Category: DES Daughters

Find all DES daughters related blog posts from my Diethylstilbestrol “Journal of a DES Daughter”.

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Possible links to the development of obesity

Diethylstilboestrol—A long-term legacy, School of Biosciences, 2012

Abstract

Obesity and type 2 diabetes levels have risen over the past century, the incidence being more marked in recent years. Both these conditions have adverse consequences and are significant public health issues. Even pets, laboratory animals and urban rats have increased in average body weight over the past decades. These trends in both humans and animals are not necessarily explicable by diet and exercise; prenatal exposure to environmental triggers (‘obesogens’), has been suggested as a possible factor, particularly to oestrogenic compounds such as DES, bisphenol A and phthalates.

Adipose tissue acts as an endocrine organ, releasing
hormones controlling appetite and energy metabolism and is a site for oestrogen synthesis. This mechanism, found in both animals and human beings, ensures a link between the food supply and the capacity to reproduce, since starvation and pregnancy are not a good combination. When low doses of DES were administered to mice pre- or neo-natally, the adult animals gained weight with altered expression of obesity-related genes and altered hormone levels. There was no difference in the number of fat cells but the cells already present increased in size.

Although it is not known at present whether DES acts as an obesogen in man, raised urinary concentrations of other environmental chemicals, such as phthalates, have been linked with the increased body weight and insulin resistance which lead to ‘metabolic syndrome’.

References

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Obesogenic endocrine disruptors and obesity

Myths and truths, Archives of Toxicology, 2017

Abstracts

Obesogenic endocrine disruptors, also known as obesogens, are chemicals potentially involved in weight gain by altering lipid homeostasis and promoting adipogenesis and lipid accumulation. They included compounds to which human population is exposed over daily life such as pesticides/herbicides, industrial and household products, plastics, detergents and personal care products.

The window of life during which the exposure happens could lead to different effects. A critical window is during utero and/or neonatal period in which the obesogens could cause subtle changes in gene expression and tissue organization or blunt other levels of biological organization leading to increased susceptibility to diseases in the adulthood.

“…the exposure to diethylstilbestrol (DES) during neonatal period resulted in increased body weight.
Interestingly, this efect was specifc for females and did not appear until 4–6 months. In male mice, the exposure to DES was accompanied by an increased number of adipocytes in the gonadal fat pad of mice.” …

… “…the prenatal exposure to DES resulted in childhood obesity at age of 7 and increased risk of adult obesity.”

Some of the reasons for this increased sensitivity include the lack of the protective mechanisms that are available in adult such as DNA repair mechanisms, a competent immune system, detoxifying enzymes, liver metabolism and the blood/brain barrier still not fully functional in the fetus or newborn.

The mechanisms of action of obesogens lay on their ability to increase the number and/or the size of the adipocytes and to alter appetite, satiety and food preferences.

The ability of obesogens to increase fat deposition results in an increased capacity for their own retention due to their lipophilic properties; thus prolonging the exposure and increasing the detrimental metabolic consequences.

References

  • Obesogenic endocrine disruptors and obesity: myths and truths, Archives of Toxicology, NCBI PubMed PMID: 28975368, 2017 Nov.
  • Image credit Siora Photography.
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Endocrine Disruptors and Obesity

DES exposure during the neonatal period predisposes to obesity in mice at 4–6 months of age

2017 Study Abstract

Purpose of Review
The purpose of this review was to summarise current evidence that some environmental chemicals may be able to interfere in the endocrine regulation of energy metabolism and adipose tissue structure.

Recent Findings
Recent findings demonstrate that such endocrine-disrupting chemicals, termed “obesogens”, can promote adipogenesis and cause weight gain. This includes compounds to which the human population is exposed in daily life through their use in pesticides/herbicides, industrial and household products, plastics, detergents, flame retardants and as ingredients in personal care products. Animal models and epidemiological studies have shown that an especially sensitive time for exposure is in utero or the neonatal period.

An especially sensitive time frame for exposure to obesogens has been found to be either prior to birth in utero or in the neonatal period. Neonatal mice exposed to the synthetic oestrogen DES have also been reported to have increased body weight. This featured image shows a representative photomicrograph at 4–6 months of age of control and neonatal DES-treated female mice: the mice were treated on days 1–5 of age with 1 μgDES/kg body weight/day, and obesity was evident by 4–6 months of age. This serves to demonstrate the obesogenic consequences of exposure to a potent oestrogen at an inappropriate developmental stage.

