, a review of recent research identifies "substantial human evidence" for the links between certain chemicals and diabetes or obesity: "Evidence is particularly strong for relations between perfluoroalkyl substances and child and adult obesity, impaired glucose tolerance, gestational diabetes, reduced birthweight .... Evidence also exists for relations between bisphenols and adult diabetes...; phthalates and ... childhood obesity, and impaired glucose tolerance." (Kahn et al. 2020). An editorial accompanying this article ("EDCs: Time to Take Action") states, "The science of endocrine disruption has also advanced considerably, but in the process far outpaced regulatory practices for control of EDCs. Overcoming this regulatory inertia is of paramount importance if citizen health and the environment are to be protected." (The Lancet Diabetes & Endocrinology, 2020).
EDCs and Type 1 Diabetes
We do not have much evidence regarding type 1 diabetes and endocrine disruptors; it is a largely unexplored field. There is growing evidence, however, that endocrine disrupting chemicals can influence the risk of type 1. For example, some androgenic chemicals are linked to type 1 (Sakkiah et al. 2017).
First, we might ask whether natural hormones can influence the development of type 1 diabetes. There is evidence that they can. For example, Gender differences are present in type 1 diabetes, and it is possible that sex hormones may influence the risk of developing type 1 diabetes in some way (Gale and Gillespie 2001). The incidence of type 1 diabetes in children peaks at puberty, a time of hormonal changes. Pregnancy, another time of hormonal change, can lead to gestational diabetes, later followed by type 1 or 2 diabetes. Stress may be a risk factor for type 1 diabetes, and while the mechanism is unknown, perhaps hormones released during stress could play a role. In addition, the hormone vitamin D appears to be protective against type 1 diabetes development. The role of height and weight as risk factors for type 1 diabetes may also involve hormones. The endocrine system is also affected by the gut microbiota and vice versa (Williams et al. 2020), which is another factor linked to type 1 diabetes (see the Diet and the Gut page).
In turn, all of these factors (puberty, pregnancy, stress, vitamin D, and height and weight), can be influenced by exposure to endocrine disrupting chemicals. For example, endocrine disruptors are a likely factor contributing to the earlier appearance of puberty, a possible accelerator of type 1 diabetes.
It is clear to me, as someone with type 1 diabetes, that hormone levels can also influence blood glucose levels and blood glucose control day-to-day. Again, times of natural hormonal changes like puberty and pregnancy make it hard to control type 1 diabetes. Even the hormonal fluctuations during the menstrual cycle can affect insulin sensitivity in women with type 1 diabetes (see Brown et al. 2015).
We do not know, however, if chemicals that interfere with the endocrine (hormone) system contribute to the development of type 1 diabetes, or affect blood sugar management. The following sections provide some evidence that this possibility exists, although this hypothesis has not yet really been tested.
The Immune System and Autoimmunity
The ability of many endocrine disruptors to interfere with the body's endocrine system may be important for the immune system, since the immune and endocrine systems interact. Evidence is growing that endocrine disruptors can affect the immune system, and autoimmunity in particular, although exactly how is still under investigation (Clayton et al. 2011; Merrheim et al. 2020; Nowak et al. 2019; Popescu et al. 2021). It is clear that exposure to endocrine disruptors can have numerous effects on the immune system, including autoimmunity (reviewed by Nowak et al. 2019). Exposure to these chemicals during development is also linked to autoimmunity (Rychlik et al. 2019).
The effects of endocrine disruptors on the immune system may be particularly important for type 1 diabetes, since it is an autoimmune disease. Yet keep in mind that the effects of endocrine disruptors on the immune system may also be involved in the development of type 2 diabetes as well (Bansal et al. 2018).
Endocrine Disruptors and Autoimmunity
Listen to Dr. Rodney Dietert of Cornell University discuss Endocrine Disruption and Immune Dysfunction on this call sponsored by the Collaborative on Health and the Environment (2014).
Because females are more susceptible than males to many autoimmune diseases, some researchers hypothesize that environmental estrogens could promote autoimmune disease (e.g., see Walker et al. 1996; Ahmed et al. 1999; Ortona et al. 2016). Gender does influence the behavior of the immune system, since sex hormones interact directly with immune system cells, although how these hormones might affect the development of type 1 diabetes is not known. Type 1 diabetes, unlike other autoimmune diseases, is not more common in females (Gale and Gillespie 2001).
