Endocrine disruptors and obesity: obesogens

Developmental effects of diethylstilbestrol and other EDCs on obesity

Abstract

Incidence and prevalence of owerweight and obesity have greatly increased over the past three decades in almost all countries around the world.

This phenomenon is not easily explained by lifestyle changes in populations with very different initial habits. This has led to consider the influence of other factors, the so-called endocrine disruptors, and more specifically obesogens.

This study reviewed the available evidence about polluting chemical substances which may potentially be obesogens in humans: DES, genistein, bisphenol A, organotins (TBT, TPT), and phthalates. The first three groups of substances mainly act upon estrogen receptors, while organotins and phthalates activate PPARγ.

It was concluded that evidence exists of the obesogenic effect of these chemical substances in tissues and experimental animals, but few data are available in humans.

References

DES DIETHYLSTILBESTROL RESOURCES

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

Environmental Estrogens and Obesity

The Developmental Exposed DES Animal Model to Study Obesity, 2009

Abstract

Many chemicals in the environment, in particular those with estrogenic activity, can disrupt the programming of endocrine signaling pathways that are established during development and result in adverse consequences that may not be apparent until much later in life. Most recently, obesity and diabetes join the growing list of adverse consequences that have been associated with developmental exposure to environmental estrogens during critical stages of differentiation. These diseases are quickly becoming significant public health issues and are fast reaching epidemic proportions worldwide. In this review, we summarize the literature from experimental animal studies documenting an association of environmental estrogens and the development of obesity, and further describe an animal model of exposure to diethylstilbestrol (DES) that has proven useful in studying mechanisms involved in abnormal programming of various differentiating estrogen- target tissues. Other examples of environmental estrogens including the phytoestrogen genistein and the environmental contaminant Bisphenol A are also discussed. Together, these data suggest new targets (i.e., adipocyte differentiation and molecular mechanisms involved in weight homeostasis) for abnormal programming by estrogenic chemicals, and provide evidence that support the scientific hypothesis termed “the developmental origins of adult disease”. The proposal of an association of environmental estrogens with obesity and diabetes expands the focus on the diseases from intervention/treatment to include prevention/avoidance of chemical modifiers especially during critical windows of development.

The developmental exposed DES animal model to study obesity

DES, a potent synthetic estrogen, was widely prescribed to pregnant women from the 1940s through the 1970s with the mistaken belief that it could prevent threatened miscarriages. It was estimated that a range of 2 to 8 million pregnancies worldwide were exposed to DES. Today, it is well known that prenatal DES treatment resulted in a low but significant increase in neoplastic lesions, and a high incidence of benign lesions in both the male and female offspring exposed during fetal life. To study the mechanisms involved in DES toxicity, we developed experimental mouse models of perinatal (prenatal or neonatal) DES exposure over 30 years ago. Outbred CD-1 mice were treated with DES by subcutaneous injections on days 9–16 of gestation (the period of major organogenesis in the mouse) or days 1–5 of neonatal life (a period of cellular differentiation of the reproductive tract, and a critical period of immune, behavioral, and adipocyte differentiation). These perinatal DES animal models have successfully duplicated, and in some cases, predicted, many of the alterations (structural, function, cellular and molecular) observed in similarly DES- exposed humans.

Although our major focus was initially on reproductive tract abnormalities and subfertility/infertility, we also examined the relationship of perinatal DES treatment with the development of obesity later in life. We sought to determine if DES was an obesogen as well as a reproductive toxicant, and if so, what were its molecular targets and the mechanisms through which it might act. For our obesity experiments, mice were treated with DES on days 1–5 of neonatal life using a low dose of 0.001 mg/day (1 μg/kg/day); this dose did not affect body weight during treatment but was associated with a significant increase in body weight as adults. The featured image is a representative photomicrograph of control and neonatal DES treated female mice at 4–6 months of age; male mice treated as neonates did not demonstrate this increase in body weight. Unlike the lower dose of DES (0.001 mg/day = 1 μg/kg/day), a higher dose of DES (1000 μg/kg/day =1 mg/kg/day) caused a significant decrease in body weight during treatment which was followed by a “catch up” period around puberty and then finally resulted in an increase in body weight of the DES treated mice compared to controls after ~2 months of age. This is reminiscent of the thrifty phenotype described earlier for humans. Additional studies indicated that the increase in body weight in these DES-exposed mice was associated with an increase in the percent of body fat as determined by mouse densitometry.