Summary
In summarising the actions of obesogens, it is noteworthy that as their structures are mainly lipophilic, their ability to increase fat deposition has the added consequence of increasing the capacity for their own retention. This has the potential for a vicious spiral not only of increasing obesity but also increasing the retention of other lipophilic pollutant chemicals with an even broader range of adverse actions. This might offer an explanation as to why obesity is an underlying risk factor for so many diseases including cancer.

References

DES DIETHYLSTILBESTROL RESOURCES
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Prenatal diethylstilbestrol exposure and risk of obesity in adult women

Journal of developmental origins of health and disease, 2015

Study Abstract

Diethylstilbestrol DES is a non-steroidal estrogen that was commonly prescribed during pregnancy from the late 1940s to 1971. A potent endocrine disruptor, prenatal DES exposure has been linked with reproductive tract malformations, adverse pregnancy outcomes, cancer, infertility and earlier menopause. DES was used for years as a growth promoter in animal production. Some animal studies suggest that prenatal DES exposure is associated with obesity and metabolic disturbances.

Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between DES and adult obesity, weight gain from age 20 to mid-life, central adiposity and height among 2871 prenatally exposed and 1352 unexposed women between 23 and 52 years of age(median 41.5) at baseline in 1994. DES exposure status was confirmed by prenatal medical record review. We used multivariable log-binomial models to calculate risk ratios (RRs) for obesity in 2006, and linear regression to calculate mean differences in body mass index, weight gain, waist circumference and height.

The adjusted RR for DES and obesity was 1.09 [95% confidence interval (CI): 0.97, 1.22],

  • and RRs were 1.23 (CI: 1.07, 1.42)
  • and 1.05 (CI: 0.91, 1.20) for low and high estimated total DES dose, respectively, compared with no exposure.
  • DES-exposed women gained slightly more weight than unexposed women [mean difference, 0.70 kg (CI: -0.27, 1.66)].

This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity.

From the “DES Follow-Up Study”

Some studies in animals suggest that prenatal DES exposure is linked to obesity and to abnormal metabolism of glucose. Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between prenatal DES exposure and adult obesity. To do this, we looked at factors like weight gain, body mass index (BMI – a measure of body fatness) and waist circumference among 2,871 women exposed to DES before their birth and also among 1,352 who were not exposed to DES.

We conducted statistical analyses to see if exposed women had a higher risk of being obese, and whether there were differences between exposed and unexposed women in BMI, weight gain, waist circumference and height. Other factors possibly related to obesity such as age, educational level and whether the woman smoked, were accounted for in the analysis. We also considered whether the mother smoked during the pregnancy with the daughter, the daughter’s use of postmenopausal hormones, her menopausal status, and how many children she had.

DES-exposed women had a 9% greater overall risk of being obese compared with unexposed women, but these findings could have been due to chance. Compared with unexposed women, the risk of obesity was 23% greater for women who were exposed prenatally to a low DES dose and 5% greater for women exposed to a high dose. Overall, most women gained around 30 pounds between the ages of 20 and the mid-fifties, and DES-exposed women gained slightly more (about 1.5 pounds) than those not exposed, although this was not statistically significant. Height and waist circumference were very similar among DES- exposed and unexposed women. This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity but not the larger differences that have been observed in some animal studies.

References

  • Prenatal diethylstilbestrol exposure and risk of obesity in adult women, Journal of developmental origins of health and disease, NCBI PobMed 25697972, 2015 Jun.
  • Image credit Sandra Cohen-Rose and Colin Rose..
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Etiology of obesity : Environmental Estrogen DES

DES exposure effects in mouse models replicate human findings

Abstract from “EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals”, 2015

Obesity requires eating more food and/or consuming less energy. To date, most of the obesity studies in animals are based in the observation that EDC exposures induce weight increases and changes in adiposity, as well as affecting hormones and adipokines involved in the regulation of food intake and energy expenditure. There are fewer studies related to how EDCs disrupt energy balance. Therefore, more studies are necessary to gain mechanistic insights into the role that EDCs play in the etiology of obesity.