In animals, some estrogenic endocrine disruptors have been found to promote autoimmunity. For example, Yurino et al. (2004) found that bisphenol A enhances autoantibody production in mice. Bisphenol A is an estrogenic compound. These researchers also found that the estrogenic pharmaceutical diethylstilbestrol (DES) had the same effects. The weakly estrogenic organochlorine pesticide chlordecone accelerates the development of autoimmune disease in mice. Its effects were similar to estradiol, but not identical (Wang et al. 2007) (described further on the persistent organic pollutants page). In animals, estrogen can cause the thymus to shrink, affect thymocytes, and promote autoimmunity; estrogenic chemicals may act similarly (Ahmed et al. 1999).
DES was given to pregnant women decades ago to prevent miscarriage (it didn't work, but instead led to various health problems in these women's offspring-- as well as in their grandchildren (Kioumourtzoglou et al. 2018)). There is some limited evidence linking autoimmunity and DES in humans: women exposed to DES in utero seem to have a higher incidence of autoimmune disease, but only when various autoimmune diseases are grouped together (Ahmed et al. 1999). Yet a more recent study that followed these women over 25 years found that there was not an overall increase in autoimmune diseases in DES exposed daughters, although type 1 diabetes was not included in this study (only four autoimmune diseases were included). However, there was an increased risk of the autoimmune disease rheumatoid arthritis in women under 45, and a lower risk in those over 45 (Strohsnitter et al. 2010).
Estrogens also have been found to protect beta cells-- this may be one reason type 1 diabetes is not more common in women as compared to men. And, while puberty leads to an increased incidence of type 1 in boys, this is not necessarily the case in girls (Mauvais-Jarvis, 2017b).
Yet other chemicals that act via different, non-estrogenic pathways also have been shown to promote autoimmunity in animals. Thus estrogenic compounds are not the only compounds of concern. Phthalates, for example, can induce autoantibodies in mice, although the resulting health effects depend on the strain of mouse (Lim and Ghosh 2005). And, dioxin exposure during immune system development has been shown to result in changes suggestive of autoimmune disease in mice (Mustafa et al. 2008). Several phthalates are anti-androgens, and dioxin acts on multiple components of the endocrine system, via the aryl hydrocarbon receptor (AhR) (Hotchkiss et al. 2008). And, some chemicals can affect a number of receptors. Bisphenol A, for example, affects the activation of not only estrogen receptors, but also androgen and AhR receptors (Krüger et al. 2008).
The hormone vitamin D is also involved in the immune system, and may be protective against some autoimmune diseases, including type 1 diabetes (Norris 2001). Some chemicals may be able to affect vitamin D levels in animals. Lilienthal et al. (2000) hypothesized that since PCBs can affect other hormones, it might make sense that they could interfere with vitamin D levels. Their study found that PCBs did reduce vitamin D levels in rats. See the vitamin D page for more studies on vitamin D, type 1 diabetes, and chemical effects on vitamin D levels.
Up to 25% of patients with type 1 diabetes have evidence of thyroid disease, the most common autoimmune disease associated with type 1 diabetes (Umpierrez et al. 2003). Endocrine disruptors can affect the thyroid hormone (for a review of the main thyroid-disrupting chemicals (PCBs, perchlorates, brominated flame retardants, and phthalates), see Jugan et al. (2010)). Since thyroid levels during pregnancy are critical to proper fetal development, these thyroid disrupting chemicals are also important during development. Thyroid hormones are also important for glucose levels and metabolism. Thus prenatal exposure to thyroid disruptors are also linked to changes in glucose and metabolism in the offspring (Molehin et al. 2016).
There is a higher rate of type 1 diabetes among transgender and gender diverse youth than in the general population (Maru et al. 2021). We don't know why, perhaps it has to do with hormones, but it could be stress or something else involved.
Glucocorticoids are other hormones involved in the immune system. Disturbed glucocorticoid action is associated with a number of conditions, including autoimmune disease, type 2 diabetes, and obesity. Chemicals that can disrupt glucocorticoid action include PCBs, organotins, arsenic, dithiocarbamate chemicals (found in some pesticides and cosmetics), and more (Odermatt et al. 2006). The mechanisms by which early life exposure to glucocorticoid-disrupting chemicals (and other environmental factors) can lead to metabolic disease later in life is reviewed by Ruiz et al. 2020.
