Effects in Men of Intra-Uterine Exposure to DES

1998 Study Abstract

The reasons for increased incidence of cryptorchidism, hypospadias and testicular cancer are unknown, but experimental data demonstrating the important role of sex steroids in the physiology of testicular descent and urethral development point to the possibility that environmental factors could cause the problem by interfering with the sex steroids. The best example of such an influence is diethylstilbestrol (DES), which has been studied extensively in both humans and experimental animals.

Millions of pregnant women in the USA and Europe were treated with DES between the late 1940s and early 1970s to prevent abortion, pre-eclampsia and other complications of pregnancy. Doubleblind, placebo-controlled trials had already demonstrated in the 1950s that the treatment was not efficacious, but despite that it was used until the 1970s when the US Food and Drug Administration banned its use during pregnancy after it had become evident that the daughters of DES-treated women had an increased risk of developing clear cell adenocarcinoma of the vagina.

Thereafter, several studies on the effects of DES on the children of exposed mothers were published. Many of the papers are based on the socalled Dieckmann cohort comprising more than 1600 pregnant women who were treated with increasing doses of DES or placebo from gestational weeks 7-20 to week 35 . The use of the medication was verified by a dye indicator in the urine. Children from these pregnancies have been followed since the 1970s, and a large number of structural and functional abnormalities in their reproductive organs have been found. For example, 20.8% of 308 men exposed to DES in utero had epididymal cysts, compared with 4.9% of 307 placebo-exposed controls. There were other structural anomalies in reproductive organs that were more frequent in DES-exposed male subjects than in controls, for example meatal stenosis (12.9% versus 1.8%), hypospadias (4.4% versus 0%), testicular abnormalities, including hypoplastic testis, cryptorchidism and capsular induration (11.4% versus 2.9%), and microphallus (4 cases versus 0 cases). The frequency of anomalies was dependent on the timing of exposure, so that the men who were exposed to DES before week 11 of gestation had a significantly higher prevalence of anomalies than those who were exposed only later, emphasizing the sensitivity of organogenesis to external disturbance. In these cohort studies, cryptorchidism was significantly more frequent in DES-exposed men than in controls, but in retrospective case-control studies, maternal oestrogen exposure was not associated with an increased incidence of cryptorchidism in the offspring. The strength of a retrospective case-control study, however, is not as good as that of a prospective cohort study, and DES can therefore be considered to be a risk factor for cryptorchidism. In a metaanalysis of 14 studies, no association was found between first-trimester exposure to sex hormones other than DES, and external genital abnormalities.

Several reports have demonstrated that the semen quality of men exposed to DES in utero is significantly worse than in placebo-exposed controls. However, the sperm concentrations of most of the DES-exposed men were well above the limit at which subfertility occurs, and it is therefore not surprising that the fertility of these men was reported to be normal.

The risk of testicular cancer among men exposed to DES in utero has been a controversial issue, and one can often read in the literature claims that the risk is not increased. This does not seem to be true. On the basis of a meta-analysis of six case-control studies, Mantel-Haenszel estimate of the odds ratio was 2.6, with 95% confidence limits of 1.1-6.1. However, more direct evidence would be necessary to assess the risk. Thus far, no data have been available for testicular cancer in the known DES-exposed cohorts.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Estrogen fetal exposure and male reproductive health alterations

Do environmental estrogens contribute to the decline in male reproductive health?

1995 Study Abstract

Several observations suggest that male reproductive health has been declining since World War II in many countries.

The incidence of testicular cancer, hypospadias, and cryptorchidism has been increasing and semen quality has been decreasing, and these may have a common etiology.

Treatment of several million pregnant women with the synthetic estrogen diethylstilbestrol led to an increase in these conditions among the sons of these women. These abnormalities probably arise during fetal development.

The similarity between these effects and the adverse change in male reproductive development and function raised the question of whether the adverse changes are attributable to altered exposures to estrogenic and other endocrine-disrupting agents during fetal development.

We speculate that alteration in exposure to estrogen in the past half-century may have caused the changes in male reproductive health.

Sources

  • Do environmental estrogens contribute to the decline in male reproductive health?, NCBI PubMed PMID: 7497651, 1995 Dec.
  • Featured image credit John Jason.
DES DIETHYLSTILBESTROL RESOURCES

Fertility disorders attributable to the use of diethylstilbestrol during intrauterine life

Women treated with distilbene during pregnancy : it seems that the increased number of miscarriages, extra-uterine pregnancies and perinatal deaths are probably due to the maternal treatment which is also responsible for semen abnormalities

1984 Study Abstract

In the early 1970s, the elevated rate of abnormalities in children of the 2-3 million US women and 260,000 French women treated with diethylstilbestrol (DES) during pregnancy began to be recognized.

