Follow-up study of male and female offspring of DES-exposed mothers

This follow-up study presents the effects of DES on the genital tract of male and female offspring of mothers who were part of a double-blind, placebo-controlled investigation during 1951 and 1952 aimed at determining the effect of DES on pregnancy

1977 Study Abstract

Epididymal cysts, hypotrophic testes, and capsular induration were the more common genital lesions found in 25% of 163 DES-exposed males as compared to 6% in 168 control males. Semen analysis data on 39 subjects of the DES-exposed group and 25 subjects of the control group showed that 26% of the DES-exposed group produced an ejaculate volume under 1.5 ml; no such cases were observed in the control group. The average values for sperm density ant total motile spermatozoa per ejaculate, although in the normal range, were more than two times lower in the DES-exposed group as compared to the controls. A quality score of greater than 10 (“severely pathologic semen”) was found in 28% of the DES-exposed group as compared to 0 in the control group. An association of pathologic semen quality with physical abnormalities was found only in the DES-exposed group. Two cases of azoospermia, one without genital abnormalities on physical examination and one with bilateral hypotrophic testes were observed so far in the DES-exposed group.

Eighteen percent of 229 DES-exposed female patients had irregular menstrual cycles (oligomenorrhea) as compared to 10% of 136 controls. The history of pregnancy revealed a lower incidence of pregnancy in the DES-exposed group (18%) than in the control group (33%). Circumferential ridges of the vagina and cervix were seen in 40% of 229 DES-exposed females but in none of 136 controls. Colposcopic findings in the vagina revealed adenosis in 66.8% of the DES-exposed females and in 3.6% of the control group. Dysplastic lesions were more prevalent in the vagina and cervix of the DES-exposed subjects.

No cases of cancer were observed in either the male or female offspring.

Sources

  • Follow-up study of male and female offspring of DES-exposed mothers, Obstetrics and gynecology, NCBI PubMed, PMID: 318736, 1977 Jan.
  • Features image credit Isaac Cabezas.
DES DIETHYLSTILBESTROL RESOURCES

Health effects : pregnancy use of diethylstilbestrol

The Journal of the Indiana State Medical Association, 1979

Abstract

The use of DES (diethylstilbestrol) to prevent pregnancy complications and miscarriages has shown effects in women who took DES and their offspring.

A University of Chicago follow-up study indicated that women who had used DES had more breast and gynecological cancers than a control group, although the results were statistically insignificant.

DES daughters have a higher occurrence of a rare malignant vaginal cancer, clear cell adenocarcinoma,

and DES-exposed males showed a history of cryptorchidism, hypoplastic testes, epididymal cysts, and low sperm counts.

A DES Task Force formed by the Office of the Assistant Secretary for Health in 1978 recommends that all persons exposed to DES be informed of health risks and that DES daughters be carefully monitored by using Pap smears, iodine staining, and colposcopy when necessary.

In addition, the Task Force recommends

  • that DES women not use estrogens,
  • that postmenopausal replacement estrogens be prescribed prudently,
  • that DES not be given to suppress lactation,
  • and that women given DES for postcoital contraception be informed of the possible health risks.

Sources

  • Health effects: pregnancy use of diethylstilbestrol, The Journal of the Indiana State Medical Association, NCBI PubMed, PMID: 458172, 1979 May.
DES DIETHYLSTILBESTROL RESOURCES

Physician advisory : health effects of the pregnancy use of diethylstilbestrol

Clinical toxicology, 1979

Abstract

A DES (diethylstilbestrol) Task Force formed in February by the Office of the Assistant Secretary for Health, examined the health effects of DES in pregnancy. This report is an outline of the Task Force’s recommendations.

Physicians should advise women to whom they prescribe the drugs of their exposure and of the need for follow-up medical care for themselves and their offspring. Physicians are also to provide patients inquiring of possible past DES exposure, complete and accurate information whenever possible, and such information should be provided free of charge.