Some endocrine disruptors have been found to affect the insulin-producing beta cells or insulin secretion from beta cells, including bisphenol A, PCBs, dioxin, and arsenic, potentially leading to beta cell stress. See those pages for information on these studies.
Nadal et al. (2009) review how the beta cell is a target of estrogenic compounds. They discuss how an excess of estrogen or estrogenic compounds such as bisphenol A could produce an excess of insulin signaling and insulin secretion, overstimulating beta cells. This signaling in turn may provoke increased insulin resistance and beta cell exhaustion. The authors argue that these compounds may thus contribute to the development of type 2 diabetes, but we should also consider the possibility that they may contribute to the development of type 1 diabetes as well. Environmental factors that stress or overload beta cells may be a factor in the increased incidence of type 1 diabetes in children (Dahlquist 2006; Ludvigsson 2006), and increased insulin resistance may accelerate the appearance of type 1 diabetes (see the beta cell stress and insulin resistance pages). Estrogen, on the other hand, can also be protective of beta cells (Mauvais-Jarvis et al. 2017c), so the whole thing is complicated-- it may also depend on ratios of estrogen and testosterone, for example.
Dioxin has also been shown to stimulate insulin secretion from beta cells (Kim et al. 2009). Other researchers, however, found that dioxin impaired insulin secretion (Kurita et al. 2009). Like bisphenol A, dioxin has been associated with type 2 diabetes in humans, and autoimmunity in animals. Other chemicals that interfere with AhR include PCBs and polychlorinated dibenzofurans (PCDFs) (Hotchkiss et al. 2008).
Li et al. (2008) tested the hypothesis that androgen hormones (testosterone is an androgen hormone) and androgen receptors could be involved in the development of type 1 diabetes, perhaps helping to explain why type 1 diabetes is not more common in women than men. To test this idea, they looked for, and found, androgen receptors in beta cells. These receptors help to control the process of beta cell apoptosis (programmed cell death). Prenatal exposure to androgens is linked to later life beta cell dysfunction, obesity, glucose intolerance, and lower insulin levels in offspring mice (Zhou et al. 2021).
Could androgenic or anti-androgenic chemicals then affect beta cells? It appears so. Male rats exposed to an anti-androgen during development had reduced beta cell mass at birth, which led to the development of glucose intolerance later in life due to decreased insulin secretion (Harada et al. 2019). Also in rats, increased androgen levels can impair insulin secretion by disrupting pancreatic beta cells (Wang et al. 2015). Androgens have been found to cause high insulin levels, glucose intolerance, affect beta cells, and increase and insulin resistance (Mishra 2018). Some endocrine disrupting chemicals can influence androgen receptor actions and can be androgenic or anti-androgenic at levels found in the environment. Masculinized female fish have been found in living in rivers contaminated with effluent from pulp mills around the world, indicating androgenic activity. Yet the responsible androgenic chemicals in this effluent have not yet been identified. Androgenic action has also been found in effluent from cattle feedlot operations in the U.S. (Hotchkiss et al. 2008). Cadmium has also been shown to have androgenic effects (Byrne et al. 2009), and has been associated with type 2 diabetes (see the heavy metals page). Anti-androgens can interfere with androgen signaling and can affect androgen-sensitive organs in animals. Some anti-androgens include the persistent organic pollutant DDE, some fungicides (vinclozolin, procymidone, and prochloraz), the herbicide linuron, several phthalates, PBDE flame retardants (Hotchkiss et al. 2008), and bisphenol A and other components of plastics (Krüger et al. 2008).
In humans, low testosterone levels predispose men to high blood glucose, but, high androgen levels predispose women to high blood glucose. Both low and high androgen levels promote obesity and insulin resistance, in both sexes (Xu et al. 2019).
While it is impossible to avoid all EDCs, there are lifestyle interventions they may help (Hennig et al. 2018; Lee and Jacobs, 2019; Lee 2018; Ruiz et al. 2018; Sargis et al. 2019). Yet since lifestyle interventions can only go so far, better regulation is urgently needed (see this 2019 editorial in the Lancet Diabetes and Endocrinology, for example).