Increased body weight in all DES treated mice, both low and high doses, was maintained throughout adulthood; however, by 18 months of age, statistical differences in body weight between DES treated and controls were difficult to show because individual animal variability within groups increased so much as they aged (data not included). Since various doses of DES resulted in obesity whether or not pups were underweight during treatment, most likely multiple pathways are involved in programming for obesity by environmental estrogens.

Densitometry images suggested DES treated mice had excessive abdominal fat which had been previously reported to be associated with cardiovascular disease and diabetes (Gillum 1987), therefore, we determined the weights of various fat pads to determine if specific fat pads were affected by DES treatment or whether it was a generalized change throughout the mouse. Fat pad weights were compared in DES treated mice (1000 μg/kg/day =1 mg/kg/day) and controls at 6–8 months of age; inguinal, parametrial, gonadal, and retroperitoneal fat pads were all increased in DES treated mice as compared to controls, but, brown fat weights were not significantly different at this age.

Although DES- treated mice were not statistically different in weight to controls at 2 months of age, DES (1000 μg/kg/day =1 mg/kg/day) mice exhibited elevated serum levels of leptin, adiponectin, IL-6, and triglycerides prior to becoming overweight and obese. This suggests that these endpoints may be important early markers of subsequent adult disease. The elevated levels of leptin are not surprising considering the increase number and size of the adipocytes in the DES treated mice but the increase in adiponectin was not expected since low levels usually correlate with diabetes. However, this may indicate insensitivity to these hormones and/or a loss of the negative feedback mechanisms that regulate adipogenesis. At 6 months of age, insulin and all of the serum markers except triglycerides were found to be significantly elevated as compared to controls.

Glucose levels were also measured in DES (1000 μg/kg/day =1 mg/kg/day) and control mice prior to the development of obesity at approximately 2 months of age (Newbold et al. 2007). Interestingly, 25% of the DES-treated mice had significantly higher glucose levels than controls; these mice also showed a slower clearance rate of glucose from the blood since higher levels were seen throughout the experiment. It is important to note that altered glucose levels were observed in these mice before they developed excessive weight. Additional glucose measurements in older mice may help determine if a higher percentage of mice are affected with age, and if higher and sustained levels of glucose can be demonstrated. To date, however, our data suggest that overweight and obesity observed in perinatal DES- treated mice will be associated with the development of diabetes, similar to the association of obesity with diabetes in humans. Earlier studies from our laboratory support a role for altered glucose metabolism since we have shown a high prevalence of islet cell hyperplasia in the pancreas of mice exposed to DES or other environmental estrogens including BPA and genistein treated mice.

Since, the balance of activity levels and food intake are known contributors to obesity, activity was measured in DES (1000 μg/kg/day =1 mg/kg/day) and control mice at 2 months of age before a difference in body weight could be detected. Individual mice were placed in an Opto-Max motor activity chamber (Columbus Instruments, Columbus, OH) and their ambulatory activity measured. Overall, there was no statistical difference in this parameter between the two groups although the DES group showed less movement as compared to controls as the experiment progressed. This difference, however, was not sufficient to explain the enhanced weight gain in DES mice as they age. Additional measures of activity including the running wheel measured during the dark photoperiod are being determined and are necessary before the role of activity in the development of obesity can be fully accessed.

Feed consumption was also measured in control and DES-treated mice (1000 μg/kg/day =1 mg/kg/day). DES-treated mice consumed more than controls over the course of the experiment (~3 grams more), but the amounts were not statistically different between the groups. Taken into account, both the marginal decrease in activity and the increase in food intake in DES treated mice as compared to controls, it is unlikely these two measurements can solely explain the development of obesity in DES treated mice.

