Tag: Dr Retha Newbold

EDCs ability to alter reproductive function and health in females

Endocrine disrupting chemicals and disease susceptibility

The ability of EDCs to alter reproductive function and health in females has been clearly demonstrated by the consequences of DES use in pregnant women. The daughters of women given DES while pregnant were shown to have rare cervicovaginal cancers, decreased fertility and increases in rates of ectopic pregnancy , and early menopause. Many of these disorders have been replicated in laboratory animals treated with DES during gestation. As Newbold points out, the lessons learned from 40 years of DES research in humans and animals are that the female fetus is susceptible to environmentally induced reproductive abnormalities,that gonadal organogenesis is sensitive to synthetic hormones and hormone mimics during critical exposure windows, and that reproductive disease may not appear until decades after exposures.

Endocrine disrupting chemicals and disease susceptibility, Journal of Steroid Biochemistry & Molecular Biology,
doi:10.1016/j.jsbmb.2011.08.007, 6 August 2011.

Proper development of ovarian follicles in the fetus is dependent on estrogen exposure during critical periods of development. For instance, mice treated with DES on postnatal day 1–5 develop multioocytic follicles as adults. Therefore,maintaining a homeostatic balance of local and systemic hormones during follicle development is necessary for normal follicle development and germ cell quality. Perturbations in hormone signaling resulting from chemical exposures during developmental periods could contribute to ovarian disorders and declining conception rates in human populations.And while the mechanisms by which EDCs alter follicle development are not fully understood, there is evidence that these chemicals are contributing to increased rates of aneuploidy, polycyctic ovary syndrome (PCOS), premature ovarian failure (POF), and altered cyclicity and fecundity. For example, studies have shown that prenatal exposure to BPA causes irregular cycles in mice, which is likely due to hypothalamic alterations in the circuitry that controls luteinizing hormone (LH) secretion and ovulation. In humans, altered cyclicity has been reported in individuals exposed to organochlorine pesticides. Indeed, cycle irregularities have been noted in women whose mothers were exposed in utero to DES.

Uterine fibroids (leiomyomas) are the most common tumor of the female reproductive system, occurring in 25–50% of all women. The risk of the development of uterine fibroids increases with age during premenopausal years, but tumors typically regress with the onset of menopause. Obesity, age at menarche and unopposed estrogen signaling have been shown to increase the risks for fibroids. The best characterized animal model for the study of uterine fibroids is the Eker rat. A mutation of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene causes females to develop spontaneous uterine fibroids at a high frequency. Studies using this model have shown that exposure to EDCs increases the incidence of fibroids in these animals. Developmental exposure to DES causes rats that are genetically predisposed to uterine tumors to develop even more tumors of a larger size, but fails to induce tumors in wild-type rats. Importantly, DES exposure imparts a hormonal imprint on the developing uterus that causes an increase in estrogen-responsive gene expression. The potential for DES to cause uterine fibroids in humans is less clear. Two studies on DES daughters came to different conclusions. In a study of 2570 women born during the period DES was prescribed, no association was found between prenatal exposure and uterine fibroids. Another study of 1188 women found a significant relationship between DES exposure and uterine fibroids. On analysis of these studies, Baird and Newbold concluded that there was a definitive increase in uterine fibroids in DES daughters and the discrepancies between the studies was due to the differences and sensitivities of the methods used to detect the tumors.

In summary, both animal and human studies suggest a role of EDCs in altering female reproductive development. Data from animal experiments show that EDC exposure during critical periods of development, both prenatal and neonatal, can induces functional changes that appear later in life. There are data gaps in understanding the mechanisms by which EDCs carry out their action, but it is clear that to reduce the risk of reproductive disorders we must take action to reduce exposure to these chemicals.

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The Evidence of the EDCs Effect on Gender: the DES Situation

Are EDCs blurring issues of gender?

Introduction

Although scientists have postulated a wide range of adverse human health effects of exposure to endocrine-disrupting chemicals (EDCs), the nexus of the debate is the concern that prenatal and childhood exposure to EDCs may be responsible for a variety of abnormalities in human sexuality, gender development and behaviors, reproductive capabilities, and sex ratios. Scientists today are asking hard questions about potential human effects: Do EDC exposures impair fertility in men or women? Can they cause sexual organ malformations, stunted reproductive development, or testicular or breast cancer? Do fetal exposures to EDCs alter sex phenotypes? Do they change later gender-related neurobiological characteristics and behaviors such as play activity and spatial ability? Could such exposures even be involved in the etiology of children born with ambiguous gender?

