Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of DES

Human Molecular Genetics, 2005

Effects of estrogen and stress on activation of the ER and repression of the WNT genes.

2005 Study Abstract

Hsp90 is a chaperone for over 100 ‘client proteins’ in the cell, most of which are involved in signaling pathways. For example, Hsp90 maintains several nuclear hormone receptors, such as the estrogen receptor (ER), as agonist-receptive monomers in the cytoplasm. In the presence of agonist, Hsp90 dissociates and the receptors dimerize, enter the nucleus and ultimately activate transcription of the target genes. Increasing evidence suggests that Hsp90 also has a role in modifying the chromatin conformation of many genes. For example, Hsp90 has recently been shown to increase the activity of the histone H3 lysine-4 methyltransferase SMYD3, which activates the chromatin of target genes. Further evidence for chromatin-remodeling functions is that Hsp90 acts as a capacitor for morphological evolution by masking epigenetic variation. Release of the capacitor function of Hsp90, such as by environmental stress or by drugs that inhibit the ATP-binding activity of Hsp90, exposes previously hidden morphological phenotypes in the next generation and for several generations thereafter. The chromatin-modifying phenotypes of Hsp90 have striking similarities to the trans-generational effects of the ER agonist diethylstilbestrol (DES). Prenatal and perinatal exposure to DES increases the predisposition to uterine developmental abnormalities and cancer in the daughters and granddaughters of exposed pregnant mice. In this review, we propose that trans-generational epigenetic phenomena involving Hsp90 and DES are related and that chromatin-mediated WNT signaling modifications are required. This model suggests that inhibitors of Hsp90, WNT signaling and chromatin-remodeling enzymes might function as anticancer agents by interfering with epigenetic reprogramming and canalization in cancer stem cells.

Sources and more information
  • Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer, NCBI PMID: 15809267, 2005 Apr 15;.
  • Full study Oxford Journals, Medicine & Health & Science & Mathematics, Human Molecular Genetics doi: 10.1093/hmg/ddi103, February 23, 2005.
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Brief exposure to low levels of environmental estrogens early in life can increase body weight

Developmental exposure to estrogenic compounds and obesity

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

2005 Study Abstract

For >20 years, research in our laboratory has focused on the effects of estrogenic compounds on development and differentiation. Our working premise has been that the developing organism is extremely sensitive to perturbation by chemicals with estrogenic or endocrine disrupting activity and that exposure to these chemicals during critical stages of differentiation may have permanent long-lasting consequences, some of which may not be expressed or detected until later in life. Diethylstilbestrol (DES) is a well-known example of such a chemical; thus, we have used DES as a model chemical to study environmental estrogens.

DES, a synthetic estrogen, was widely prescribed from the 1940s through the 1970s for the prevention of threatened miscarriage. A range of 2–8 million treated pregnancies worldwide has been estimated. Today it is well recognized that prenatal DES treatment results in a low incidence of neoplasia in the female offspring and a high incidence of benign abnormalities in both the male and female offspring.

To study the mechanisms involved in the toxicity of DES, we developed an animal model using outbred CD-1 mice treated with DES by subcutaneous injections on GD 9–16 (the period of major organogenesis in the mouse) or days 1–5 of neonatal life (a period of cellular differentiation of the reproductive tract and a critical period of immune and behavioral differentiation). The prenatal DES animal model has successfully duplicated and, in some cases, predicted many of the alterations (structural, function, cellular, and molecular) observed in similarly DES-exposed humans.

