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. Many substances can interfere with the endocrine system of animals, including humans, and they are called "endocrine disruptors." Endocrine disruption is important because hormones play a critical role in controlling how the body develops. A number of environmental contaminants (as well as other substances, such as some pharmaceuticals) are endocrine disruptors (Hotchkiss et al. 2008).

 

Gore et al. (2006) list some common characteristics of how endocrine disruptors can act:

A number of the contaminants considered here, including arsenic, some persistent organic pollutants (POPs) such as PCBs and dioxin, bisphenol A, phthalates, some pesticides, and possibly nitrate, are considered endocrine disruptors. Please visit those pages for studies on these contaminants.

 

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, including estradiol (an estrogen), testosterone (an androgen), insulin, glucagon, glucocorticoid, and thyroid hormones, and more. Vitamin D is also considered to be a secosteroid, a type of steroid hormone.

 

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).

 

Most research has focused on estrogenic compounds, or those that can act like estrogens. However, other endocrine disrupting compounds may act in other ways, as androgens, anti-androgens, and anti-thyroid substances for example. Endocrine disruptors can act by various mechanisms, including by inhibiting hormone synthesis, affecting certain cells, affecting hormone secretion, binding or blocking with various hormone receptors, and more (Hotchkiss et al. 2008).

First, we might ask whether natural hormones can influence the development of type 1 diabetes. There is some evidence that they can. Gender differences are present in type 1 (and type 2) 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 (see the puberty page). Pregnancy, another time of hormonal change, can lead to gestational diabetes, later followed by type 1 or 2 diabetes (see the types of diabetes page). Psychological stress may be a risk factor for type 1 diabetes (see the stress page), 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 (see the vitamin D page). The role of taller height and excess weight as risk factors for type 1 diabetes may also involve hormones (see the height and weight page).

 

We do not know, however, if contaminants that interfere with the endocrine (hormone) system contribute to the development of type 1 diabetes. The following sections provide some evidence that this possibility exists, although this hypothesis has not yet been tested.

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, although exactly how is still under investigation (Clayton et al. 2010).

 

The effects of endocrine disruptors on the immune system may be particularly important for type 1 diabetes, since it is an autoimmune disease.

 

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). 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) (see the gender and age page).

 

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 contaminants 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). 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).

 

Yet other contaminants 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 contaminants can affect a number of receptors. Bisphenol A, for example, affects the activation of not only estrogen receptors, but also androgen and AhR receptors (Kruger 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 contaminants 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 contaminant effects on vitamin D levels.

 

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. Contaminants that can disrupt glucocorticoid action include PCBs, organotins, arsenic, dithiocarbamate chemicals (found in some pesticides and cosmetics), and more (Odermatt et al. 2006).

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).

 

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 contaminants 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 (see the gender and age page). 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).

 

Could androgenic or anti-androgenic contaminants then affect beta cells? This question has not yet been researched. Some endocrine disruptors can influence androgen receptor actions and can be androgenic or antiandrogenic at levels found in the environment, although the health effects investigated so far are related to the reproductive system. 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 (Kruger et al. 2008).

Some endocrine disrupters have been found to increase insulin resistance, including bisphenol A, some persistent organic pollutants (including dioxin, and PCBs), some pesticides, and phthalates. See those pages for information on these studies. See the insulin resistance page for information on the role of increased insulin resistance in type 1 diabetes.

 

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).

 

The May 25, 2009 issue of the journal Molecular and Cellular Endocrinology published a special issue on the role of environmental endocrine disrupting contaminants 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 contaminant exposures in early life. Grün and Blumberg (2009) review the evidence that a variety of endocrine disrupting contaminants can influence fat formation and obesity. Newbold et al. (2009) review the mechanisms involved in endocrine disruption and obesity. And, as mentioned above, Nadal et al. (2009) discuss how estrogenic compounds target beta cells.

 

Some endocrine disruptors have been shown to increase the formation of fat cells; see the height and weight page for these studies and for more information on how increased weight is a risk factor for type 1 diabetes.

Endocrine disrupters are also a likely environmental factor contributing to the earlier appearance of puberty, a possible accelerator of type 1 diabetes (see the puberty page for information).

 

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). The effect of endocrine disruptors on the thyroid hormone is another area that is beginning to be researched. For a review of the main thyroid-disrupting contaminants (PCBs, perchlorates, brominated flame retardants, and phthalates), see Jugan et al. (2010).

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 book Our Stolen Future (Colborn et al. 1996) is a good background on endocrine disruptors and their effects on the reproductive system, and the Our Stolen Future website provides information on further studies and the health effects of these substances.

 

We do not know if endocrine disruptors or endocrine disruption contribute to the development of type 1 diabetes or the increased incidence of the disease in children, but judging from their effects on animals, the potential certainly exists, and should be investigated. It is critical to keep in mind that the health effects discussed on this page were almost all seen at very low doses, such as we encounter in the environment.