Are EDCs Blurring Issues of Gender?, Environnement Health Perspectives, NCBI PubMed PMC1281309, 2005 Oct.

EDCs include a spectrum of substances that can be loosely classified according to their known or suspected activity in relation to sex hormone receptors and pathways. The most-studied and best known are the environmental estrogens, which mimic estradiol and bind to estrogen receptors (ERs). ER agonists include the pesticide methoxychlor, certain polychlorinated biphenyls (PCBs), bisphenol A (BPA; a high production volume chemical used to make polycarbonate plastic), pharmaceutical estrogens such as diethylstilbestrol (DES) and ethinyl estradiol, and phytoestrogens, which occur naturally in many plants, most notably in soybeans in the form of genistein and related substances. There are a few known ER antagonists, or antiestrogens. Antiandrogens, or androgen receptor (AR) antagonists, include the fungicide vinclozolin, the DDT metabolite p,p′-DDE, certain phthalates (a group of chemicals used to soften polyvinyl chloride plastics), and certain other PCBs. And there are other types of EDCs that affect particular endocrine targets. The various EDCs differ greatly in their potencies relative to natural hormones, and in their affinity for target receptors. Some have been shown to act via non–receptor-mediated mechanisms, for example by interfering with hormone synthesis.

In many well-documented cases of high-level fetal exposures to known EDCs such as DES, certain PCBs, and DDT, the answer to the question of whether exposure is associated with gender-related effects is clearly yes. But high-level exposures such as these are relatively rare and isolated. The debate today centers on low-dose exposures—generally defined as doses that approximate environmentally relevant levels—and the idea that low-dose intrauterine exposure to some EDCs during certain critical windows of development can have profound, permanent impacts on subsequent fetal development and adult outcomes.

Critics of this idea maintain that thus far there is no credible evidence to suggest that low-dose exposures cause any adverse human health effects. But if low-dose exposures were confirmed to be the threat that proponents of the concept insist they are, public health would clearly be at risk, regulatory agencies’ risk assessment approach would need to be revised, and certain common chemicals—including some that are massively produced and economically important—would likely disappear from the marketplace.

In a June 2000 EHP review article on human health problems associated with EDCs, Stephen Safe, director of the Center for Environmental and Genetic Medicine at Texas A&M University, concluded that

“the role of endocrine disruptors in human disease has not been fully resolved; however, at present the evidence is not compelling.”

Frederick vom Saal, a developmental biologist at the University of Missouri–Columbia, disagrees, particularly in light of the research that’s been presented in the years since that review. He says

“The jury is not out on human effects. In terms of the amount of information we have in animals and the amount of information we have in humans, clearly there is a huge difference, but that’s a lot different than saying the jury is out on whether EDCs influence humans.”

One thing both scientists might agree on, though, is that right now there are still more questions than answers.

Evidence of Effects: the DES situation

The Global Assessment further states that the only evidence showing that humans are susceptible to EDCs is currently provided by studies of high exposure levels. There is, in fact, clear evidence that intrauterine EDC exposures can alter human reproductive tract development and physiology. The most thoroughly characterized example is DES, the synthetic estrogen prescribed to millions of pregnant women in the United States and elsewhere from the 1940s to the 1970s to prevent miscarriage. The drug is known to have caused a rare form of vaginal cancer in thousands of daughters of women who took DES, as well as a variety of adverse reproductive tract effects in both the daughters and sons of those women.

The DES situation could be seen as a worst-case scenario for prenatal EDC exposure—the deliberate delivery of a potent estrogenic chemical in high doses. Viewed another way, it has provided researchers a rare opportunity to study the effects of prenatal EDC exposure in a relatively controlled fashion, with a well-defined population and well-characterized exposure to a single potent agent.

Over the course of her research, Newbold has developed a mouse model of DES exposure that has proven extremely useful in studying the effects of DES and other environmental estrogens, particularly those outcomes that may be manifested only later in life. She says

“With the experimental model, there are a lot of questions we can ask with DES that will tell us about the weaker environmental estrogens. We can change the timing of exposure and the amount of exposure, and we can look at different target tissues.”