Studies of rodents that were prenatally, neonatally, or perinatally exposed to EDCs support the obesogen hypothesis. For example, DES exposure effects in mouse models replicate human findings. DES is an estrogenic chemical that binds with high affinity to the ERs, ERα and ERβ, which play an important role in adiposity regulation as well as central and peripheral energy balance. Developmental exposure to DES in mice induced adipogenesis and caused mice to become obese or overweight.

Other chemicals classified as environmental estrogens, particularly BPA, produced similar effects. Perinatal exposure to low doses of BPA caused increased body weight; adiposity; alterations in blood levels of insulin, leptin, and adiponectin; as well as a decrease in glucose tolerance and insulin sensitivity in an age-dependent manner.

References

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Environmental Estrogens, Obesity, and Metabolism

Perinatal exposure to DES and latent development of high body weight and obesity

Abstract from “Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement”, 2009

White adipose tissue metabolism is under the control of the sympathetic nervous system and is modulated by hormones including sex steroids. The impact of environmental estrogens on adipose tissue may be through direct modulation of lipogenesis, lipolysis, and adipogenesis, or indirect by affecting food consumption and leptin secretion targeting the central nervous system or lipid homeostasis in liver.

The estrogenic pharmaceutical chemical DES illuminates the relationship between perinatal exposures and latent development of high body weight and obesity. Moreover, there is a complex relationship between the concentration of estrogen to which pregnant animals are exposed and the weight of the offspring in adulthood. Specifically, according to a recent experiment by Newbold et al., mice neonatally exposed to DES experience increased body weight in adulthood associated with excess abdominal body fat. Interestingly, the dose of DES determines the chronic manifestation of the observed alterations, with high doses leading to initially decreased body weight and a peripubertal “catch-up” and low doses causing an increase in weight detectable only in adulthood. Moreover, the timing is important because gestational administration in rodents results in the offspring’s low birth weight, an unchanged metabolic characteristic throughout life. Along with an increase in body fat stores, the adipokines leptin and adiponectin, IL-6 (an inflammatory marker), and triglycerides were all elevated in DES-exposed mice.

An in vitro study using a culture system of 3T3-L1 preadipocytes showed that 4-nonylphenol and BPA stimulated lipid accumulation, accelerating their differentiation to mature adipocytes in a time- and concentration-dependent way. The underlying mechanism appeared to involve up-regulation of gene expression involved in lipid metabolism and adipocyte differentiation. In the second part of the experiment, fat accumulation was observed in human hepatocellular carcinoma cell lines exposed to those endocrine disruptors. These findings are consistent with previous in vitro studies using mouse fibroblast cell lines in which a link between environmental chemicals including nonylphenol, BPA, and genistein in the development of body weight imbalance was suggested.

References

  • Full study (free access) : Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement, Endocrine Society endocrine reviews, PMC2726844, 2009 Jun.
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Pharmacologic sex hormones in pregnancy in relation to offspring obesity

2014 Study objective : to assess the association between in utero exposure to either diethylstilbestrol (DES) or an oral contraceptive in pregnancy and offspring obesity

What is already known about this subject

  • In animal models, in utero exposure to exogenous estrogenic agents is associated with offspring adiposity.
  • In in vitro and animal models, diethylstilbestrol exposure has led to an increase in stem cell differentiation into preadipocytes and adipocytes.

What this study adds

  • An evaluation of the association between in utero exposure to pharmacologic estrogens and subsequent obesity in humans.
  • A novel approach to studying the potential for developmental origins of obesity as conferred through in utero exposure to estrogenic agents.

Abstract

Methods
Using data from the Collaborative Perinatal Project (1959-1974), a multicenter prospective study of pregnant women and their offspring, we examined overweight or obesity among 34,419 children with height and weight data at age 7 years. Generalized linear models to estimate the adjusted odds ratio (aOR) for overweight or obesity (≥85th percentile) or obesity (≥95th percentile) in the offspring according to exposure during different months of pregnancy were used.

Results
Oral contraceptive use during pregnancy was positively associated with offspring overweight or obesity and obesity. The magnitude of association was strongest in the first 2 months of pregnancy for obesity (aOR 2.0, 95% CI: 1.1, 3.7). DES use was also associated with offspring overweight or obesity and obesity, with the association being strongest for exposure beginning between months 3 and 5 (e.g., for exposure beginning in months 3-4, the aOR for obesity was 2.8, 95% CI: 1.3, 6.3).