A recent study describes a role for developmental genes in the origins of obesity and body fat distribution in mice and humans. Therefore, exposure to environmental chemicals with hormonal activity may be altering gene expression involved in programming adipocytes during development. Several genes have been implicated in altering adipocyte differentiation and function such as Hoxa5, Gpc4 and Tbx15 and fat cell distribution such as Thbd, Nr2f1 and Sfrp2. We investigated changes in gene expression by microarray analysis in uterine samples from DES treated mice (1000 μg/kg/day =1 mg/kg/day) compared to controls at 19 days of age. In these samples, genes involved in adipocyte differentiation were not altered in the uterus following neonatal DES exposure, however, genes involved in fat distribution were. Thbd and Nr2f1 were significantly down regulated and Sfrp2 was significantly up regulated in DES treated uteri compared to controls. These findings support the idea that environmental estrogens may play a role in regulating the expression of obesity-related genes in development.

Although the data summarized in this review describes only neonatal exposure to a high dose of DES, lower doses and exposure during prenatal life have also been shown to be associated with obesity later in life. Interestingly, high prenatal DES doses caused lower birth weight compared to controls, followed by a “catch-up period”, and finally resulted in obesity; low prenatal DES doses had no effect on birth weight but it still resulted in obesity later in life. Thus, it appears that the effects of DES on adipocytes may depend on the time of exposure and the dose, and that multiple mechanisms maybe altered resulting in the same obesity phenotype.

References

  • Full study (free access) : Environmental Estrogens and Obesity, Molecular and cellular endocrinology, PMC2682588, 2009 May 25.
  • Featured image PMC2682588/figure/F1.
DES DIETHYLSTILBESTROL RESOURCES

Effects of endocrine disruptors on obesity

The Developmental Exposed DES Animal Model to Study Obesity, 2008

Summary

Environmental chemicals with hormone-like activity can disrupt the programming of endocrine signalling pathways that are established during perinatal life and result in adverse consequences that may not be apparent until much later in life. Increasing evidence implicates developmental exposure to environmental hormone mimics with a growing list of adverse health consequences in both males and females. Most recently, obesity has been proposed to be yet another adverse health effect of exposure to endocrine disrupting chemicals (EDCs) during critical stages of development. Obesity is quickly becoming a significant human health crisis because it is reaching epidemic proportions worldwide, and is associated with chronic illnesses such as diabetes and cardiovascular disease. In this review, we summarize the literature reporting an association of EDCs and the development of obesity, and further describe an animal model of exposure to diethylstilbestrol that has proven useful in studying mechanisms involved in abnormal programming of various oestrogen target tissues during differentiation. Together, these data suggest new targets (i.e. adipocyte differentiation and mechanisms involved in weight homeostasis) of abnormal programming by EDCs, and provide evidence that support the scientific term ‘the developmental origins of adult disease’. The emerging idea of an association of EDCs and obesity expands the focus on obesity from intervention and treatment to include prevention and avoidance of these chemical modifiers.

The developmental exposed DES animal model to study obesity

The role of environmental chemicals in the development of obesity is an emerging area of research which is focusing on the identification of obesogens, their possible molecular targets and potential cellular mechanisms through which they might act. Thus, to determine if environmental chemicals with hormone‐like activity are playing a role in the development of obesity and, further, study potential mechanisms involved, we used an experimental mouse model of perinatal DES exposure which was developed and characterized in our laboratory to study altered developmental programming of the reproductive tract which is well known to result in disease and dysfunction.

To study the mechanisms involved in DES toxicity, we developed an animal model using outbred CD‐1 mice treated with DES by subcutaneous injections on days 9–16 of gestation (the period of major organogenesis in the mouse) or days 1–5 of neonatal life (a period of cellular differentiation of the reproductive tract and a critical period of immune, behavioral and adipocyte differentiation). The developmental DES animal model has been used to successfully duplicate, and in some cases, predict, many of the alterations (structural, function, cellular and molecular) observed in similarly DES‐exposed humans.

Although our major focus has been on reproductive tract abnormalities and subfertility/infertility, we also examined the effects of DES on body weight. Treatment of female mice with DES on days 1–5 of neonatal life using a low dose of 0.001 mg/day did not affect body weight during treatment but was associated with a significant increase in body weight as adults. Further, data indicated that the increase in body weight in these DES‐exposed mice was associated with an increase in the percent of body fat as determined by mouse densitometry. Featured image schematically shows the weight patterns of low dosed DES‐treated mice and controls.