The animal model has replicated numerous abnormalities reported in DES-exposed humans, and has also predicted some human outcomes.

“We have published documentation [see, for example, the October 1985 issue of Cancer Research and volume 5, issue 6 (1985) of Teratogenesis, Carcinogenesis, and Mutagenesis] that a number of the reproductive anomalies seen in DES-exposed mice, such as retained testes and abnormalities in the oviduct in females, were also later reported in DES-exposed humans,”

says Newbold.

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Developmental Exposure to Endocrine Disruptors and the Obesity Epidemic

Environmental chemicals are contributing to overweight and obesity

image of Control-and-DES-treated-Mice
Image captured with PIXImus™ mouse densitometry at 6 months of age. Images are representative of control (left) and DES (right) treated mice. Note that DES mice are significantly larger. Image by NCBI, 2007.

2007 Study 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.

Sources
  • Developmental Exposure to Endocrine Disruptors and the Obesity Epidemic, Retha R. Newbold, Elizabeth Padilla-Banks, Ryan J. Snyder,1 Terry M. Phillips and Wendy N. Jefferson, Reprod Toxicol doi: 10.1016/j.reprotox.2006.12.010, NCBI PMCID: PMC1931509, 2007 Jan 17.
  • All images, PMC 17321108, 2007.
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The DES Mouse at Six Months of Age

Environmental Estrogens and Obesity – Molecular Cellular Endocrinology

DES mouse and control
Representative photograph of Control and DES-treated Mice, Mol Cell Endocrinol. 2010.
  • A. Photograph shows the difference in body size of the two groups at ~ 6 months of age.
  • B. Images of Control and DES treated mice as generated by Piximus densitometry.

Note that the DES mouse is much larger than the control at 6 months of age.

  • Image sources: Environmental estrogens and obesity, NCBI PMCID: PMC2682588 and figure/F1, 2010 May 25.
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Environmental Estrogens and Obesity, Body Weight following DES Exposure

Environmental Estrogens and Obesity

Control-and-DES-treated-Mice image
Representative photograph of control and DES-treated mouse at ~ 6months of age. Image via NCBI.  Complex events including exposure to environmental chemicals during development may be contributing to the obesity epidemic.

2010 Study 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 (BPA) 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.

Summary and Conclusions

The data included in this review supports the idea that brief exposure, early in development to environmental chemicals with estrogenic activity, increases body weight gain with age and alters markers predictive of obesity in experimental animals. Epidemiology studies support the findings in experimental animals and show a link between exposure to environmental chemicals (such as PCBs, DDE, and persistent organic pollutants) and the development of obesity. Furthermore, the use of soy-based infant formula containing the estrogenic component genistein has been positively associated with obesity later in life.

Using the DES animal model as an important research tool to study “obesogens”, the mechanisms involved in altered weight homeostasis (direct and /or endocrine feedback loops, i.e., ghrelin, leptin, etc.) by environmental estrogens can be elucidated. In addition, hopefully this animal model may shed light on areas of prevention. Public health risks can no longer be based on the assumption than overweight and obesity are just personal choices involving the quantity and kind of foods we eat combined with inactivity, but rather that complex events including exposure to environmental chemicals during development may be contributing to the obesity epidemic.

Sources
  • Environmental Estrogens and Obesity, Retha R. Newbold, Elizabeth Padilla-Banks, and Wendy N. Jefferson, NCBI PMCID: PMC2682588, 2010 May 25.
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Environmental Estrogens and Obesity: the Developmental Exposed DES Animal Model

Environmental Estrogens and Obesity, Molecular Cellular Endocrinology, 2009

obese-women image
In this 2009 study, 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. Image Sandra Cohen-Rose.

2009 Study Abstract

Diethylstilbestrol 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 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.

Sources
  • Environmental Estrogens and Obesity, NCBI PMCID: PMC2682588, Retha R. Newbold,1 Elizabeth Padilla-Banks, and Wendy N. Jefferson, Mol Cell Endocrinol. Author manuscript; available in PMC 2010 May 25.
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Perinatal exposure to environmental estrogens and the development of obesity

DiEthylStilbestrol DES, environmental estrogens and obesity

image of obesity
Since various doses of DES resulted in obesity, most likely multiple pathways are involved in programming for obesity by environmental estrogens. Jeans image by Sandra Cohen-Rose and Colin Rose.