Although our major focus has been on reproductive tract abnormalities, we also examined the effects of DES on body weight over a wide dose range of exposure. High prenatal DES doses (10–100 μg/kg of maternal body weight) caused a decrease in the offspring’s adult body weight; likewise, high neonatal DES doses (1000 μg/kg/day on days 1–5 [1 mg/kg/day]) caused a decrease in body weight later in life. However, low doses of DES (either prenatal or neonatal) caused an increase in body weight; Figure 1 illustrates control and neonatal DES 0.001 mg/kg/day treatment (DES-0.001). Note that body weight was not different between DES-exposed and unexposed controls during the time of treatment and shortly thereafter, but it gradually reached significance by 6 weeks of age. Further, data from our laboratory indicate that this increase in body weight in DES-exposed mice is associated with an increase in the percentage of body fat. Using Lunar PIXImus mouse densitometry (Lunar PIXImus, GE Healthcare, Waukesha, WI), we measured the percentage of fat in untreated controls and neonatal DES-treated mice at 16 weeks of age. As seen in the image, mice treated neonatally with DES are markedly larger than controls. Measurements obtained from densitometry show a significant increase in the estimated body weight, estimated fat weight, and percent fat compared to controls. Neonatal exposure to other estrogens such as 2OH estradiol (20 mg/kg/day) and 4OH estradiol (0.1 mg/kg/day), which are approximately equal estrogenic doses to DES-0.001, also caused an increase in body weight at 4 months of age, suggesting that DES is not a unique estrogenic chemical in causing this increased obesity. Further, neonatal exposure to the naturally occurring phytoestrogen genistein at 50 mg/kg/day, an approximately equal estrogenic dose to DES, caused a significant increase in body weight at 3 and 4 months of age compared to untreated controls. We are currently comparing the weight of fat depots from mice exposed neonatally to various environmental estrogens to determine possible alterations in adipose tissue, including size of specific fat pads and hormone levels (e.g., leptin, adiponectin). By 18 months age, differences in body weight between genistein-treated and untreated controls are difficult to determine due to large individual animal variability within groups.

Taken together, our data support the idea that brief exposure to low levels of environmental estrogens early in life increases body weight as the mice age. Whether our results can be extrapolated to humans, as in the reproductive abnormalities from the DES mouse model, remains to be determined, but this is a fruitful area for further research. In addition, the use of this mouse model to study mechanisms involved in altered weight homeostasis (direct and/or endocrine feedback loops, e.g., ghrelin, leptin) by environmental endocrine disrupting chemicals is an important basic research area that may shed light on the future prevention and treatment of obesity.

Sources and Full Study
  • Developmental exposure to estrogenic compounds and obesity, NIEHS Symposium Proceedings, Retha R. NewboldMay, DOI: 10.1002/bdra.20147, 15 JUN 2005.
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Hypospadias in sons of women exposed to diethylstilbestrol in utero

DES increases the risk of risk of reproductive tract abnormalities in offspring

father-baby image
Moderate increase risk of hypospadias in the DES Sons regarding this 2005 study.

2005 Study Abstract

BACKGROUND:
Diethylstilbestrol (DES) is a synthetic estrogen that was widely prescribed to pregnant women before 1971. DES increases the risk of breast cancer in women who took the drug and the risk of reproductive tract abnormalities in their offspring. Dutch investigators have reported a 20-fold increase in risk of hypospadias among sons of women who were exposed to DES in utero. We assessed this relation in data from an ongoing study of DES-exposed persons.

METHODS:
Several U.S. cohorts of women with documented exposure in utero to DES have been followed by mailed questionnaires since the 1970s. Comparison subjects are unexposed women of the same ages. In 1997, participants were asked about congenital abnormalities in their children. We calculated prevalence odds ratios for the risk of hypospadias in sons of exposed mothers relative to sons of unexposed mothers using generalized estimating equations to adjust for multiple sons per mother and controlling for maternal age at the son’s birth.

RESULTS:
We obtained data from 3916 exposed and 1746 unexposed women. These women reported a total of 13 liveborn sons with hypospadias (10 exposed, 3 unexposed). The prevalence odds ratio for risk of hypospadias among the exposed was 1.7 (95% confidence interval = 0.4-6.8).

CONCLUSIONS:
Our findings do not support a greatly increased risk of hypospadias among the sons of women exposed to DES in utero, as has been previously reported.