Unlike the low dose of DES (0.001 mg/kg), the high neonatal DES dose of 1 mg/day caused a significant decrease in body weight of female mice during treatment on days 1–5 but this was followed by a ‘catch up’ period lasting until about 2 months of age and then finally resulting in a significant increase in body weight of DES‐treated mice as compared with controls. The high body weight in all DES‐treated mice, both low and high doses, was maintained throughout adulthood. These data suggest that numerous pathways are probably involved in programming for obesity because DES at different doses resulted in obesity whether or not pups were under weight during treatment.

As the densitometry images suggested DES‐treated mice had excessive abdominal fat which has been previously reported to be associated with cardiovascular disease and diabetes, weights of various fat pads were measured to determine if specific fat pads were affected by DES treatment or whether it was a generalized effect throughout the mouse. At 6–8 months of age, fat pad weights were compared in DES‐treated mice (1 mg/kg) and controls; inguinal, parametrial, gonadal and retroperitoneal fat pads were all increased in DES‐treated mice as compared with controls; however, brown fat weights were not significantly different between DES and controls.

A recent study describes a role for developmental genes in the origins of obesity and body fat distribution in mice and humans. Therefore, exposure to environmental chemicals with hormonal activity may be altering gene expression involved in programming adipocytes. Several genes have been implicated in altering adipocyte distribution and function such as Hoxa5, Gpc4 and Tbx15 and fat cell distribution such as Thbd, Nr2f1 and Sfrp2. We investigated changes in gene expression by microarray analysis in uterine samples from DES‐treated mice (1 mg/kg) compared with controls at 19 days of age. In these samples, genes involved in adipocyte distribution were not altered in the uterus following neonatal DES exposure, however, genes involved in fat distribution were. Thbd and Nr2f1 were significantly downregulated and Sfrp2 was significantly upregulated in DES‐treated uteri compared with controls. These findings support the idea that environmental oestrogens may play a role in regulating the expression of obesity‐related genes in development.

Although DES‐treated mice were similar in weight to controls at 2 months, high dose DES (1 mg/kg) mice exhibited elevated serum levels of leptin, adiponectin, IL‐6 and triglycerides before overweight and obesity developed suggesting these endpoints may be important early markers of subsequent adult disease. The elevated levels of leptin and adiponectin may indicate insensitivity to these hormones and/or a loss of the negative feedback mechanisms that regulate adipogenesis. Further, at 6 months of age, insulin and all of the serum markers except triglycerides were found to be significantly elevated as compared with controls.

As, the balance of activity levels and food intake are known contributors to obesity, activity was measured in DES (1 mg/day) and control mice at 2 months of age before a difference in body weight could be detected. Individual mice were placed in an Opto‐Max motor activity chamber (Columbus Instruments, Columbus, OH, USA) and their ambulatory activity measured. Overall, there was no statistical difference in this parameter between the two groups although the DES group showed less movement as compared with controls as the experiment progressed. This difference, however, was not sufficient to explain the enhanced weight gain in DES mice as they aged. Additional measures of activity will be necessary before decrease in activity can be ruled out as a contributing factor to the development of obesity in these mice.

Feed consumption was also measured over a 2‐week period for control and DES‐treated mice (1 mg/kg). Although DES‐treated mice ate more than controls over the course of the experiment (approximately 3 g more), the amounts were not statistically different from controls. Taken into account, both the marginal decrease in activity and the increase in food intake in DES‐treated mice as compared with controls, it is unlikely these two measurements can solely explain the development of obesity in DES‐treated mice.

