Developmental effects of diethylstilbestrol and other EDCs on obesity

Developmental exposure to endocrine-disrupting chemicals programs for reproductive tract alterations and obesity later in life

Abstract

Many chemicals in the environment, especially those with estrogenic activity, are able to disrupt the programming of endocrine signaling pathways established during development; these chemicals are referred to as endocrine-disrupting chemicals. Altered programming can result in numerous adverse consequences in estrogen-target tissues, some of which may not be apparent until later in life. For example, a wide variety of structural, functional, and cellular effects have been identified in reproductive tract tissues. In addition to well-documented reproductive changes, obesity and diabetes have joined the list of adverse effects that have been associated with developmental exposure to environmental estrogens and other endocrine-disrupting chemicals.

Obesity is a significant public health problem reaching epidemic proportions worldwide. Experimental animal studies document an association of developmental exposure to environmental estrogens and obesity. For example, a murine model of perinatal exposure to diethylstilbestrol has proven useful in studying mechanisms involved in abnormal programming of differentiating estrogen-target tissues, including reproductive tract tissues and adipocytes. Other environmental estrogens, including the environmental contaminant bisphenol A, have also been linked to reproductive problems and obesity later in life. Epidemiology studies support similar findings in humans, as do studies of cells in culture.

Together, these findings suggest new targets for abnormal programming by estrogenic chemicals and provide evidence supporting the scientific concept termed the developmental origins of adult disease. Furthermore, the association of environmental estrogens with obesity and diabetes expands the focus on these diseases from intervention or treatment to include prevention or avoidance of chemical modifiers, especially during critical windows of development.

Developmental effects of diethylstilbestrol and other EDCs on obesity

Obesity and overweight have dramatically increased in prevalence in wealthy industrialized countries over the past 2 to 3 decades and also in poorer underdeveloped nations, where it often coexists with undernutrition. Obesity has now reached epidemic proportions in the United States, although a recent study found that its increase has stopped its upward spiral in the past few years; however, there is no indication of any decreases in prevalence. Common causes of obesity have usually been attributed to high-calorie, high-fat diets and a lack of exercise combined with a genetic predisposition for the disease. However, the current alarming rise in obesity cannot be solely explained by only these factors; an environmental component must be involved. It has been suggested that exposure to EDCs during critical stages of adipogenesis is contributing to the obesity epidemic. The term obesogens has been coined for environmental chemicals that stimulate fat accumulation, referring to the idea that they inappropriately regulate lipid metabolism and adipogenesis to promote obesity.

Experimental animal studies support the idea of involvement of EDCs in obesity; developmental exposure to numerous chemicals — including diethylstilbestrol, other estrogens, and other chemicals, such as tributyl tin — has been associated with obesity or overweight and adipogenesis. Recently, there has been much interest in the chemical bisphenol A (BPA) because of its high production volume and its potential for widespread environmental contamination. Numerous studies have now shown an association of BPA exposure with increased body weight and adiposity. The later study suggests that an increase in body weight is sex specific, but that timing and dose may contribute to the complexity of these findings because other investigators report effects in both males and females. Interestingly, a recent article describes similar increases, as previously reported, in the body weights of pups obtained from moms fed BPA in their diets during pregnancy; the doses were low and were considered “ecologically relevant” at 1 μg BPA/kg diet (1 ppb). However, unlike previous reports, the differences in body weight at weaning disappear as the mice age. This is probably due to the palatability of the diet, which was substituted at weaning because both control and BPA mice did not continue to gain weight on the new diets.

In vitro studies with BPA provide additional evidence of a role for this chemical in the development of obesity and further suggest specific targets; BPA causes 3T3-L1 cells (mouse fibroblast cells that can differentiate into adipocytes) to increase differentiation and, in combination with insulin, accelerates adipocyte formation. Other in vitro studies have shown that low doses of BPA, similar to diethylstilbestrol, impair calcium signaling in pancreatic α cells, disrupt β cell function, and cause insulin resistance (48, 49). Low environmentally relevant doses of BPA have also been reported to inhibit adiponectin and stimulate the release of inflammatory adipokines, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), from human adipose tissue, which suggests that BPA is involved in obesity and the related metabolic syndrome. Furthermore, other studies have linked BPA exposure to disruption of pancreatic β cell function and blood glucose homeostasis in mice, which suggests changes indicative of the metabolic syndrome.

Epidemiologic studies also support an association of BPA with obesity. BPA was detected at higher concentrations in both nonobese and obese women with polycystic ovarian syndrome than in nonobese healthy women, which suggests the possible involvement of BPA in polycystic ovarian syndrome and/or obesity.

References

  • Full study (free access) : Developmental exposure to endocrine-disrupting chemicals programs for reproductive tract alterations and obesity later in life, The American journal of clinical nutrition, PMC3364077, 2011 Dec.
  • Featured image Sandra Cohen-Rose and Colin Rose..
DES DIETHYLSTILBESTROL RESOURCES

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