Sources
  • Hypospadias in sons of women exposed to diethylstilbestrol in utero,
    NCBI PMID: 15951681, Epidemiology. 2005 Jul;16(4):583-6.
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Risk of benign gynecologic tumors in relation to prenatal diethylstilbestrol exposure

DES daughters haved 2-3 times the risk of being diagnosed with paraovarian cysts

DES Follow-up Study Summary

National Cancer Inst logo image
This 2005 study found that DES daughters had 2-3 times the risk of being diagnosed with paraovarian cysts.

We investigated the association between prenatal Diethylstilbestrol DES exposure and benign gynecologic tumors among women participating in the DES collaborative follow-up study. A total of 85 cases of uterine fibroids and 168 cases of ovarian or paraovarian cysts were confirmed by medical records. After adjustment for age, no association was found between prenatal DES exposure and ovarian cysts or uterine fibroids. DES daughters had 2-3 times the risk of being diagnosed with paraovarian cysts, which are cysts that originate from remnants of the Mullerian ducts and are located near the ovary and fallopian tubes. Paraovarian cysts are not known to cause any health problems.

We recommend caution when interpreting the results for paraovarian cysts. First, the pathologist making the initial diagnosis was not blinded as to the patient’s exposure status. Therefore, the pathologist’s knowledge of a patient’s DES status may have influenced the recording of cysts, particularly those that have little clinical significance (e.g., paraovarian cysts), which in the absence of such exposure history were often not recorded. Second, the lining of the Mullerian duct derives from coelomic epithelium, as does the covering of the ovary from which epithelial cysts arise. It is unlikely that DES exposure would be associated with an increase in cysts of Mullerian origin (e.g., paraovarian), but not of ovarian epithelial origin (e.g., cystadenomas). Thus, greater incidental detection of paraovarian cysts among DES daughters, or more likely the absence of recording in non-exposed daughters, could have produced the positive association observed in our study.

2005 Study Abstract

OBJECTIVE:
To investigate the association between prenatal diethylstilbestrol (DES) exposure and risk of benign gynecologic tumors.

METHODS:
We conducted a collaborative follow-up study of women with and without documented intrauterine exposure to DES. We compared the incidence of self-reported ovarian cysts, paraovarian cysts, and uterine leiomyomata confirmed by medical record in DES-exposed and unexposed women.

RESULTS:
A total of 85 cases of uterine leiomyomata and 168 cases of ovarian or paraovarian cysts were confirmed histologically. After adjustment for age, no association was found between prenatal DES exposure and ovarian cysts or uterine leiomyomata. Prenatal DES exposure was positively associated with paraovarian cysts.

CONCLUSION:
The present results do not support the hypothesis that prenatal DES exposure increases risk of uterine leiomyomata or ovarian cysts. Prenatal DES exposure was associated with an increased risk of paraovarian cysts, but detection bias cannot be ruled out as an explanation of this finding.

Sources

  • Risk of benign gynecologic tumors in relation to prenatal diethylstilbestrol exposure,NCBI, PMID: 15625159, Obstet Gynecol. 2005 Jan;105(1):167-73.
  • NCI, DES Follow-up Study Published Papers.
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Breast cancer incidence in women prenatally exposed to maternal cigarette smoke

Prenatal hormone exposure may affect future breast cancer risk

DES Follow-up Study Summary

National Cancer Inst logo image
These 2005 study results provide further evidence supporting the hypothesis that prenatal hormone exposure may affect future breast cancer risk.