EDCs and Type 2 Diabetes
It is becoming clear that numerous endocrine disruptors are linked to the development of type 2 diabetes. The strongest evidence exists for persistent organic pollutants (see Lee et al. 2014; Taylor et al. 2013) and arsenic (Wang et al. 2014; Maull et al. 2012). There is growing evidence for many other endocrine disrupting chemicals as well (see pages on individual chemicals for details) (reviewed by Chevalier and Fénichel 2015; Fénichel and Chevalier 2017; Firmin et al. 2016; Kumar et al. 2020; Schulz and Sargis 2021). Endocrine disruptors also play a role in the development of insulin resistance (reviewed by Vanni et al. 2020).
Papalou et al. 2019 state, "EDCs unleash a coordinated attack toward multiple components of human metabolism, including crucial, metabolically-active organs such as hypothalamus, adipose tissue, pancreatic beta cells, skeletal muscle, and liver. Specifically, EDCs' impact during critical developmental windows can promote the disruption of individual or multiple systems involved in metabolism, via inducing epigenetic changes that can permanently alter the epigenome in the germline, enabling changes to be transmitted to the subsequent generations. The clear effect of this multifaceted attack is the manifestation of metabolic disease, clinically expressed as obesity, metabolic syndrome, diabetes mellitus, and non-alcoholic fatty liver disease. Although limitations of EDCs research do exist, there is no doubt that EDCs constitute a crucial parameter of the global deterioration of metabolic health we currently encounter."
A systematic review and meta-analysis of 49 studies from diverse populations found that both persistent (PCBs, dioxin, chlorinated pesticides) and non-persistent (BPA, phthalates) endocrine disruptors were associated with type 2 diabetes, impaired fasting glucose, and insulin resistance (Song et al. 2016). Endocrine disruptors are also implicated in complications and diseases that relate to type 2 diabetes, including atherosclerosis and cardiovascular disease (Helsley and Zhou, 2017; Kirkley and Sargis, 2014).
In fact, there is so much research on this topic (explored all over this website), that researchers are now calling these chemicals "metabolism disrupting chemicals" (Nadal et al. 2017). These chemicals are implicated not only in type 2 diabetes, but also metabolic syndrome, obesity, non-alcoholic fatty liver disease (NAFLD) (Foulds et al. 2017), and more. They can affect metabolism using a variety of mechanisms (Kassotis and Stapleton, 2019; Mimoto et al. 2017).
Androgenic chemicals are linked to diabetes in human and animal studies (Sakkiah et al. 2017). It is clear that sex hormones play a role in type 2 diabetes (Tramunt et al. 2019), so it does make sense that chemicals that mimic these hormones do as well (Liu and Sun 2018). In fact sex hormones play a role in other types of diabetes as well, as well as obesity and metabolic syndrome, and in impaired fasting glucose and glucose intolerance (Mauvais-Jarvis 2018; Mauvais-Jarvis 2017). Early exposure to androgens during development may in fact be involved in the later development of insulin resistance, and help explain how numerous environmental factors (including chemical exposures, diet, stress, etc.) are linked to later insulin resistance (Puttabyatappa et al. 2020).
EDCs and Insulin Resistance and Body Weight
Estradiol helps to maintain normal insulin sensitivity and beta cell function. Estrogen levels that are either too high or too low may promote insulin resistance and type 2 diabetes (Nadal et al. 2009). In fact, men with higher levels of natural estrogens are of at higher risk of type 2 diabetes, according to a large, long-term study (Jasuja et al. 2013). In obese women, levels of chemicals that act like estrogen are pervasive, and associated with inflammation, metabolic abnormalities, and cardiovascular risk (Teixeira et al. 2015).
Transitioning gender is associated with changes in insulin resistance. In transgender people, insulin sensitivity tends to increase with masculinization and to decrease with feminization (Shadid et al. 2019).
Castration, which reduces testosterone levels, leads to weight gain in laboratory animals (Baik et al. 2020).
Other hormone receptors involved in obesity and insulin resistance are PPAR receptors. These receptors control metabolism, and some chemicals can interfere with them (Casals-Casas et al. 2008) (see the organotins and phthalates pages, for example). More and more chemicals are being screened for their ability to interact with PPAR receptors, and thereby be labeled as potential obesogens. For example, components of the crude oil dispersant used in the Deepwater Horizon oil spill was found to activate these receptors (Temkin et al. 2016). Sex hormones also play a role in the function of the PPAR receptors (Sato et al. 2014). Exposure to excess testosterone during development can also lead to adult metabolic disorders in animals (Abi Salloum et al. 2015; Lu et al. 2016). In sheep, those exposed to testosterone in the womb show insulin resistance and other metabolic effects later in life that could predispose them to metabolic diseases (Padmanabhan and Veiga-Lopez, 2014; Puttabyatappa et al. 2017). Prenatal testosterone also causes disrupted pancreatic islet development in female sheep during fetal and adult ages (Jackson et al. 2020).