Glucose levels were also measured in DES (1mg/kg) and control female mice at 2 months of age prior to the development of obesity (Newbold et al., 2007a,b). Twenty‐five percent of the DES‐treated mice had significantly higher glucose levels than controls; these mice also showed a slower clearance rate of glucose from the blood because higher levels were seen throughout the experiment. It is important to note that altered glucose levels were observed in these mice before they developed excessive weight. Perhaps additional glucose measurements in older mice may help determine if a higher percentage of mice are affected with age, and if higher and sustained levels of glucose can be demonstrated. To date, however, our data suggest that overweight and obesity observed in perinatal DES‐treated mice will be associated with the development of diabetes, similar to the association of obesity with diabetes in humans. Interestingly, earlier studies from our laboratory have shown a high prevalence of islet cell hyperplasia in the pancreas of DES‐treated mice supporting the idea that these mice have abnormal glucose metabolism.

Although female mice exposed to DES at low or high doses developed obesity as adults, these phenomena were not apparent in similarly exposed males. In fact, DES‐treated males were smaller than corresponding controls and the decrease weight was dose dependent. This sex‐specific effect is not surprising because organizational effects of sex steroids during critical developmental periods have been well known for years to cause changes in the long‐term anatomy and function of the hypothalamic nuclei which regulates reproduction as well as body weight. Certainly, additional studies are necessary to investigate the effects of EDCs on male weight homeostasis and adipocytes because it is not clear whether this is a compound‐specific effect, an oestrogenic effect or typical of EDCs with other hormonal activities. Again, our findings point out the complexities of the mechanisms associated with the development of obesity.

References

DES DIETHYLSTILBESTROL RESOURCES

Perinatal exposure to environmental estrogens and the development of obesity

Brief exposure early in life to DES increases body weight as the mice age

“We can no longer simply assume that overweight and obesity are just personal choices based on the foods we eat, but that complex events including exposure to environmental chemicals during development may be contributing to (the) obesity (epidemic).”

Abstract

Dietary substances and xenobiotic compounds with hormone-like activity can disrupt the programming of endocrine signaling pathways that are established during perinatal differentiation. The consequences of this disruption may not be apparent until later in life but increasing evidence implicates developmental exposure to environmental hormone-mimics with a growing list of adverse health effects including reproductive problems and increased cancer risks.

Obesity has recently been proposed to be yet another adverse health consequence of exposure to endocrine disrupting substances during development. There is a renewed focus on identifying contributions of environmental factors to the development of obesity since it is reaching worldwide epidemic proportions, and this disease has the potential to overwhelm healthcare systems with associated illnesses such as diabetes and cardiovascular disease.

Here, we review the literature that proposes an association of perinatal exposure to endocrine disrupting chemicals, in particular those with estrogenic activity, with the development of obesity later in life. We further describe an animal model of developmental exposure to diethylstilbestrol (DES) to study mechanisms involved in programming for obesity.

Our experimental data support the idea that adipocytes and the mechanisms involved in weight homeostasis are novel targets of abnormal programming of environmental estrogens, some of which are found in our foods as naturally occurring substances or inadvertently as contaminants.

References

  • Perinatal exposure to environmental estrogens and the development of obesity, Molecular nutrition & food research, PMID: 17604389, 2007 Jul.
  • Image credit commons.wikimedia.
DES DIETHYLSTILBESTROL RESOURCES

Perturbed nuclear receptor signaling by DES linked to obesity

DES effects on body weight may depend both on the time of exposure and on the dose–response

Abstract

The modern world is plagued with expanding epidemics of diseases related to metabolic dysfunction. The factors that are driving obesity, diabetes, cardiovascular disease, hypertension, and dyslipidemias (collectively termed metabolic syndrome) are usually ascribed to a mismatch between the body’s homeostatic nutrient requirements and dietary excess, coupled with insufficient exercise.

The environmental obesogen hypothesis proposes that exposure to a toxic chemical burden is superimposed on these conditions to initiate or exacerbate the development of obesity and its associated health consequences. Recent studies have proposed a first set of candidate obesogens (diethylstilbestrol, bisphenol A, phthalates and organotins among others) that target nuclear hormone receptor signaling pathways (sex steroid, RXR-PPARgamma and GR) with relevance to adipocyte biology and the developmental origins of health and disease (DOHaD).

Perturbed nuclear receptor signaling can alter adipocyte proliferation, differentiation or modulate systemic homeostatic controls, leading to long-term consequences that may be magnified if disruption occurs during sensitive periods during fetal or early childhood development.