Four kinds of cervicovaginal anomalies have been observed in women exposed to DES in utero:

  1. 22-58% have been estimated to have morphologic anomalies with the timing of exposure to DES more important than the total dose
  2. a high proportion has an insufficient cervical mucus not corrected by exogenous administration of estrogen
  3. a high proportion develop cervical stenosis after cryosurgery, electrocoagulation, or conization
  4. and the increased incidence of prematurity in infants of DES-exposed mothers has been attributed to cervical incompetence.

69% of 267 women studied had hysterographically demonstrated uterotubal malformations. A characteristic aspect was a T-shaped uterus but other anomalies were noted. Hysterographic anomalies were correlated with cervico-isthmic anatomic anomalies, anomalies of the vaginal epithelium, and with the date of 1st exposure to DES in utero. The total dose of DES did not affect the frequency of genital anomalies. Possible tubal anomalies have not been well studied, although 1 author has observed short and narrow tubes and other abnormalities.

The number of extrauterine pregnancies is known to be elevated in women exposed to DES in utero. The possibility of an increased incidence of menstrual irregularity, dysmenorrhea, or oligomenorrhea in DES-exposed women has been suggested but remains controversial.

The responsibility of DES exposure in utero for later reduced fertility is also in dispute. Higher rates of spontaneous abortion, extrauterine pregnancy, prematurity, and perinatal death have been reported in DES-exposed women.

Increased incidence of stenosis of the meatus, hypospadias, epididymal cysts, testicular hypoplasia and other anomalies, cryptorchidism, microphallus, and varicocele have been reported in men exposed to DES in utero. Reduced sperm counts and anomalies in the volume of the ejaculate, percentage of sperm mobile, and sperm morphology have been reported in exposed men. Sperm anomalies may be responsible for reduced fertility in exposed men, but the exact extent is unknown.

Sources

  • Fertility disorders attributable to the use of diethylstilbestrol during intrauterine life, NCBI PubMed PMID: 6397835, 1984 Apr.
  • Featured image credit Edward Cisneros.
DES DIETHYLSTILBESTROL RESOURCES

Urogenital tract abnormalities in DES sons

DES-exposed male offspring urogenital tract abnormalities, 1976

Study Abstract

Since in utero exposure to diethylstilbestrol (DES) is known to cause abnormalities of the female genital tract later in life, exposed male offspring were located, surveyed by mail, and compared with unexposed male offspring from the same period and medical practices.

The exposed and unexposed respondents appeared comparable and did not differ in their response to most medical questions. However, a larger proportion of exposed than of unexposed boys had experienced problems in passing urine (12.9% vs. 1.8%, P = .0003) and abnormalities of the penile urethra (4.4% vs. 0%; P = .017).

Remark : a DES-induced abnormality of the male urethra is embryologically consistent with DES-induced abnormalities of the vagina whether the latter are of Mullerian or urethral fold origin.

The findings suggest that more detailed historical and clinical examination of such boys is warranted.

Sources

  • Urogenital tract abnormalities in sons of women treated with diethylstilbestrol, NCBI PubMed PMID: 972792, 1976.
  • SELECTED MEDICAL HISTORIES IN DES-EXPOSED AND DES-UNEXPOSED MALES featured image credit PMID: 972792.
DES DIETHYLSTILBESTROL RESOURCES

Increased breast cancer risk in DES daughters, granddaughters and great granddaughters

The effects of maternal diethylstilbestrol exposure are not limited to the F1 generation

2014 Study Abstract

The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression. Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, 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.

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.

Developing germ cells undergo epigenetic erasure when they, as primordial germ cells, enter into the fetal gonads around embryonic day 10 to 11 (in mice and rats), and then undergo gender-specific reprogramming as germ cells. It is now clear that reprogramming of these cells is susceptible to modifications caused by changes in fetal hormonal environment, such as resulting from an exposure to DES or other endocrine disruptors. Consequently, these exposures can leave a permanent biochemical footprint on the genome of the F1 generation germ cells, and this change may be inherited by the F2 generation germ line and several subsequent generations.