The incidence of clear cell adenocarcinoma for DES-exposed daughters is between 1.4/100 to 1.4/10,000. Periodic examination, rather than active therapeutic intervention (e.g., surgery) is recommended for patients with adenosis. For asymptomatic DES daughters, periodic screening examinations should start at age 14 or at menarche; vaginal bleeding/discharge should be promptly evaluated. Hystersosalpingography should not be used as a routine screening procedure in DES daughters but should be reserved for cases of repeated pregnancy loss or infertility.

Asymptomatic DES mothers should have routine screening (e.g., annual pelvic exam including bimanual palpation and Pap smear; breast exam) appropriate for women with no prior estrogen exposure.

DES exposed males have been known to have:

  1. history of cryptochirdism;
  2. hypoplastic testes;
  3. epididymal cysts;
  4. and sperm abnormalities (low sperm counts, decreased motility).
    DES males should have physical examination, appropriate medical follow-up or corrective measures, as the case may be.

Use of DES postcoital contraception should be limited to situations where the fully informed patient or her physician deems that there is no alternative.

Sources

  • Induction of urogenital anomalies and some tumors in the progeny of mice receiving diethylstilbestrol during pregnancy, Clinical toxicology, NCBI PubMed, PMID: 37020, 1979 Mar.
  • Features image Michael Marusin
DES DIETHYLSTILBESTROL RESOURCES

Does the Administration of Diethylstilbestrol during Pregnancy have Therapeutic Value ?

Diethylstilbestrol usage was questioned by WJ Dieckmann in 1953

Conclusions

A strictly controlled clinical trial of the therapeutic value of diethylstilbestrol administered to patients during pregnancy in reducing the hazards of some of the late complications of pregnancy for mothers and babies has been reported.

The various complications were studied in the total unselected group of patients divided into primigravidas, primiparas, and multiparas. Then the groups were again studied after all groups were corrected to compare with the Smiths’.

The results of the administration of diethylstilbestrol in graduated amounts to 840 patients according to a schedule suggested by the Smiths were compared with the results of an identical placebo tablet given to 806 patients. Stilbestrol did not reduce the incidence of abortion, prematurity, or postmaturity. Premature babies of stilbestrol-treated mothers were no longer nor more mature for their gestational ages than comparable prematures in the control group of placebo-treated mothers. It did not decrease the incidence of perinatal mortality. It did not decrease the frequency of the toxemias of pregnancy.

Discussion Abstracts

“We too are disappointed, and apologetic., because we were instrumental in putting them to so much trouble in acquiring results that are still inconclusive.
“We also wish we had given a placebo to our controls.”
“We omitted from our analyses all patients who aborted prior to viability and did not accept those who had threatened to abort at any time early in pregnancy or include such cases in our control series.”

DR. GEORGE van S. SMITH, Brookline, Mass.

“We have never said that it should be given to all during pregnancies.”
“We do not recommend stilbestrol for pregnancy complications, …”

DR. OLIVE W. SMITH, Brookline, Mass.

“The one general conclusion to be drawn from this very painstaking study of Dieckmann and co-workers must be obvious to each of us; stilbestrol is no panacea.”
“We have a similar study in progress. At the present time 350 patients have completed their pregnancies. Treatment was begun prior to the sixteenth week. There seems no need to give the details of the results. The material was analyzed in much the same manner as that of Dieckmann and the results were virtually identical. In short, there was no difference in size of newborn infants, duration of pregnancy, occurrence of premature labor or of toxemia in the two groups. This short series gave the same results as the much longer series. It would seem to me, therefore, that these results indicate that stilbestrol for routine use has little value.

DR. WILLARD ALLEN, St. Louis, Mo

“We have followed Dr. Olive Smith’s work very carefully.

This experiment was designed in an attempt to learn whether diethylstilbestrol has therapeutic value. Our problem was to find out whether it is worth the time and effort and money to administer the drug to large segments of our population in an attempt to cut flown on the hazards of some of these pregnancy complications.

We have not proved that it is of value. All of om data are filed on IBM cards. These are available to any of you who wish to examine them. Concerning the length of time that the drug was taken by the patients, 15 weeks is the average time and 5 weeks i~ the minimum period.