Fetal exposure to maternal pregnancy hormones may influence future breast cancer risk and cigarette smoking is among the factors believed to alter pregnancy hormone levels. Specifically, total pregnancy estrogen levels are slightly decreased among pregnant women who smoke relative to women who do not. More pronounced reductions of pregnancy estiol (E3) and estradiol (E2) were observed among smoking women. Possibly, women prenatally exposed to maternal cigarette smoke may have reduced breast cancer risk as an adult. The National Cooperative DES Adenosis (DESAD) Project was a prospective study of the effects of prenatal Diethylstilbestrol (DES) exposure. When women were enrolled in the study from 1975 through 1981, their mothers were questioned about their health habits including cigarette smoking during their pregnancy with the study participant. Using responses to this question provided by the mothers at the start of the study, investigators were able to compare the breast cancer rates among women who were and were not prenatally exposed to maternal cigarette smoke. Investigators observed a 51% decrease in breast cancer rates among women whose mothers smoked while pregnant with them compared to women who were not prenatally exposed to maternal cigarette smoke. Daughters of women who smoked 15 or fewer cigarettes per day during the pregnancy appeared to have a 65% reduction in breast cancer rates compared to women whose mothers did not smoke during pregancy. The adverse effects of prenatal cigarette smoke exposure far outweigh any benefit from possible reduction of breast cancer risk. These study results do, however, provide further evidence supporting the hypothesis that prenatal hormone exposure may affect future breast cancer risk.

2005 Study Abstract

BACKGROUND:
Clinical studies show that maternal cigarette smoking reduces pregnancy estrogen levels. Women prenatally exposed to maternal cigarette smoke may, therefore, have a lower breast cancer risk because the fetal mammary gland’s exposure to maternal estrogen is decreased. Associations between prenatal maternal cigarette smoke exposure and breast cancer, however, have not been observed in previous case-control studies that relied on exposure assessment after the onset of cancer. At the start of this study, cigarette smoking history was obtained directly from the mother.

METHODS:
The National Cooperative DES Adenosis project was a follow-up study of health outcomes in women prenatally exposed to diethylstilbestrol (DES). At the start of the study, women’s mothers provided information about cigarette smoking habits during the time they were pregnant with the study participant. In the current study, the breast cancer rates are compared among 4031 women who were or were not prenatally exposed to maternal cigarette smoke. The resultant relative rate (RR) is adjusted for potential confounding by other breast cancer risk factors using Poisson regression modeling.

RESULTS:
Fetal exposure to maternal cigarette smoke appeared to be inversely associated with breast cancer incidence (RR = 0.49; 95% confidence interval [CI] = 0.24-1.03). The inverse association was more apparent among women whose mothers smoked 15 cigarettes or fewer per day than among daughters of heavier smokers. There were, however, too few cases to precisely estimate a possible dose-response relationship.

CONCLUSION:
These results support the hypothesis that in utero exposure to maternal cigarette smoke reduces breast cancer incidence.

Sources

  • Breast cancer incidence in women prenatally exposed to maternal cigarette smokeNCBI, PMID: 15824550, 2005 May;16(3):342-5.
  • NCI, DES Follow-up Study Published Papers.
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The History of DES, Lessons to be learned

Health care professionals have to know the history of DES to prevent future disasters with drugs prescribed

Abstract

image of PubMed NCBI The Endocrine Society logo
Health care professionals have to know the history of DES to prevent future disasters with drugs prescribed.

Since the 1940s, Diethylstilbestrol (DES) has been used by millions of pregnant women to prevent miscarriages and many other disorders in pregnancy. In 1971, it became clear that this apparently innocent treatment proved to be a time bomb for the infants exposed to DES during the first trimester of pregnancy. DES is now associated with an increased risk of breast cancer, clear cell adenocarcinoma (CCAC) of the vagina and cervix, and reproductive anomalies. This article summarises the potential long-term health implications of DES on the mother, DES daughters and DES sons, and the possible side effects on the third generation. Health care professionals have to know the history of DES to prevent future disasters with drugs prescribed.

Sources
  • The history of DES, lessons to be learned,
    NCBI, PMID: PubMed 16096877, 2005 Jun;27(3):139-43.
  • Full text: Springer, June 2005, Volume 27, Issue 3, pp 139-143.
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Management of breast cancer in patients prenatally exposed to diethylstilbestrol: are we prepared?