Some researchers have begun to investigate whether the effects of maternal DES exposure during pregnancy extend to the third generation in humans. Although there is no evidence that DES granddaughters have cervical and ovarian abnormalities similar to DES daughters, there is evidence that they may have more menstrual irregularities and a higher rate of infertility than non-exposed granddaughters. In addition, DES granddaughters may have a slightly higher risk of ovarian cancer. The granddaughters are still too young to assess whether they might also be at an increased risk of developing breast cancer.

Millions of women in the US, Europe and Australia have been exposed to DES in the womb, and consequently exhibit about a two times higher breast cancer risk than unexposed women. The increase in risk may not be limited to the DES-exposed daughters, but could also increase breast cancer risk in granddaughters and great granddaughters. Such outcome would be consistent with the findings we obtained in studies using a synthetic estrogen ethinyl estradiol (EE2). If DES has similar effects to ethinyl estradiol on the transgenerational increase in breast cancer risk, it is urgent to find ways to stop the cycle of inheritance, and also prevent breast cancer in DES-exposed granddaughters and great granddaughters.

To achieve this goal, we need to understand how maternal DES exposure during pregnancy increases a daughter’s breast cancer risk. A plausible model is proposed in feature image. It is evident from studies done in animal models that in utero DES exposure induces epigenetic changes in reproductive tract tissues and the breast. DES exposure might also have induced epigenetic changes in primordial germ cells and consequently germ cells, and further be detectable in the somatic cells in granddaughters and great granddaughters. We are not aware of any study that has compared epigenetic changes in germ cells and the next generation somatic cells in individuals exposed to DES or other endocrine disruptors in utero. Second, we should investigate whether the transgenerational increase in breast cancer risk can be prevented with drugs that reverse epigenetic modifications. Our preliminary studies in mice suggest that this is achievable in daughters by using the well-tolerated and non-toxic histone deacetylase inhibitor valproic acid and DNMT inhibitor hydralazine. However, whether these compounds also prevent an increase in granddaughters and great granddaughters in experimental models remains to be investigated.

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

  • 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

Epigenetics and transgenerational effects of DES

EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals

Selected Abstracts

Prenatal exposure to DES caused hypermethylation of the Hoxa10 gene in the uterus of mice and was linked to uterine hyperplasia and neoplasia later in life. Beyond the effects of prenatal exposure to DES on the daughters exposed in utero are suggestions that this leads to transgenerational effects of the chemical on the reproductive system, although whether this is linked to DNA methylation changes in humans is unknown.

DES caused histone deacetylation in the promoter region of the cytochrome P450 side chain cleavage (P450scc) gene.

Neonatal DES exposure also caused the differential expression of 900 genes in one or both layers of the uterus. Specifically, DES altered multiple factors in the PPARγ pathway that regulate adipogenesis and lipid metabolism, and it perturbed glucose homeostasis, suggesting that DES affects energy metabolism in the uterus. In the mouse uterus, DES altered the expression of chromatin-modifying proteins and Wnt signaling pathway members, caused epigenetic changes in the sine oculis homeobox 1 gene, and decreased the expression of angiogenic factors. DES also altered the expression of genes commonly involved in metabolism or endometrial cancer in mice, and it activated nongenomic signaling in uterine myometrial cells and increased the incidence of cystic glands in rats.

Studies in mice showed that DES induced vaginal adenosis by down-regulating RUNX1, which inhibits the BMP4/activin A-regulated vaginal cell fate decision; induced epithelial cell proliferation and inhibited stromal cell proliferation; and caused persistent down-regulation of basic-helix-loop-helix transcription factor expression (Hes1, Hey1, Heyl) in the vagina, leading to estrogen-independent epithelial cell proliferation. Neonatal exposure to DES caused persistent changes in expression of IGF-1 and its downstream signaling factors in mouse vaginas. It also up-regulated Wnt4, a factor correlated with the stratification of epithelial cells, in mouse vaginas. Interestingly, the simultaneous administration of vitamin D attenuated the ability of DES to cause hyperplasia of the vagina in neonatal mice.

In mice treated prenatally with DES there was a significant increase in enhancer of Zeste homolog 2 (EZH2) protein and EZH2 activity (measured by increased mammary histone H3 trimethylation)—a histone methyltransferase that may be linked to breast cancer risk and epigenetic regulation of tumorigenesis, as well as an increase in adult mammary gland EZH2.