We think that the number of patients studied and the methods useJ showed that stilbestrol has no therapeutic value in pregnancy. It is possible that that answer may not he correct, but it will take at least as many more patients just as carefully controlled to prove that stilbestrol administered prophylactically to normal or abnormal pregnant patients has any value in the prevention of the specific complications of pregnancy.”

DR. DAVIS (Closing)

Sources

From the Department of Obstetrics and Gynecology of the University of Chicago and the Chicago Lying-in Hospital Chicago, Ill.
DES DIETHYLSTILBESTROL RESOURCES

Mise au point des connaissances en 2002

image de connaissances

Thesis, Walter-Kull Agnès, June 2002

Abstract

Le diéthylstilbestrol (Distilbène®) était le premier oestrogène de synthèse nonstéroïdien à apparaître sur le marché français en 1950. Son utilisation s’imposait d’abord aux USA à la suite des travaux menés par Smith dans le cadre de la prévention de certaines complications de la grossesse.

Après 25 ans d’utilisation, Herbst découvrait que le diéthylstilbestrol était responsable d’adénocarcinomes vaginaux à cellules claires chez les filles exposées in utero.

Après avoir retracé les principales étapes de « l’affaire Distilbène® » et rappelé les principales propriétés pharmacologiques de la molécule, l’ensemble des effets secondaires lié à l’utilisation du diéthylstilbestrol est abordé. Un cas clinique vient illustrer ces propos en exposant une malformation utérine (utérus en T) chez une jeune femme consultant pour stérilité secondaire et ayant été exposée au diéthylstilbestrol in utero. Une augmentation du risque de cancer du sein chez les mères traitées pendant leur grossesse est en outre rapporté ainsi qu’un nombre accru de malformations uro-génitales chez les garçons exposés in utero.

L’ensemble de ces données a amené le corps médical et paramédical à préconiser une prise en charge gynécologique, obstétricale et médico-psychologique de la population exposée. En 2002, soit 25 ans après l’interdiction de son utilisation chez la femme enceinte, de nouvelles données apparaissent et on parle pour la première fois d’une transmission transgénérationnelle des effets secondaires du médicament.

Sources

Le Distilbène DES, en savoir plus

Entre mère et fille, le DES, aspects psychologiques

image d'aspect psychologique

The psychological impact of DES exposure in women : a comparison of short-term and long-term effects in several generations of DES-exposed

2008 Study Abstract

Les aspects psychologiques liés à la prise du DES n’ont jusqu’ici que rarement fait l’objet d’études spécifiques. Ce sont principalement les équipes américaines qui ont fait des recherches dans ce domaine. Les auteurs se sont préoccupés essentiellement du vécu des femmes exposées in utero, de leurs réactions à l’annonce de cette exposition, et des conséquences qui en résultent : effets neurologiques, endocriniens qui peuvent entraîner des conséquences au développement intellectuel, psychique et sexuel de ces femmes ayant reçu du DES.

Ils concluent qu’il n’y a aucun effet du DES sur le plan cognitif. En revanche, il semblerait que sur le plan du comportement sexuel les femmes ayant reçu du DES in utero ont plus de difficultés dans leur vie sexuelle – “Psychosexual milestones in women prenatally exposed to diethylstilbestrol” – “Sexual activity level and sexual functioning in women prenatally exposed to diethylstilbestrol” – que les femmes du groupe témoin. De même, ils trouvent que ces femmes sont plus dépressives et montrent plus de difficultés psychologiques. Ils concluent que cette vulnérabilité psychologique est due à l’inquiétude consécutive aux problèmes gynécologiques et obstétricaux qu’elles rencontrent.