Karin Russ, RN, is concerned about the health impacts of endocrine disrupting chemical exposure, especially during gestation and early in life.
Researchers are looking into other mechanisms that may be involved as well. For example, some one study aimed to identify an environmentally relevant shared receptor target for endocrine and metabolism disrupting chemicals. The authors found a common mechanism of action through epidermal growth factor receptor (EGFR) inhibition for three diverse classes of metabolic disrupting chemicals (Hardesty et al. 2018). The insulin-like growth factor system is also involved in growth and metabolism, and may be a target for endocrine disrupting chemicals (Talia et al. 2020).
Some endocrine disruptors have been shown to increase the formation of fat cells. For example, both nonylphenol and DES promote the formation of fat cells in laboratory studies, and increase body weight in mice (Hao et al. 2012a, Hao et al. 2012b). Certain parabens, chemicals found in cosmetics and other consumer products, increase fat cell development and are potential obesogens (Hu et al. 2017; Hu et al. 2016; Pereira-Fernandes et al. 2013). Wastewater discharged from water treatment plants also contains endocrine disrupting compounds, and mice who drank this water gained more fat (Biasiotto et al. 2016). For studies on other endocrine disrupting compounds linked to obesity, see the individual chemical pages.
The effects of endocrine disruptors are important during development. For example, a study found that higher levels of environmental estrogens in the placenta were associated with higher birth weight in boys (Vilahur et al. 2013). Other studies have found exposure to endocrine disrupting chemicals to be associated with low birth weight (Birks et al. 2016).
There are other periods of life in which people are susceptible to endocrine disrupting chemicals as well, aside from early development. Menopause, when estrogen levels go down, is one such time. It seems that the body's hormone levels may interact in complex ways with the hormone-disrupting effects of chemicals to influence metabolism-related diseases such as diabetes and obesity (Julien et al. 2019).
The May 25, 2009 issue of the journal Molecular and Cellular Endocrinology published a special issue on the role of environmental endocrine disrupting chemicals in the development of obesity and diabetes. For example, Heindel and vom Saal (2009) propose that the recent increase in obesity is due to both nutrition and environmental chemical exposures in early life. Grün and Blumberg (2009) review the evidence that a variety of endocrine disrupting chemicals can influence fat formation and obesity. Newbold et al. (2009) review the mechanisms involved in endocrine disruption and obesity.
Numerous reviews also find that early-life exposure to endocrine disrupting compounds may play a role in the development of obesity (Botton et al. 2017; Braun 2017; Giulivo et al. 2016; Gutiérrez-Torres et al. 2018; Hall and Greco 2019; Heindel et al. 2017; Heindel et al. 2015; Holmes 2016; Janesick and Blumberg 2016; Kim and Lee 2017; Legler 2013; Lind et al. 2016; Maradonna and Carnevali, 2019; Nappi et al. 2016; Petrakis et al. 2017; Ribeiro et al. 2020; Russ and Howard 2016; Shafei et al. 2018; Wang et al. 2016).
One review focused on exposure to obesogens among Latinx/Hispanic youth in the Americas (Perng et al. 2021). It found a few consistent trends, which might also be applicable to people of other ethnicities. These findings include:
Prenatal exposure to POPs (PFAS, PBDEs, DDE/DDT) was linked to lower birthweight;
Prenatal exposure to POPs was linked to higher fat mass among boys but not girls;
Prenatal exposure to phthalates and bisphenols was linked to fat mass by gender as well, but inconsistently;
Childhood exposure to phthalates and bisphenols was linked to higher fat mass in girls but lower in boys;
In general, early life exposure to multiple chemicals is linked to weight-related measures in children.
EDCs and Gestational Diabetes
There is a dearth of research on endocrine disrupting compounds and gestational diabetes, although research has linked a few endocrine disrupting chemicals to gestational diabetes (search this website for gestational diabetes to see where links have been found, and for a review of the topic, see Ehrlich et al. 2016).