EDC exposures to pregnant animals have been shown to cause multigenerational or transgenerational effects on a number of disease endpoints, particularly reproduction, neurobehavior, and adiposity. This work needs much more follow-up to better determine the underlying mechanisms, which are likely to include epigenetic molecular programming changes. Moreover, research is needed in human populations. Some work has been conducted in grandchildren of DES-exposed women who took this estrogenic pharmaceutical during pregnancy. The consequences on the offspring (F1 generation) are well-studied, and research is beginning to be published on the grandchildren (F2 generation). For environmental chemicals, several ongoing projects need continued funding.

Sources

  • Full study (free access) : EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, NCBI PubMed PMC4702494, 2015 Nov 6.
  • Featured image credit Craig Whitehead.
DES DIETHYLSTILBESTROL RESOURCES

Endocrine Disruptor Induction of Epigenetic Transgenerational Inheritance of Disease

DES phenotypes found to be due to abnormal epigenetic programming of some organs and critical genes

2014 Study Abstract

Environmental exposures such as toxicants, nutrition and stress have been shown to promote the epigenetic transgenerational inheritance of disease susceptibility. Endocrine disruptors are one of the largest groups of specific toxicants shown to promote this form of epigenetic inheritance. These environmental compounds that interfere with normal endocrine signaling are one of the largest classes of toxicants we are exposed to on a daily level. The ability of ancestral exposures to promote disease susceptibility significantly increases the potential biohazards of these toxicants. Therefore, what your great-grandmother was exposed to during pregnancy may influence your disease development, even in the absence of any exposure, and you are going to pass this on to your grandchildren. This non-genetic form of inheritance significantly impacts our understanding of biology from the origins of disease to evolutionary biology. The current review will describe the previous studies and endocrine disruptors shown to promote the epigenetic transgenerational inheritance of disease.

DES Epigenetics

One of the best examples of a human model is in the late 1950’s and early 1960’s when women in the late stages of pregnancy were exposed to the pharmaceutical diethylstilbesterol (DES) which was shown to promote abnormal uterine and cervical development in the female offspring and grand-offspring. Subsequently the phenotypes were found to be due to abnormal epigenetic programming of these organs and critical genes.

Sources

  • Full study (free access) : Endocrine disruptor induction of epigenetic transgenerational inheritance of disease, Molecular and cellular endocrinology, NCBI PubMed PMC4262585, 2014 Jul 31.
  • Epigenetic and genetic cascade of events involved in development featured image credit PMC4262585/figure/F1.
DES DIETHYLSTILBESTROL RESOURCES

Reductions in fertility in DES sons and daughters

Diethylstilbestrol Revisited: A Review of the Long-Term Health Effects

1995 Research Abstract

DES Sons

Some investigators have reported abnormalities of the urogenital system in DES sons, whereas others have found no increase in such abnormalities compared with men who were not exposed to DES. Gill and coworkers examined 308 men exposed to DES and 307 men receiving placebo who were traced from Dieckmann and colleagues’ cohort and found that the prevalence of epididymal cysts and hypotrophic testes was four times greater among exposed men. In men with testicular hypoplasia, cryptorchidism was observed in 65% (17 of 26) of men exposed to DES compared with 17% (1 of 6) of controls. No significant differences were found in mean circulating follicle-stimulating hormone, luteinizing hormone, or testosterone levels in the two groups. Spermatozoa were analyzed in 134 men (44%) exposed to DES and in 84 men (27%) who received placebo. The average sperm density of the group exposed to DES was lower than that of the placebo group (91 sperm cells X 106 /mL compared with 115 sperm cells X 106 /mL; P = 0.05). Semen quality was compared using the average Eliasson score, a scoring system that assesses sperm concentration, percentage of motile sperm, motility, and morphology. A score of 1 is classified as normal; a score of 5 to 10 is classified as pathologic; and a score of greater than 10 is classified as severely pathologic. The average Eliasson score was higher in the group exposed to DES than in the group exposed to placebo (4.9 compared with 2.5; P = 0.01); more men exposed to DES than controls had severe semen pathologic disorders (an Eliasson score > 10) (24 of 134 men exposed to DES [18%] compared with 7 of 87 controls [8%]; P = 0.05). In contrast, a study done by the Mayo Clinic found no significant differences between men who were and were not exposed to DES in the proportion of testicular or penile anomalies, sperm density or Eliasson score, or the number of pregnancies attained by their wives. These conflicting results may be related to differences in the maternal DES dose levels, heterogeneous hormone (non-DES) exposures, or different methods of recruiting study participants in the reported studies.