Par ailleurs, une équipe s’est plus particulièrement attachée à la recherche des effets psychiatriques sur le comportement humain des individus ayant reçu du distilbène in utero. Trois sur quatre jeunes adultes masculins psychotiques présentaient un électroencéphalogramme (EEG) perturbé. Tous les quatre avaient reçu du DES in utero. Les auteurs pensent que cette prérecherche est suffisamment significative pour qu’elle soit poursuivie. D’autres cliniciens se sont attachés à repérer quelle pourrait être la détresse des mères qui ont pris ce médicament. Ils ont rencontré des femmes qu’ils décrivent comme anxieuses, craintives et à la fois très mécontentes vis-à-vis du DES. Les plus âgées sont les plus atteintes.

Sources

  • Entre mère et fille, le DES, aspects psychologiques, Springer International Publishing AG, Le Distilbène® trente ans après, pp 83-91, février 2008.
  • Featured image Alex Blăjan.
DES DIETHYLSTILBESTROL RESOURCES

Greater Levels of Anger, Anxiety, Concern, Distress, Fear and Worry in DES Daughters

image of distress

Long-term distress subsequent to pregnancy drug administration: women with in utero diethylstilbestrol (DES) exposed daughters

1986 Study Abstract

Diethylstilbestrol (DES) is linked to cancer and reproductive loss in females exposed in utero. To examine levels of distress among mothers with in utero DES exposed daughters, we conducted interviews with 60 DES mothers. DES related distress was measured by a scale of 19 items and included such facets of emotional response as worry, fear, anger, and guilt. We also assessed levels of demoralization, a measure of generalized psychological symptomatology. In addition, information was gathered on age, education, psychological treatment history, DES health effects to daughter, certainty of drug exposure and knowledge regarding the efficacy and safety of DES.

We found worry, concern, fear, and anxiety to be the strongest type of response at both discovery and the current time. Likewise, anger was a prominent emotion at both time periods while guilt was not as focal a response as had been suggested by a previous study. We collapsed our multiple DES distress items into two reliable scales and found a highly significant decline from distress levels at discovery to the current time. We compared the extent to which variables explaining levels of current DES distress also explain demoralization levels. As would be expected, DES distress at discovery was the strongest predictor of current DES distress. Significant effects were also found for age and DES knowledge, as well as a trend for DES health effects to daughter to exacerbate levels of DES distress. Psychological treatment history had no significant effect. In contrast, present demoralization was best explained by past psychological treatment, while all other factors, including DES situational factors, were not significant predictors.

We conclude that there is no direct relationship between current DES distress and psychological problems but that the controversial record regarding the safety and efficacy of DES did contribute to greater distress.

Sources

  • Long-Term Distress Subsequent to Pregnancy Drug Administration: Women with in Utero Diethylstilbestrol (DES) Exposed Daughters, Journal of Psychosomatic Obstetrics & Gynecology, doi.org/10.3109/01674828609016742, 1986.
  • Featured image Milada Vigerova.
DES DIETHYLSTILBESTROL RESOURCES

DES Developmental Programming and Fetal Origins of Adult Disease

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

Introduction

The 2007 Summit on “Environmental Challenges to Reproductive Health and Fertility” convened scientists, health care professionals, community groups, political representatives and the media to hear presentations on the impact of environmental contaminants on reproductive health and fertility and to discuss opportunities to improve health through research, education, communication and policy. Environmental reproductive health focuses on exposures to environmental contaminants, particularly during critical periods of development, and their potential effects on future reproductive health, including conception, fertility, pregnancy, adolescent development and adult health. Approximately 87,000 chemical substances are registered for use in commerce in the US, with ubiquitous human exposures to environmental contaminants in air, water, food and consumer products. Exposures during critical windows of susceptibility may result in adverse effects with lifelong and even intergenerational health impacts. Effects can include impaired development and function of the reproductive tract and permanently altered gene expression, leading to metabolic and hormonal disorders, reduced fertility and fecundity and illnesses such as testicular, prostate, uterine and cervical cancers later in life. This executive summary reviews effects of pre- and post-natal exposures on male and female reproductive health and provides a series of recommendations for advancing the field in the areas of research, policy, health care and community action.

Abstracts

Developmental Programming and Fetal Origins of Adult Disease

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.