2007 Study 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.

Sources
  • Perinatal exposure to environmental estrogens and the development of obesity,Newbold RR1, Padilla-Banks E, Snyder RJ, Jefferson WN, Mol Nutr Food Res. 2007 Jul;51(7):912-7. NCBI PMID: 17604389.
  • Full study: DOI 10.1002/mnfr.200600259, Mol. Nutr. Food Res. 2007, 51, 912 – 917.
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Early-life exposure to DES induces life reprogramming of the mouse uterine epigenome

Neonatal exposure to DES induced permanent alterations in DNA methylation status of specific genes in mouse uteri

lab-mouse
Neonatal exposure to DES induced permanent alterations in DNA methylation status of specific genes in mouse uteri.

2008 Study Summary

We have provided evidence that early-life exposure of the mice to the xenoestrogen Diethylstilbestrol (DES) or the phytoestrogen GEN induces life reprogramming of the mouse uterine epigenome. Specific genes with no previously documented associations with the uterus were identified by an unbiased methylation profiling methodology. These genes encode proteins involved in a wide-range of cellular functions. Detailed studies were conducted on one of the reprogrammable genes, Nucleosomal Binding Protein 1 (Nsbp1), which is a nucleosome binding and transcriptional activation element. Our data support the paradigm that manifestation of early-life epigenetic reprogrammed gene expression in the mouse uterus is dependent on adult ovarian steroids and changes over the course of natural aging of the animal. The complex interplay among the type of estrogen, timing of exposure, reproductive status, and aging time line all significantly contribute to the phenotypical outcome of the epigenetic reprogramming in this model system.

Sources and Full Study
  • Persistent Hypomethylation in the Promoter of Nucleosomal Binding Protein 1 (Nsbp1) Correlates with Overexpression of Nsbp1 in Mouse Uteri Neonatally Exposed to Diethylstilbestrol or Genistein, NCBI, Endocrinology. 2008;149(12):5922-5931. doi:10.1210/en.2008-0682, PMC2613067, Dec 2008.
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Brief exposure to low levels of environmental estrogens early in life can increase body weight

Developmental exposure to estrogenic compounds and obesity

Fatmouse
This 2005 study data supports the idea that brief exposure to low levels of environmental estrogens early in life can increase body weight with age.

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.

Sources and Full Study
  • Developmental exposure to estrogenic compounds and obesity, NIEHS Symposium Proceedings, Retha R. NewboldMay, DOI: 10.1002/bdra.20147, 15 JUN 2005.
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Developmental exposure to DES alters uterine response to estrogens in mice: low versus high dose effects

The uterus response differs following high versus low doses of neonatal exposure

lab_mice image
In this 2004 study, the uterus response differed following high versus low doses of neonatal exposure.

2004 Study Abstract

Outbred CD-1 mice received subcutaneous injections on neonatal days 1-5 with DES (0.0001-1000 microg/kg per day), a model xenoestrogen. At 17 days of age, uterine wet weight increase in response to estrogen was altered in neonatally DES-treated mice compared to controls. The response varied depending on the neonatal DES dose; a low dose (0.01 microg/kg) caused an enhanced uterine response but higher neonatal doses dampened the response. Western blots and immunolocalization of estrogen receptor alpha (ERalpha) showed high ER levels at DES 0.01 microg/kg, but decreased levels at higher doses compared to controls. Genes responding through ER-mediated pathways (c-fos, proliferating cell nuclear antigen (PCNA), and lactoferrin (LF)) mirrored altered wet weight responses, i.e., enhancement at low doses and dampening at higher doses. A similar dose-response curve was seen in 4 months old ovariectomized DES-treated mice suggesting the altered response was long-term. These data suggest xenoestrogen exposure during critical developmental windows alters hormone programming so that the uterus responds abnormally to estrogen later in life, and that the response differs following high versus low doses of neonatal exposure.

Sources and Full Study
  • Developmental exposure to diethylstilbestrol (DES) alters uterine response to estrogens in prepubescent mice: low versus high dose effects, Reprod Toxicol. 2004 May;18(3):399-406. PMID: 15082075.
  • Full study, sciencedirect, doi:10.1016/j.reprotox.2004.01.007, pii/S0890623804000140, May 2004.
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