Natural hormone levels are linked to an increased risk of gestational diabetes development (Hur et al. 2017). The incidence of gestational diabetes has risen in tandem with exposure to endocrine disrupting chemicals over time, and these chemicals likely play a role in its development (Kunysz et al. 2021). Exposures to these chemicals are discussed throughout this website.
Effects Across Generations
When a pregnant woman is exposed to an environmental chemical, the exposure extends not only to herself (F0) and her unborn child (F1), but also to the germ cells of her granddaughter developing within the fetus (F2). The F3 generation (her great-granddaughter) is the first generation not directly exposed. Animal studies have demonstrated chemical effects that extend to the F3 and later generations, while human studies have shown effects through the F2 generation.
Figure by Joseph Tart/EHP, from Schmidt 2013, EHP.
Identifying and Regulating Endocrine Disruptors
There are a variety of methods to identify endocrine disrupting chemicals. The Endocrine Disruption Exchange hosted an online searchable list of potential endocrine disrupting chemicals. As of October, 2018, there were over 1400 chemicals on that list.
The U.S. Environmental Protection Agency (EPA) is supposed to be identifying endocrine disruptors using its Endocrine Disruption Screening Program, but they are way behind and have barely made a dent in screening chemicals. Money for this program may also be cut by the Trump administration.
The EPA wants to use more modern techniques than animal studies to screen chemicals. The advantage of these approaches is that they can screen hundreds of chemicals in a very short time. The disadvantage, so far, is that they may not be accurate. The debate continues.
While we wait for them to figure this out, we are experimenting on ourselves (but without an unexposed control group). For example, some scientists analyzed 65 compounds that migrate from polycarbonate plastic baby bottles (into milk), and found that 53 of them showed some endocrine activity (Simon et al. 2016). Exposing babies to these chemicals is just not ethical.
In the European Union, meanwhile, they are trying a little harder to regulate endocrine disrupting chemicals, for example through the REACH program, which stands for Registration, Evaluation, Authorisation and Restriction of Chemicals. Interestingly, one expert workshop recently provided recommendations on how to measure insulin in toxicology studies (Kucheryavenko et al. 2019). I've never seen diabetes-related measurements included in formal regulatory programs before.
Some scientists advocate for redoing regulations on EDCs. They state, "In the EU, general principles for EDCs call for minimisation of human exposure, identification as substances of very high concern, and ban on use in pesticides. In the USA, screening and testing programmes are focused on oestrogenic EDCs exclusively, and regulation is strictly risk-based. Minimisation of human exposure is unlikely without a clear overarching definition for EDCs and relevant pre-marketing test requirements. We call for a multifaceted international programme (eg, modelled on the International Agency for Research in Cancer) to address the effects of EDCs on human health-an approach that would proactively identify hazards for subsequent regulation." (Kassotis et al. 2020).
Economic Costs of Endocrine Disruptors
Some researchers have tried to estimate the economic costs of exposure to endocrine disrupting chemicals. For example, an expert panel of scientists has determined that exposure to 3 types of endocrine disrupting chemicals (BPA, DDE, and phthalates) in the European Union leads to economic costs of at least €18 billion per year -- for obesity and diabetes alone (not including other diseases) (Legler et al. 2015). Another study calculated that a reduction of chemical exposures (to phthalates, DDE, PCBs, and PFASs) could lead to a 13% reduction in diabetes. Extrapolating to Europe, they estimate that reducing chemical exposures could prevent 152,481 cases of diabetes in Europe and €4.51 billion/year in associated costs, compared with 469,172 cases prevented by reducing BMI (Trasande et al. 2017). Of course, these estimates are just estimates, and the true cost could be lower or higher. In fact, the estimates can vary quite a bit depending on what method is used to calculate them. Costs tend to be much higher when using human studies vs toxicological studies (Prichystalova et al. 2017). An expert panel estimated that exposure to endocrine disrupting chemicals has a median annual economic cost of €163 billion in the European Union. This estimate includes costs related to childhood obesity, adult obesity, and adult diabetes (Trasande et al. 2016). In the U.S., cost estimates of EDCs are even higher-- exceeding 2% of GDP (Attina et al. 2016).
Another study finds that environmental chemical exposures contribute costs that may exceed 10% of the global domestic product (Grandjean and Bellanger, 2017).