Reproductive Effects of Early Life Exposures in Females

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, NCBI PubMed, PMC2440710, 2009 Feb 1.
  • Featured image credit Kiệt Hí.
DES DIETHYLSTILBESTROL RESOURCES

The Role of Parental and Grandparental Epigenetic Alterations in Familial Cancer Risk

image of arental and Grandparental Epigenetic

Some epigenetic alterations that influence cancer risk are inherited through the germline from the DES-exposed to offspring and are observed in multiple DES generations of victims

2008 Study Abstract

Epigenetic alterations of the genome such as DNA promoter methylation and chromatin remodeling play an important role in tumorigenesis. These modifications take place throughout development with subsequent events occurring later in adulthood. Recent studies, however, suggest that some epigenetic alterations that influence cancer risk are inherited through the germline from parent to child and are observed in multiple generations. Epigenetic changes may be inherited as Mendelian, non-Mendelian, or environmentally induced traits. Here, we will discuss Mendelian, non-Mendelian, and environmentally induced patterns of multigenerational epigenetic alterations as well as some possible mechanisms for how these events may be occurring.

Diethylstilbestrol

One example of multiple generations in families showing effects of an environmental agent are daughters of mothers who were exposed to diethylstilbestrol (DES) during the first trimester.

The daughters show developmental abnormalities and an increased risk of developing a rare type of clear-cell adenocarcinoma. DES daughters also show a 2.5-fold increase in breast cancer risk after 40 years of age. To prove that this indeed is an inherited transgenerational effect, granddaughters and great granddaughters of the exposed mothers will need to show a DES phenotype. This analysis has not yet been completed.

Mouse studies have shown that the F2 generation from a DES-exposed pregnant female had strikingly similar effects as the F1 generation, including abnormal uterine development and uterine cancer. The proposed mechanism of action of DES is aberrant CpG methylation of key uterine cancer genes. The changes in CpG methylation may be stable throughout gametogenesis, providing insight into the transgenerational effects of DES.

Sources and more information
  • Full study (free access) : The Role of Parental and Grandparental Epigenetic Alterations in Familial Cancer Risk, Perspectives in Cancer Research, NCBI PubMed PMC4423451, 2008 Nov.
  • Epigenetics featured image credit NestleNutritionInstitute.
DES DIETHYLSTILBESTROL RESOURCES

Epigenetic alterations induced by in utero diethylstilbestrol exposure

image of Epigenetic alterations induced by in utero diethylstilbestrol exposure

Proposed model to explain an increase in breast cancer risk in daughters, and possibly granddaughters and great granddaughters, of mothers who took diethylstilbestrol during pregnancy

Gene expression can be altered as a consequence of mutations or epigenetic changes. In contrast to gene mutations within the DNA, epigenetic changes involve post-transcriptional modifications; that is, methylation of gene promoter regions, histone modifications, deposition of certain histone variants along specific gene sequences and microRNA (miRNA) expression. Although both changes are heritable, an important distinction between the two is that mutations are not reversible, but epigenetic modifications generally are.

Probably the most common mechanism of epigenetic gene silencing is methylation, and it might also be the most important. DNA methyltransferases (DNMTs) catalyze the methylation of genomic DNA by adding a methyl group (CH3) onto the 5-carbon of the cytosine ring within CpG dinucleotides. Histone modifications are complex, as they involve not just histone methylation but also acetylation, deacetylation and other post-translational changes. These modifications occur in the amino-terminal tails of histones and affect the ‘openness’ of the chromatin, which determines whether a gene is expressed or silenced (for example, acetylation allows transcription, while deacetylation represses transcription). Trimethylation of histone H3 at lysine K27 is catalyzed by the Polycomb group (PcG) protein enhancer of Zeste-2 (EZH2) and results in gene silencing. PcG/H3K27me3 interact with DNMTs, and together they establish and maintain silencing of PcG target genes. Over 2,000 different PcG target genes have been identified and they include some tumor suppressor genes. Many of the PcG target genes regulate cell fate, including apoptosis, proliferation and stem cell differentiation. As discussed in more detail below, methylation of PcG target genes is linked to increased breast cancer risk.