DES Daughters

Developmental abnormalities in the female reproductive tract frequently occur after DES exposure. Among DESAD participants at the Baylor College of Medicine who were exposed to DES, 50 of 282 (18%) were found to have gross anatomical changes of the cervix (absent pars vaginalis, coxcomb, hypoplastic cervix collar, or pseudopolyp). Among a subgroup of DESAD participants recruited for a fertility study, 154 of 293 (53%) were found to have abnormal hysterosalpingograms. These abnormalities included T-shaped and hypoplastic uteri; constriction of the upper, middle, or cornual regions; and irregular uterine margins. Data from the Dieckmann and colleagues’ cohort have consistently shown reductions in fertility in DES daughters. On the basis of data analyzed until 1986, 33% of the exposed women compared with 14% of the unexposed women reported primary infertility. Secondary infertility was also reported significantly more often among the exposed women. Vaginal epithelial changes and cervicovaginal ridges were found more often among the exposed women with primary infertility. In contrast, an early analysis of data from the DESAD cohort found that exposed and unexposed daughters were similar in the number achieving pregnancy, the total number of pregnancies, and age at first pregnancy. However, these women may have been studied too early in their reproductive life span to detect major differences in fertility. Kaufman and associates found no difference in the proportion of women with normal and abnormal hysterosalpingograms who had difficulty with conception, suggesting that structural abnormalities of the uterus alone did not account for failure to conceive. Some clinical studies and case reports have suggested that hormonal changes in DES daughters occur, including elevated testosterone and prolactin levels. However, a prospective cohort study suggested that although in utero DES exposure was related to a reduction in the duration and amount of menstrual bleeding, exposure did not affect cycle length and variability of cycle length. This suggests that gross endocrine function was not disturbed. Failure of implantation and alterations in ovarian steroidogenesis have also been postulated as possible causes of infertility in these women. Once pregnancy is achieved, DES daughters are at high risk for an unfavorable pregnancy outcome. In a review of English-language articles, Swan estimated that, overall, DES daughters are 8.6 times more likely to have an ectopic pregnancy, 1.8 times more likely to have a miscarriage, and 4.7 times more likely to have a premature birth than unexposed women. Among women with an abnormality of the cervix, vagina, or uterus, the relative risks for ectopic pregnancy, miscarriage, and premature birth are even higher (13.5, 2.6, and 9.6, respectively).

Sources

DES DIETHYLSTILBESTROL RESOURCES

Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits

DES adverse impact on fetal germ cells, impairing neurodevelopment of offspring

Abstracts

We conducted a large-scale cohort analysis to assess the association between use of diethylstilbestrol during pregnancy and third-generation ADHD. The observed associations were robust to covariate adjustment and sensitivity analyses. Despite animal evidence of adverse multigenerational consequences—including neurodevelopmental disorders—of EDC exposure, to date only a few studies have explored the potential multigenerational implications of EDC exposure in humans. These studies have only considered diethylstilbestrol exposure, and none has studied neurodevelopmental outcomes. Some studies have reported increased risk of hypospadias in grandsons of women exposed to diethylstilbestro during pregnancy. Titus-Ernstoff et al found delayed menstrual regularization, higher odds of irregular menstrual periods, and fewer live births among women whose grandmothers used diethylstilbestrol during pregnancy. Birth defects have also been found in grandchildren of women who used diethylstilbestrol when pregnant.

2018 Study Key Points

Question
Is exposure to diethylstilbestrol during pregnancy associated with adverse multigenerational neurodevelopmental outcomes?

Findings
A cohort study of 47 450 women in the Nurses’ Health Study II found significantly elevated odds for attention-deficit/hyperactivity disorder in the grandchildren (third generation) of users of diethylstilbestrol, a potent endocrine disruptor.

Meaning
Exposure to endocrine disruptors during pregnancy may be associated with multigenerational neurodevelopmental deficits.

IMPORTANCE

Animal evidence suggests that endocrine disruptors affect germline cells and neurodevelopment. However, to date, the third-generation neurodevelopmental outcomes in humans have not been examined.

OBJECTIVE

To explore the potential consequences of exposure to diethylstilbestrol or DES across generations—specifically, third-generation neurodevelopment.

DESIGN, SETTING, AND PARTICIPANTS

This cohort study uses self-reported health information, such as exposure to diethylstilbestrol during pregnancy and attention-deficit/hyperactivity disorder (ADHD) diagnosis, from 47 540 participants enrolled in the ongoing Nurses’ Health Study II. The 3 generations analyzed in this study were the participants (F1 generation), their mothers (F0 generation), and their live-born children (F2 generation). MAIN OUTCOMES AND MEASURES Participant- and mother-reported exposure to diethylstilbestrol during pregnancy and physician-diagnosed child ADHD.