Diethylstilbestrol (DES)

Between the 1940–1980s, the synthetic estrogen diethylstilbestrol was prescribed to women for estrogen deficient states as hormone replacement therapy and to an estimated 2–8 million pregnant women at risk of miscarriage. Subsequent studies established the long-term endocrine disrupting consequences of DES exposure for multiple generations.

DES exposed mothers have an increased risk of developing breast cancer, whereas DES daughters display a high incidence of reproductive tract abnormalities, cervical and vaginal neoplasias, infertility and autoimmune disorders; DES sons also exhibit increased health risks.

A prenatal mouse exposure model recapitulates many of these alterations. Consistent with its estrogenic activity, DES doses between 10–100 μg kg−1 day−1 result in a depressed birth weight that is subsequently maintained. Surprisingly though, a dose of 1 μg kg−1 day−1 did not alter birth weight. Rather it was associated with a significant rise in adult body weight.

New data from Newbold et al. now demonstrate that high doses of DES (1 mg kg−1 day−1) administered between postnatal day 1–5 (during the period of adipocyte differentiation), cause an initial body weight reduction, followed by a period of “catch-up” growth around puberty and a sustained increase in adult body weight. This increase was associated with a higher percent body fat and preceded by elevated serum levels of adipokines and triglycerides.

Hence, it appears that the pro- or anti-adipogenic effects of this estrogenic insult may depend both on the time of exposure and on non-monotonic aspects of the dose–response curve.

References

DES DIETHYLSTILBESTROL RESOURCES

Developmental Exposure to Endocrine Disruptors and the Obesity Epidemic

Brief exposure early in life to DES increases body weight in mice as they age

Abstract

Xenobiotic and dietary compounds with hormone-like activity can disrupt endocrine signaling pathways that play important roles during perinatal differentiation and result in alterations that are not apparent until later in life. Evidence implicates developmental exposure to environmental hormone-mimics with a growing list of health problems. Obesity is currently receiving needed attention since it has potential to overwhelm health systems worldwide with associated illnesses such as diabetes and cardiovascular disease. Here, we review the literature that proposes an association of exposure to environmental endocrine disrupting chemicals with the development of obesity. We describe an animal model of developmental exposure to diethylstilbestrol (DES), a potent perinatal endocrine disruptor with estrogenic activity, to study mechanisms involved in programming an organism for obesity. This experimental animal model provides an example of the growing scientific field termed “the developmental origins of adult disease” and suggests new targets of abnormal programming by endocrine disrupting chemicals.

Summary and Conclusions

Taken together, our data supports the idea that brief exposure early in life to environmental endocrine disrupting chemicals, especially those with estrogenic activity like DES, increases body weight as the mice age. These data also suggest that these chemicals may contribute to overweight and obesity and other obesity-associated diseases such as type 2 diabetes and cardiovascular disease. Whether our results can be extrapolated to humans as the reproductive abnormalities from the DES mouse model did, remain to be determined but it provides a fruitful area of further research. In addition, the use of this animal model to study “obesogens” and mechanisms involved in altered weight homeostasis (direct and/or endocrine feedback loops, i.e., ghrelin, leptin, etc.) by environmental endocrine disrupting chemicals is an important basic research area that may be addressed by using this model. No longer can we assume than overweight and obesity are simply personal choices, but we have to consider that complex events including environmental chemicals are contributing to this mounting human health problem.

References

  • Full study (free access) : Developmental Exposure to Endocrine Disruptors and the Obesity Epidemic, Reproductive toxicology, NCBI PybMed, PMC1931509, 2007 Jan 17.
  • Image credit PMC1931509/figure/F1.
DES DIETHYLSTILBESTROL RESOURCES

Developmental exposure to estrogenic compounds and obesity

DES fetal life influence on body weight

2005 Study Abstract

For >20 years, research in our laboratory has focused on the effects of estrogenic compounds on development and differentiation. Our working premise has been that the developing organism is extremely sensitive to perturbation by chemicals with estrogenic or endocrine disrupting activity and that exposure to these chemicals during critical stages of differentiation may have permanent long-lasting consequences, some of which may not be expressed or detected until later in life. Diethylstilbestrol (DES) is a well-known example of such a chemical; thus, we have used DES as a model chemical to study environmental estrogens.