Exposure to DES also results in an increased risk of breast cancer in the offspring

Abstract

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There is some preliminary evidence to support that exposure to DES will also result in an increased risk of breast cancer in the offspring.

The use of diethylstilbestrol (DES) for high risk pregnancy has exposed millions of mothers to an increased risk of breast cancer, and also resulted in a generation of women with genital tract abnormalities, such as vaginal adenosis. It is still too early to say that exposure to DES will also result in an increased risk of breast cancer in the offspring, though there is some preliminary evidence to support this. The employment of optimal hormonal therapy (for breast cancer) in this special population may be hampered by the fact that agents with oestrogen agonistic activity (such as tamoxifen) may be contraindicated. Though some of the newer hormonal agents, such as the pure anti-oestrogen Fulvestrant and the aromatase inhibitors, could be considered interesting alternatives for postmenopausal patients, their safety in this population has never been evaluated. Finally, the prevalence prenatal exposure to DES may have been underestimated patients diagnosed with breast cancer, though this information might have major implications in their management. We report on the interesting example of a young woman with a history of vaginal adenosis, who was also diagnosed with early breast cancer.

Sources
  • Management of breast cancer in patients prenatally exposed to diethylstilbestrol: are we prepared?
    NCBI, PMID: PubMed 16216745, Oct 2005.
  • Full text: TheBreastOnline, S0960-9776(04)00230-9,
    November 11, 2004.
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Pregnant DES Daughters and their Offspring

DES Exposure can have a Trans-Generational Effect

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Third-generation women should be examined carefully for presence of DES-associated changes. An increased rate of hypospadias has recently been reported in third-generation men

QUESTION
I am a 34-year-old woman in my second trimester of pregnancy. My mother took diethylstilbestrol when she was pregnant with me. Could my expected child be affected by this?

ANSWER
Animal studies suggest the child could be affected, but little data on humans strongly support this. You could plan to have your child monitored for a potential, though unlikely, effect.

Diethylstilboestrol (DES)  is a potent synthetic estrogen widely prescribed to pregnant women between 1938 and 1971 to improve outcome of pregnancy. Results of several epidemiologic studies in the early 1970s showed that use of DES during pregnancy was associated with a substantial increase in vaginal and cervical clear-cell adenocarcinoma and genital tract abnormalities in adolescent girls exposed to DES in utero. There was also an increased risk of first- and second-trimester spontaneous abortions, ectopic pregnancies, and preterm deliveries among daughters who had been exposed.

An association between in utero exposure to DES and abnormalities of men’s urogenital systems was also found. The most common abnormalities are epididymal cysts, undescended testes, and small testes. A recent study suggested an increased incidence of testicular cancer among men exposed in utero to DES.

When early reports of increased frequency of uterine and ovarian adenocarcinoma in offspring of mice exposed in utero to DES were first published in the mid-1980s, they raised concern regarding possible adverse effects on the third generation of humans exposed to DES.

A study of 28 daughters (mean age 20 years) of women exposed to DES in utero showed that these third-generation women had no abnormalities of the genital tract, and no cases of endometrial, ovarian, cervical, or vaginal carcinoma, or intraepithelial neoplasia of the cervix or vagina were detected. Review of their mothers’ records indicated that 61.5% of the mothers exposed to DES in utero had structural changes of the cervix, upper vagina, or vaginal epithelium. The main limitations of this study were the small sample size and the age of the women, who might have been too young to reflect the true rate of subsequent genital malignancies.

The absence of abnormalities of the lower genital tract in third-generation women compared with the high frequency of these abnormalities in their mothers suggests that third-generation carry-over effects of DES exposure are rare.

A recent case report of an ovarian malignancy in a third-generation adolescent raised the possibility of an association between her malignancy and her grandmother’s use of DES. The authors described a 15-year-old girl with small cell carcinoma of the ovary whose maternal grandmother had been taking DES while she was pregnant with the patient’s mother. