DES exposure can disrupt developing organ systems and cause abnormalities that only appear in the subsequent generation

Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: Executive Summary

2008 Manuscript Abstracts

The DES Example – Prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen and thus EDC, provides an unfortunate example of developmental programming. DES was given to U.S. pregnant women between 1938 and 1971 under the erroneous assumption that it would prevent pregnancy complications.

In fact, in utero exposure to DES alters the normal programming of gene families, such as Hox and Wnt, that play important roles in reproductive tract differentiation.

As a result, female offspring exposed to DES in utero are at increased risk of clear cell adenocarcinoma of the vagina and cervix, structural reproductive tract anomalies, infertility and poor pregnancy outcomes, while male offspring have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. These observed human effects have been confirmed in numerous animal models which have also provided information on the toxic mechanisms of DES. Animal experiments have also predicted changes later found in DES-exposed humans, such as oviductal malformations, increased incidence of uterine fibroids and second-generational effects such as increased menstrual irregularities and possibly ovarian cancer in DES-granddaughters and increased hypospadias in DES-grandsons.

DES is but one example of how exposure to EDCs can disrupt developing organ systems and cause abnormalities, many of which only appear much later in life or in the subsequent generation, such as endometriosis, fibroids and breast, cervical and uterine cancer in women; poor sperm quality and increased incidence of cryptorchidism and hypospadias in men; and subfertility and infertility in men and women.

Epigenetic studies have also shown that DES causes alterations in uterine tissue architecture and morphology and heightens susceptibility to uterine adenocarcinoma by inducing permanent changes in several estrogen-responsive uterine genes. These are but a few examples of how the field of epigenetics has and will continue to contribute to our mechanistic understanding of the impact of environmental contaminants on reproductive health.

Uterus Development and the Environment – Women exposed to DES in utero during critical periods of reproductive tract development developed several types of reproductive tract abnormalities, as well as an increased incidence of cervical-vaginal cancer later in life. Animal studies that simulate the human DES experience have since shown that exposure of the developing reproductive tract of CD-1 mice to DES imparts a permanent estrogen imprint that alters reproductive tract morphology, induces persistent expression of the lactoferrin and c-fos genes and induces a high incidence of uterine adenocarcinoma. Experiments in rats have shown exposure to DES during the critical window of uterine development leaves a hormonal imprint on the developing uterine myometrium in rats that were genetically predisposed to uterine leiomyoma, increasing the risk for adult uterine leiomyoma from 65% to greater than 90% and increasing tumor multiplicity and size. DES-induced developmental programming appears to require the estrogen receptor α, suggesting that signaling through this receptor is crucial for establishing developmental programming.

Sources

  • Full study (free access) : Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: Executive Summary, Fertility and Sterility, PMC2440710, 2008 Feb.
  • Featured image Dmitry Ratushny.
DES DIETHYLSTILBESTROL RESOURCES

Epigenetics, Evolution, Endocrine Disruption, Health, and Disease

image of Epigenetics, Evolution, Endocrine Disruption, Health, and Disease

A possible mechanism for how DES exerts its action epigenetically has been proposed recently

2006 Study Abstracts

Endocrine-disrupting chemicals (EDCs) in the environment have been linked to human health and disease. This is particularly evident in compounds that mimic the effects of estrogens. Exposure to EDCs early in life can increase risk levels of compromised physical and mental health. Epigenetic mechanisms have been implicated in this process. Transgenerational consequences of EDC exposure is also discussed in both a proximate (mechanism) and ultimate (evolution) context as well as recent work suggesting how such transmission might become incorporated into the genome and subject to selection. We suggest a perspective for exploring and ultimately coming to understand diseases that may have environmental or endocrine origins.

That epigenetic mechanisms may play a role in endocrine disruption helps explain the transgenerational effects of some hormonally active chemicals. Treatment with diethylstilbestrol (DES) during pregnancy results in vaginal adenocarcinoma in female offspring in humans and mice. Female offspring of mice exposed to DES during pregnancy, when mated to control males, produce a second generation of females who, although not exposed to DES themselves, express this same rare genital tract cancer. This transgenerational transmission of a specific reproductive tract lesion would be hard to explain without invoking an epigenetic mechanism for heritable change and, given the finding of altered DNA methylation patterns in a specific uterine gene in mice treated developmentally with DES, we think a strong case can be made for such a conclusion. Newbold and colleagues next showed that specific, rare genital tract cancers (rete testes cancers) are also expressed and therefore transmitted to the male offspring of females treated in utero with DES. In colloquial terms, this demonstrated the occurrence of reproductive tract tumors in the grandsons and granddaughters of mothers treated with DES. A possible mechanism for how DES exerts its action epigenetically has been proposed recently. The transmission of uniquely specific changes in the program of development in mice has implications for similarly exposed humans as well as the biology of hormonally induced disease.

We have already mentioned that DES treatment of mice during development results in reproductive tract cancers, persistent up-regulation of key estrogen-responsive genes, and altered patterns of gene methylation in the affected genes and that the cancer can be transmitted through two generations. In addition to DES, methoxychlor has been reported to increase global DNA methylation in uterine ribosomal DNA after in utero exposure; the alteration in methylation remains months after treatment.

To understand the role of estrogens in development, there is hardly a more powerful model than that of the outcomes observed in humans and mice developmentally exposed to the synthetic estrogen DES. Female offspring of humans or mice exposed prenatally to DES have a risk for vaginal clear cell adenocarcinoma. The mechanisms underlying these developmentally induced lesions have been sought for three decades. There was the suggestion by clinical investigators that DES had altered the normal differentiation of the epithelial cells of the fetal cervix and vagina such that they responded abnormally to estrogen at puberty, because no cancers had been seen in prepubescent girls. Similarly, ovariectomy of developmentally DES-treated mice prevented the subsequent expression of uterine adenocarcinomas.

Epigenetic change in the molecular program of cell differentiation in the affected tissues may be a common mechanism. The clear cell cancers of the vagina in DES-exposed women displayed genetic instability consistent with epigenetic imprints in the absence of any expected mutation in classical oncogenes or tumor suppressor genes. Using a well validated mouse model for DES genital tract tumors, Li and colleagues discovered that one of the estrogen-inducible genes in the mouse uterus, lactotransferrin, that had been shown earlier to be persistently up-regulated by developmental DES exposure, had an altered pattern of CpG methylation in the promoter region of the gene upstream from the estrogen response element. Subsequent work demonstrated that other developmentally up-regulated genes such as fos and jun also had persistent changes in the pattern of methylation of the gene after DES exposure during development. These experiments raise the possibility that DES (and other environmental estrogens) alter the program of differentiation of estrogen target cells in the reproductive tract through an epigenetic mechanism.

Other studies support this hypothesis. In addition to cervicovaginal adenocarcinomas in female mice and humans exposed prenatally to DES and uterine adenocarcinoma in mice, it has been shown that developmental exposure to DES results in excess risk of uterine leiomyomas (fibroids) in mice, rats, and women. It was also recently reported that sea lions in areas contaminated with EDCs have a higher prevalence of uterine fibroids. The Eker rat carries a germ-line mutation in a tumor suppressor gene and is predisposed to uterine leiomyoma. Cook and colleagues used this model system to demonstrate a DES-induced alteration in developmental imprinting as analyzed by tumor suppressor gene penetrance, concluding that developmental programming by estrogen works in concert with preexisting genetic change. In a population of 819 black and 504 white women, fibroid status was determined by ultrasound screening or surgical record review, whereas prenatal DES exposure was determined by interview. DES-exposed women had a significantly greater risk for uterine fibroids and tended to have larger tumors. The authors conclude that their study, as well as animal studies, indicate a role for prenatal estrogen in the etiology of uterine leiomyoma in women.

Sources

  • Full study (free access) : Epigenetics, Evolution, Endocrine Disruption, Health, and Disease, Endocrinology, Volume 147, Issue 6, Pages s4–s10, doi.org/10.1210/en.2005-1122, June 2006.
  • Featured image academic.oup.
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Transgenerational neuroendocrine disruption of reproduction

2011 summary of epigenetic and transgenerational effects of DES

Key points

  • The hypothalamic neuroendocrine systems develop in a sexually dimorphic manner, largely because of differences in levels of gonadal steroids
  • Environmental endocrine disrupting chemicals (EDCs) impair the function of the neuroendocrine systems that control reproduction
  • Developmental exposure to EDCs, particularly during embryonic and early postnatal periods, permanently impairs functions and predisposes individuals to disease later in life owing to altered epigenetic programming
  • The mechanisms of EDC action include effects on the epigenetic molecular machinery that controls gene expression in hypothalamic and reproductive tissues
  • Effects of EDCs may be transmitted transgenerationally through molecular changes to the germline or through context-dependent modifications to somatic cells by continued exposures to EDCs or the individual’s social or environmental context

DES and epigenetic transmission

Transgenerational epigenetic effects of the estrogenic EDC diethylstilbesterol (DES) began with observations of rare vaginal clear-cell carcinomas and reproductive tract abnormalities in young women whose mothers had been prescribed DES in a misguided effort to avert miscarriage. These observations provided the first evidence for developmental programming or the fetal basis of adult disease caused by exogenous estrogens in humans. A potent estrogenic pharmaceutical, DES not only failed to reduce miscarriage risk, but it also exposed the developing daughters and sons to high levels of prenatal estrogens and predisposed them to adult diseases. Animal studies have replicated many of these effects of prenatal DES treatment and have begun to reveal the molecular mechanisms by which DES programs developing tissues. The case of DES is important because it is one of the first to link fetal exposure to a hormonally active compound with the latent development of disease years or even decades after the insult. This example in humans has laid the groundwork for much of the work on the effect of other EDC exposures to the fetus.

Epidemiological studies have also found that DES is associated with a small but significant increase in birth defects in grandchildren of women given DES during pregnancy. The granddaughters reported an increase in heart conditions,  slight but significant differences in their menstrual cycles and a reduction in live births when compared with women whose grandmothers were not exposed to DES.  Another study found an increase in the risk of hypospadias in the sons of women who were exposed to DES in utero,  and there was the single clinical observation that the 15-year-old granddaughter of a woman who took DES while she was pregnant developed a small-cell carcinoma of the ovary  Although the sample sizes in the last two studies were exceedingly small (28 and 1, respectively), they provide preliminary evidence for the potential of transgenerational effects of EDCs in the human population.

Rodent studies have revealed transgenerational epigenetic effects of DES. DES exposure of the F1 generation during embryonic and early postnatal development at a range of dosages had adverse consequences in the F2 generations. In F2 males, the incidence of proliferative lesions of the testes was increased, and serum estradiol concentration was reduced. In F2 females, the incidence of uterine adenocarcinomas and other tumors of the reproductive tract was increased in a subset of the dosage groups. Exposure of newborn (postnatal day 1–5) F1 female mice to 2 μg of DES led to demethylation of the estrogen-sensitive gene lactotransferrin promoter at two CpG dinucleotides (−464 and −454) in the uterus, and to upregulation of uterine expression of lactotransferrin in both F1 female mice and their F2 female offspring.  Female F1 animals exposed to the same dosing paradigm had decreased methylation of exon 4 of the Fos gene on postnatal day 5 and increased Fos mRNA expression in the uterus in adulthood.  Additionally, mice exposed gestationally to 10 μg/kg of DES from embryonic days 9–16 resulted in increased methylation of the homeobox A10 promoter and intron and increased Hox-A10 protein expression in the postnatal uterus (day 14).

Treatment of newborn, female and male mice on post-natal days 1–5 with 3 μg per pup per day of DES changed total DNA methylation in reproductive tissues. DES also altered expression of the enzymes that regulate DNA methylation. For example, expression of DNA methyltransferases 1, 3a and 3b was increased in the epididymis, and DNA methyltransferases 1 and 3b were increased in the uterus of mice exposed to DES compared with animals exposed to the vehicle control. Finally, in rats treated with 1 mg/kg DES on postnatal days 10–12, the exposure decreased global histone trimethylation at lysine 27 in the uterus on postnatal day 12 and altered the expression of several estrogen-sensitive genes in the uterus of the neonatal and adult exposed animals. Although most of these studies have only been conducted in tissues from F1 individuals, they provide insight into the potential targets for molecular epigenetic modifications that merit further study in subsequent generations in rodents.

Sources

  • Transgenerational neuroendocrine disruption of reproduction, Endocrinology, NCBI PubMed PMC3976559, 2011 Jan 25.
  • Summary of epigenetic and transgenerational effects of DES featured image PMC3976559/table/T1.
DES DIETHYLSTILBESTROL RESOURCES

Epigenetic mechanisms in the actions of endocrine-disrupting chemicals

Gonadal effects and role in female reproduction

2014 Study Abstract

There is a heightened interest and concern among scientists, clinicians, and regulatory agencies as well as the general public, regarding the effects of environmental endocrine-disrupting chemicals (EDCs). In this review, we identify the main epigenetic mechanisms and describe key ovarian processes that are vulnerable to the epigenetic actions of EDCs. We also provide an overview of the human epidemiological evidence documenting the detrimental effects of several common environmental EDCs on female reproduction. We then focus on experimental evidence demonstrating the epigenetic effects of these EDCs in the ovary and female reproductive system, with an emphasis on methoxychlor, an organochlorine pesticide. We conclude the review by describing several critical issues in studying epigenetic effects of EDCs in the ovary, including transgenerational epigenetic effects.

Diethylstilbestrol DES

The most convincing human evidence that estrogenic EDC exposure during development can permanently affect female reproduction comes from reports of the effects of DES, a nonsteroidal synthetic estrogen. From the 1940s to the 1970s, DES was prescribed at doses of 5–150 mg⁄ day to prevent miscarriages. Numerous abnormalities in the reproductive, cardiovascular, and immune systems have since been reported in both male and female offspring of women treated with DES, and similar effects have been demonstrated in animal models. Some of these effects, such as irregular cylicity or ovarian cancer, are being observed in the granddaughters of DES-treated women as well. In light of this multigenerational aspect, whether epigenetic mechanisms are involved is a significant question.

Experimental evidence from in vivo studies regarding the effects of EDCs in the ovary

Characteristic sets of defects in the ovary are the hallmark of EDC exposure in rodent models. For example, mice injected as little as a single dose of 10 μg/kg DES on E15 and examined at 7 months of age had numerous atretic follicles, and no corpora lutea (an indicator of ovulation). Other studies in rodents of varying doses of DES administered either in utero (E9-16) or neonatally (PND1-5) demonstrated similar defects by adulthood. Estrous cyclicity was completely disrupted and high levels of testosterone were found. A vacuolated interstitial tissue with lipid droplet inclusions and hemorrhagic cysts were also observed. A recent study proposes that while increased lipid droplet are caused by impaired steroidogenesis due to suppressed LH levels, the hemorrhagic follicles are results of direct effects of DES in the ovary. Furthermore, there was a dose-dependent reduction in the number of litters as well as the number of oocytes ovulated after stimulation with exogenous gonadotropins with such oocytes when used in IVF showing lower levels of fertilizability, suggesting reduced oocyte quality. Most striking of all, an excessive number of MOFs is found in adult ovaries; such a finding is considered to be an indicator of reduced reproductive lifespan.

Such estrogenic actions of these EDCs are mediated via the ER signaling pathway. Recent studies have shown that MOFs induced by neonatal exposure to 3 μg/kg DES is mediated by ERβ and not ERα. DES exposure was shown to reduce oocyte apoptosis (potentially suppressing oocyte nest breakdown) via ERβ signaling mechanisms. Furthermore, it was hypothesized that alterations in the germ cell–to–somatic cell ratio may affect the invasion of pregranulosa cells and basement membrane remodeling during primordial follicle formation. In contrast to ERβ signaling mechanisms involved in mediating ovarian effects, Couse and colleagues reported that ERα is essential for the mediation of DES effects in the uterus: αERKO female mice exhibited a complete resistance to the effects of DES while βERKO mice did not.

Epigenetic mechanisms associated with the female reproductive system

Although there are now well-documented studies of the physiological and morphological effects of EDCs on the ovary, the early research providing evidence of an epigenetic component of EDC actions was predominantly on the uterus. For example, it is well known that DES caused T-shaped uteri and clear cell adenocarcinoma of the uterus, cervix, and vagina in women whose mothers were exposed to DES during pregnancy. In the numerous animal studies validating these human reports, developmentally DES-treated mice manifest malformations of the uterus, squamous metaplasia of the luminar and glandular epithelium, endometrial hyperplasia and leiomyomas, and oviductal proliferative lesions. Ovariectomized animals when supplemented with E2 are able to respond by a transient increase in gene expression and concomitant uterine proliferation and growth. When such a stimulus was removed, the uterus returned to its unstimulated state. However, when DES or E2 is administered during neonatal development, expression of immediate early genes such as c-fos, c-jun, and c-myc as well as lactoferrin and EGF are upregulated even into adulthood. This was associated with hypomethylation of the promoter region of the lactoferrin gene in the adult uterus. However, if animals were exposed for the same interval during adulthood, no such methylation or expression defects were observed, indicating the importance of developmental exposure. Subsequently, it was also found that exon 4 of the c-fos gene was extensively hypomethylated while the promoter region and intron 1 were unaffected, thereby potentially allowing for the upregulation of c-fos expression. Furthermore, recent work by Block and coworkers has shown that DES disrupts the regionalization of expression of Hoxa-9 and Hoxa-10 and the homeotic anterior transformations associated with hypermethylation in the promoter and intron 1 regions of Hoxa-10 gene. Additionally, ERα induction is necessary for activation of estrogen-responsive gene expression in the uterus, including that of the lactoferrin and c-fos genes. Since many of the above genes are downstream of ER signaling, which is involved in direct actions of EDCs, it is imperative to thoroughly examine the potential role of epigenetic mechanisms in the regulation of ER expression after EDC exposure. In addition, PI3K/Akt signaling downstream of membrane-associated ER signaling caused reduction in trimethylation of the histone H3K27 in response to E2 and DES exposures. More interestingly, activation of this non-genomic signaling caused reprogramming of the uterine gene expression profile . Another example is that of the investigation by Tang and colleagues, wherein it was demonstrated that neonatal DES/genistein exposure reduced DNA methylation and increased gene expression of nucleosomal binding protein 1 in adult uteri. These studies highlighted the age-dependent aspect of epigenetic reprogramming and also its interaction with steroid hormones.

Sources

  • Full study (free access) : Epigenetic mechanisms in the actions of endocrine-disrupting chemicals: Gonadal effects and role in female reproduction, HHS Author Manuscripts, NCBI PubMed PMC4151320, 2014 Sep 2.
  • Featured image by Christian Perner.
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Environmental Epigenetics and Its Implication on Disease Risk and Health Outcomes

image of Environmental Epigenetics

2012 Study Abstracts

Introduction

This review focuses on how environmental factors through epigenetics modify disease risk and health outcomes. Major epigenetic events, such as histone modifications, DNA methylation, and microRNA expression, are described. The function of dose, duration, composition, and window of exposure in remodeling the individual’s epigenetic terrain and disease susceptibility are addressed. The ideas of lifelong editing of early-life epigenetic memories, transgenerational effects through germline transmission, and the potential role of hydroxylmethylation of cytosine in developmental reprogramming are discussed. Finally, the epigenetic effects of several major classes of environmental factors are reviewed in the context of pathogenesis of disease. These include endocrine disruptors, tobacco smoke, polycyclic aromatic hydrocarbons, infectious pathogens, particulate matter, diesel exhaust particles, dust mites, fungi, heavy metals, and other indoor and outdoor pollutants. We conclude that the summation of epigenetic modifications induced by multiple environmental exposures, accumulated over time, represented as broad or narrow, acute or chronic, developmental or lifelong, may provide a more precise assessment of risk and consequences. Future investigations may focus on their use as readouts or biomarkers of the totality of past exposure for the prediction of future disease risk and the prescription of effective countermeasures.

Implications of Lifelong Editing of Early-Life Epigenetic Memories

The concept of continued editing of early-life epigenetic markings or memories during adult life has been proposed on the basis of evidence from limited experimental studies. Exposure of mice to diethylstilbestrol (DES, a xenoestrogen) or genistein (a phytoestrogen) during the perinatal period induced specific epigenetic markings in their uteri. However, some of these epigenetic markings (hypomethylation of Nsbp1) remained “hidden” during prepuberty life and appeared in adulthood only in the exposed intact females but not in their ovariectomized counterparts, suggesting that adult exposure to ovarian steroids may cause these markings to “surface.” Coincidentally, the prevalence of uterine cancer was higher in neonatally exposed intact mice, but not in mice ovariectormized before puberty.

Epigenetic Factors Shown to Trigger Epigenetic Events and Affect Disease States

Exposure to EDCs during early developmental periods is a major health concern because it can cause persistent changes in gene expression through epigenetic reprogramming in somatic cells, as well as germ-line cells, and subsequently promote transgenerational inheritance. The xenoestrogen DES was widely used in cattle and other livestock industries and is still an EDC in many populations. Early-life exposure of mice to DES increases risk of uterine cancer that is accompanied by demethylation of an estrogen-responsive gene, lactoferrin, in the mouse uterus. In utero exposure of mice to DES triggered hypermethylation of the homeobox A10 with attended uterine hyperplasia and neoplasia in later life. A more recent report documented hypermethylation of nucleosome binding protein 1 (Nsbp1 or Hmgn5) as a hidden uterine epigenetic mark after neonatal DES exposure that only appeared upon sexual maturation of the exposed mice but failed to manifest if the animals were ovarietomized before puberty. Of significant interest is the transgenerational effect of developmental exposure of mice to DES that promoted c-fos expression, hypomethylation of specific exon CpGs, and increased susceptibility to tumorigenesis in the F2 generation. These experimental data support the hypothesis that epigenetic reprogramming is responsible for the devastating consequences observed in the offspring of women who took DES during pregnancy. The DES effects include female genital abnormalities, vaginal cancer, and male urogenital disorders. The adverse effects may be reverberating in the grandchildren of these women.

Sources

  • Full study (free access) : Environmental Epigenetics and Its Implication on Disease Risk and Health Outcomes, ILAR Journal, NCBI PubMed PMC4021822, 2012 Dec.
  • Featured image by h heyerlein.
DES DIETHYLSTILBESTROL RESOURCES

Transgenerational Inheritance of DES Exposure

Mechanisms of the Maternal Exposome and Implications for Health Outcomes

2016 Study Abstract

It is well established that the environment contributes to health. However, few studies have evaluated environmental exposures in women that may influence future health of their offspring. Knowledge gained may inform nursing how to better advocate for patients and families; and provide individualized interventions and education. Therefore, a more comprehensive investigation of the maternal exposome to uncover mechanistic insight into complex disease in offspring is warranted. To advance understanding of biological mechanisms that contribute to high-risk birth outcomes and offspring predisposition to disease, it will be necessary to measure a range of exposures and biomarkers before and during pregnancy.

Evidence for Trans-generational Inheritance of Exposures

Exposures of the gametes, including those that occur during the prenatal period and early development, have been found to play a large role in risk of disease over the lifespan. Studies in animal models have documented epigenetic changes that persist from generation to generation. For example, in murine models, the methylation changes associated with DES exposure persist into the third generation suggesting in utero exposures may have a lasting impact on the health of future generations. The same chemical clearly demonstrates a link between environment and germ-line mutations in humans as a trans-generational alteration in DNA methylation patterns of the fetus caused by exposure to DES in utero. DES is a synthetic estrogen that was administered to pregnant women to prevent spontaneous abortions prior to the mid 1970’s. DES causes hypermethylation of the homeobox protein Hox-A10 (HOXA10), a gene that controls uterine organ development, resulting in reproductive tract anomalies that persist into adulthood. Hypermethylation of HOXA10 was specific to the fetus and did not occur in laboratory experiments using cell lines or the somatic cells of pregnant women who received DES, suggesting that this molecular alteration is unique to in utero exposure.