DES, a synthetic estrogen, was widely prescribed from the 1940s through the 1970s for the prevention of threatened miscarriage. A range of 2–8 million treated pregnancies worldwide has been estimated. Today it is well recognized that prenatal DES treatment results in a low incidence of neoplasia in the female offspring and a high incidence of benign abnormalities in both the male and female offspring.

To study the mechanisms involved in the toxicity of DES, we developed an animal model using outbred CD-1 mice treated with DES by subcutaneous injections on GD 9–16 (the period of major organogenesis in the mouse) or days 1–5 of neonatal life (a period of cellular differentiation of the reproductive tract and a critical period of immune and behavioral differentiation). The prenatal DES animal model has successfully duplicated and, in some cases, predicted many of the alterations (structural, function, cellular, and molecular) observed in similarly DES-exposed humans.

Although our major focus has been on reproductive tract abnormalities, we also examined the effects of DES on body weight over a wide dose range of exposure.

  • High prenatal DES doses (10–100 μg/kg of maternal body weight) caused a decrease in the offspring’s adult body weight;
  • likewise, high neonatal DES doses (1000 μg/kg/day on days 1–5 [1 mg/kg/day]) caused a decrease in body weight later in life.
  • However, low doses of DES (either prenatal or neonatal) caused an increase in body weight; Figure 1 illustrates control and neonatal DES 0.001 mg/kg/day treatment (DES-0.001).
  • Note that body weight was not different between DES-exposed and unexposed controls during the time of treatment and shortly thereafter, but it gradually reached significance by 6 weeks of age.
  • Further, data from our laboratory indicate that this increase in body weight in DES-exposed mice is associated with an increase in the percentage of body fat. Using Lunar PIXImus mouse densitometry (Lunar PIXImus, GE Healthcare, Waukesha, WI), we measured the percentage of fat in untreated controls and neonatal DES-treated mice at 16 weeks of age. As seen in the image, mice treated neonatally with DES are markedly larger than controls. Measurements obtained from densitometry show a significant increase in the estimated body weight, estimated fat weight, and percent fat compared to controls.
  • Neonatal exposure to other estrogens such as 2OH estradiol (20 mg/kg/day) and 4OH estradiol (0.1 mg/kg/day), which are approximately equal estrogenic doses to DES-0.001, also caused an increase in body weight at 4 months of age, suggesting that DES is not a unique estrogenic chemical in causing this increased obesity.
  • Further, neonatal exposure to the naturally occurring phytoestrogen genistein at 50 mg/kg/day, an approximately equal estrogenic dose to DES, caused a significant increase in body weight at 3 and 4 months of age compared to untreated controls.

We are currently comparing the weight of fat depots from mice exposed neonatally to various environmental estrogens to determine possible alterations in adipose tissue, including size of specific fat pads and hormone levels (e.g., leptin, adiponectin). By 18 months age, differences in body weight between genistein-treated and untreated controls are difficult to determine due to large individual animal variability within groups.

Taken together, our data support the idea that brief exposure to low levels of environmental estrogens early in life increases body weight as the mice age. Whether our results can be extrapolated to humans, as in the reproductive abnormalities from the DES mouse model, remains to be determined, but this is a fruitful area for further research. In addition, the use of this mouse model to study mechanisms involved in altered weight homeostasis (direct and/or endocrine feedback loops, e.g., ghrelin, leptin) by environmental endocrine disrupting chemicals is an important basic research area that may shed light on the future prevention and treatment of obesity.

References

DES DIETHYLSTILBESTROL RESOURCES

Childhood influences on adult disease

Developmental exposure to estrogenic compounds and obesity

1998 Abstract

There is increasing evidence that events in fetal and infant life can ‘programme’ the function of a number of organ systems.

These changes may lead to the evolution of adult illnesses, e.g. hypertension and coronary artery disease.

In addition many children with chronic illness survive into adulthood so that these diseases and/or their treatment may pose problems for health professionals involved in their care.

References

DES DIETHYLSTILBESTROL RESOURCES