DNMTs may be key players in regulating histones and the entire epigenomic machinery, since DNA methylation events often precede histone modifications. Upregulation of DNMTs increases the expression of EZH2 and other polycombs; this may happen by DNMTs inducing methylation of non-coding miRNAs that target the polycombs.

We and others have observed that the expression of DNMTs is persistently altered in estrogen-regulated tissues following estrogenic exposures during early life. In utero exposure to DES is reported to increase the expression of DNMT1 in the epididymis and uterus . We found that DNMT1 expression is increased in the mammary glands of adult rat offspring of dams exposed to ethinyl estradiol during pregnancy. These changes provide a key regulatory layer to influence gene expression in the mammary gland and perhaps breast tumors of individuals exposed to DES or other estrogenic compounds in utero.

Promoter methylation

In utero DES exposure alters methylation patterns of several genes in estrogen’s target tissues, including Hox genes, c-fox, and Nsbp1, but it has not been studied whether changes in methylation patterns occur in the mammary gland. We have explored changes in methylation in the mammary glands of adult rats exposed in utero to the synthetic estrogen ethinyl estradiol using global sequencing approaches. Among the genes that exhibited increased promoter methylation were several PcG target genes, suggesting that a maternal exposure to synthetic estrogens during pregnancy causes long-lasting changes in the methylation of genes that regulate cell fate, including stem cell differentiation.

Histone modifications

As an increase in EZH2 expression in the mammary glands of mice exposed to DES in utero has been reported, histone modifications also seem to be influenced by maternal exposure to synthetic estrogens during pregnancy. Jefferson and colleagues recently investigated whether upregulation of lactoferrin and sine oculis homeobox 1 (Six1) in the uterus of adult mice exposed to DES neonatally is caused by histone modifications. Their data indicate that neonatal DES exposure induces changes during the early postnatal period in the expression of multiple chromatin-modifying proteins but these changes do not last to adulthood. However, alterations in epigenetic marks at the Six1 locus in the uterus were persistent. Similarly, changes in the methylation of Nsbp1 and expression of DNMTs in the uterus of DES-exposed offspring are different in the early postnatal period compared to adulthood. This suggests that some epigenetic alterations are further influenced by factors operating during postnatal development, such as a surge of estrogens and progesterone from the ovaries at puberty onset.

microRNAs

Maternal exposures during pregnancy have been found to induce persistent changes in miRNA expression in the offspring. miRNAs are short non-coding single-stranded RNAs composed of approximately 21 to 22 nucleotides that regulate gene expression by sequence-specific base-pairing with the 3’ untranslated region of target mRNAs. miRNA binding induces post-transcriptional repression of target genes, either by inducing inhibition of protein translation or by inducing mRNA degradation. Expression of many miRNAs is suppressed by estrogens. Although the effects of maternal DES exposure during pregnancy on miRNA expression in the offspring have not been investigated, it is known that many other manipulations, such as maternal low protein diet, alter miRNA patterns among the offspring. We recently found that in utero exposure to ethinyl estradiol lowers the expression of many of the same miRNAs in the adult mammary gland as are downregulated by E2 in MCF-7 human breast cancer cells. Since miRNAs can be silenced by methylation or as a result of increased PcG expression, and they target DNMTs, histone deacetylases and polycomb genes, the observed increase in DNMT expression, histone marks and EZH2 in the in utero DES-exposed offspring may be a result of epigenetic silencing of miRNAs that target them.

2014 Study Conclusions

In summary, women exposed to DES in utero are destined to be at an increased risk of developing breast cancer, and this risk may extend to their daughters and granddaughters as well. It is of critical importance to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.

Sources and more information
  • Full text (free access) : Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters, Breast Cancer Research, NCBI PubMed, PMC4053091, 2014 Apr 30.
  • Proposed model to explain an increase in breast cancer risk in daughters, and possibly granddaughters and great granddaughters, of mothers who took diethylstilbestrol during pregnancy featured image credit PMC4053091/figure/F1.
DES DIETHYLSTILBESTROL RESOURCES