Investigations are ongoing in grandchildren of women given DES. Current clinical evidence suggests DES granddaughters have more menstrual irregularities, infertility, and stillbirths; and both granddaughters and grandsons exhibit more birth defects. This accumulating evidence supports that epimutations occur from exposure during gonadal sex determination, a highly vulnerable period when the germ line DNA is demethylated and remethylated in a sex specific manner. The chemically-induced modifications in epigenetic programming of the germ line results in differentially altered epigenomes and transcriptomes in all tissues propagated from the affected sperm or ovum, which can influence development of disease in later life. Although data is sparse related to trans-generational effects of environmental exposures in human studies, there is a need to better inform clinicians and patients about this critically vulnerable period during, and prior to, pregnancy. Confirmation of animal models of trans-generational effects will require the enrollment at least 3 generations of participants (grandparent, parent, and child).

Sources

  • Full study (free access) : Mechanisms of the Maternal Exposome and Implications for Health Outcomes, ANS Adv Nurs Sci, NCBI PubMed, PMC4860277, 2016 Apr-Jun.
  • Exposome Penetrance featured image PMC4860277/figure/F2.
DES DIETHYLSTILBESTROL RESOURCES

DES transgenerational transmission of defects

image of transgenerational transmission

Adverse health effects in children of women exposed in utero to diethylstilbestrol (DES)

2016 Abstract

OBJECTIVE
Exposure to diethylstilbestrol (DES) in utero is associated with adverse health effects, including genital anomalies in women and men, and cancers in women. Animal studies showed birth defects and tumors in the offspring of DES exposed mice, revealing transgenerational transmission of DES effects. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to further assess the health effects in children of prenatally exposed women.

METHODS
In a retrospective cohort study, the reports of women exposed to DES in utero on their 4409 children were compared with those of unexposed women on their 6203 children. Comparisons used odd ratios (OR) between children of exposed and unexposed women and standardized incidence rate (SIR) with the general population. These cohorts were recruited on a voluntary basis to answer questionnaires.

RESULTS
There was a global increase of defects in children born to exposed women when compared with those born to unexposed (OR 2.29, 95% CI: 1.80-2.79, P<0.001) and with the general population (SIR 2.39, 95% CI: 2.11-2.68). Increased defects were observed in male genital tract, esophagus, lip or palate, musculoskeletal and circulatory systems. For female genital tract anomalies, there was no significant increase. However, this cohort being relatively young, further follow-up is needed. An increase of cerebral palsy was revealed. The incidence of cancers was not increased, in particular for breast, uterus and ovary.

CONCLUSION
Our results confirmed a transgenerational transmission of defects in male genital tract. With caution due to possible bias associated with this method, our data suggest an increase of defects for esophagus, lip or palate, musculoskeletal and circulatory system in children of exposed women.

Sources

  • Adverse health effects in children of women exposed in utero to diethylstilbestrol (DES), Therapie, NCBI PubMed, PMID: 27203157, 2016 Feb 5.
  • Featured image Thought Catalog.
DES DIETHYLSTILBESTROL RESOURCES

Transgenerational transmission of environmental effects through epigenetic modifications

The history of Distilbène® (Diethylstilbestrol) told to grandchildren – the transgenerational effect

2015 Study Abstract

The Distilbène® story is a dramatic episode which belongs to the history of medicine. It provided several useful lessons such as the importance of evidence-based medicine and the hazard to develop treatments during pregnancy without careful animal verifications. However, this experience has also provided unexpected progress by suggesting new pathophysiological concepts: fetal programming of adult diseases and/or transgenerational transmission of environmental effects through epigenetic modifications.

Overview

  • Introduction
  • History
  • Diseases reported in second generation after foetal exposure to DES
    • Developmental and reproductive anomalies
    • Non-reproductive anomalies
  • Diseases reported in the third generation after the grandmother was treated with DES during pregnancy
    • Human abnormalities
    • Concordance with rodent model
  • Which molecular mechanisms?
    • Exposure window
    • Chemical nature of estrogens
    • The mechanisms involved in foetal programming of adult diseases – epigenetic modifications
    • Transgenerational transmission mechanisms
  • Conclusion
  • Disclosure of interest

Sources

  • Full paper (free access) : The history of Distilbène® (Diethylstilbestrol) told to grandchildren–the transgenerational effect, ANNALES D’ENDOCRINOLOGIE, EM Consulte, article/990390, 22/07/15.
  • Featured image Isaiah Rustad.
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