RESULTS

The total number of women included in this study was 47 540. Of the 47 540 F0 mothers, 861 (1.8%) used diethylstilbestrol and 46 679 (98.2%) did not while pregnant with the F1 participants. Use of diethylstylbestrol by F0 mothers was associated with an increased risk of ADHD among the F2 generation: 7.7% vs 5.2%, adjusted odds ratio (OR), 1.36 (95% CI, 1.10-1.67) and an OR of 1.63 (95% CI, 1.18-2.25) if diethylstilbestrol was taken during the first trimester of pregnancy. No effect modification was observed by the F2 children’s sex.

CONCLUSIONS AND RELEVANCE

This study provides evidence that diethylstilbestrol exposure is associated with multigenerational neurodevelopmental deficits. The doses and potency level of environmental endocrine disruptors to which humans are exposed are lower than those of diethylstilbestrol, but the prevalence of such exposure and the possibility of cumulative action are potentially high and thus warrant consideration.

Sources

  • Full study (free access) : Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits, JAMA Pediatrics doi:10.1001/jamapediatrics.2018.0727, May 21, 2018.
  • Featured image by Andre Hunter.
DES DIETHYLSTILBESTROL RESOURCES

Fetal and early postnatal environmental exposures and reproductive health effects in the female

image of fetal exposure

DES exposure induces changes in the expression of many genes such as Wnt7a, Hoxa9, Hoxa10, Hoxa11, lactoferrin and c-fos genes

2008 Study Abstracts

Current studies are investigating the possibility that neonatal estrogen exposure may alter activin signaling in the ovary, thereby leading to ovarian pathologies. We have examined the effect of neonatal DES and E2 exposure on the mRNA and protein levels of the key factors involved in activin signaling in the mouse ovary. Preliminary results demonstrate that neonatal estrogen exposure decreases activin subunit gene expression and impacts activin signaling, indicating that activin genes are targets of estrogen action in the mouse ovary. Future studies will further characterize the mechanisms underlying the effects of premature estrogen and activin exposure on adult ovarian and follicular function.

From the 1940s to 1970s, the xenoestogen DES was extensively prescribed to pregnant women at risk for miscarriage. 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. Since DES is readily metabolized and cleared within days after exposure, the persistent alterations resulting from developmental DES exposure cannot simply be explained by residual body burden of the compound. DES exposure also induces changes in the expression of several uterine genes involved in tissue patterning, such as Wnt7a, Hoxa9, Hoxa10 and Hoxa11, contributing to changes in tissue architecture and morphology. DES-induced developmental programming appears to require the estrogen receptor α (ERα), suggesting that signaling through this receptor is crucial for establishing developmental programming. These initial observations with DES firmly established the developmental period as a window of susceptibility during which an inappropriate xenoestrogen exposure can induce developmental programming and increase risk for diseases, including cancer, later in life.

We have recently demonstrated that developmental programming can increase the risk for developing uterine leiomyoma in adulthood the adult. Utilizing rats carrying a germline defect in the tuberous sclerosis complex 2 (Tsc-2) tumor suppressor gene that are predisposed to uterine leiomyomas, we found that an early life exposure to DES during development of the uterus increased risk for uterine leiomyoma from 65% to greater than 90% and increased tumor multiplicity and size in genetically predisposed animals, but failed to induce tumors in wild-type rats. Importantly, we found that DES exposure imparted a hormonal imprint on the developing uterine myometrium in both wild-type and carrier rats, causing an increase in expression of estrogen-responsive genes prior to the onset of tumors. Thus, when developmental programming of estrogen-responsive genes was combined with the presence of the Tsc-2 tumor suppressor gene defect, the result was an increased risk of developing hormone-dependent leiomyoma in adult animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor suppressor gene penetrance in genetically susceptible individuals. Developmental programming occurred as a result of the hormonal imprint imparted on the developing uterus by the brief early life exposure to DES.

Sources

  • Full study (free access) : Fetal and Early Postnatal Environmental Exposures and Reproductive Health Effects in the Female, Fertility and Sterility, NCBI PubMed PMC2527475, 2008 Feb.
  • Featured image Mel Elías.
DES DIETHYLSTILBESTROL RESOURCES