Conclusions
Pharmacologic sex hormone use in pregnancy may be associated with childhood obesity. Whether contemporary, lower dose oral contraceptive formulations are similarly associated with increased risk of childhood obesity is unclear.

References

  • Full study (free access) : Pharmacologic sex hormones in pregnancy in relation to offspring obesity, Obesity (Silver Spring), PMID: 20688618, 2014 Nov.
  • Featured image i yunmai.
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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

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Ability to produce offspring significantly diminished by DES exposure

Avian transgenerational reproductive toxicity test with in ovo exposure

2006 Study Abstract

Ecological risk assessment of environmental pollutants requires effective laboratory assays and extrapolation of the resultant data to wild species. Because avian reproductive disorder and accumulation of persistent compounds in wild birds and their eggs have long been observed in polluted regions, we have developed an assay for investigating whether pollutants accumulated in eggs impair the reproduction of the exposed birds and the survival of the next generation using the Japanese quail.

A typical estrogenic compound, diethylstilbestrol (DES), dissolved in olive oil was injected into the air-chamber of fertilized eggs on day 10 of incubation.

After sexual maturation of hatched chicks, we mated pairs of male and female quails following an observation period of egg production and collected their eggs. The collected eggs were incubated and checked for the fertility and hatchability, and then the hatchlings were raised and observed in growth for 3 weeks.

A dosage of 5 ng/g per egg of DES caused eggshell thinning in eggs laid by exposed females and reduction in eggshell strength. DES also induced shortening of the left oviduct and unexpected development of the right oviduct, while testis weight was reduced symmetrically.

The ability of quail pairs to produce offspring was significantly diminished by exposure of females to DES independently of exposure of males, which mainly arose from production of abnormal and inviable eggs. Fertility of normal-shelled eggs and hatchability of fertilized eggs were unchanged regardless of treatments.

External morphological abnormalities, which were mostly unopened toes of the foot, were frequently observed in hatchlings from exposed males independently of exposure of females.

Additionally, we attempted to extrapolate the experimental results to the northern bobwhite and to predict population trends for quails in a polluted habitat using a population projection model composed of a combination of a Leslie matrix and the logistic equation.

In the event of accumulation of an estrogenic compound equivalent to a dosage of 5 ng/g DES in quail eggs,

  • the average population size was predicted to decrease by 20.2% after 1 year,
  • to approximately half after 4 years,
  • and to a fifth after 14 years.

When observed weakening of individuals and the risk of egg breakage are taken into consideration, the decline in population was further accelerated. The proposed assay appears to be suitable not only for assessing adverse effects of chemicals on avian reproduction but for population projection of affected wild birds.

References

  • Avian transgenerational reproductive toxicity test with in ovo exposure, Archives of toxicology, NCBI PubMed PMID: 16758213, 2006.
  • Featured image credit jiangxulei1990.
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Epigenetics, brain, behavior, and the environment

Some studies looked at whether DNA methylation (a process at the DNA level which affects which genes get turned on and turned off) has a link to increased risk for schizophrenia or schizophrenia-like conditions among the DES-exposed

Both men and women exposed to diethylstilbestrol (DES) in utero (hence having a body burden of the chemical) are more prone to depression compared to their unexposed siblings. Indeed, an issue of national concern is the significant environmental exposure to common-use chemicals in the household, a factor suggested as contributing to the increased incidence of affective disorders in the general population.

2010 Review Abstract

Early experiences can modify regulatory factors affecting gene expression in such a way that, although the DNA sequence itself is not changed, the individual’s physiology and behavior is substantially influenced.

In some instances these epigenetic effects are exerted upon exposure, while in other instances they are transmitted across generations via incorporation into the germline. Examples of both types of epigenetic effects are presented.

First, experience with siblings (littermates) organizes behaviors and their underlying neural substrates in such a way that, as adults, rats and knockout mice behave differently. Second, exposure to the fungicide vinclozolin early in pregnancy imprints the male lineage in such a manner that rats exhibit distinct behavioral profiles as well as unique patterns of gene expression in relevant brain regions.

Taken together, this work demonstrates that present and past environments alike modify both social and affiliative related behaviors and their related metabolic activity in specific brain nuclei as well as influencing the abundance of specific genes altering the epigenome in the target brain areas.

References

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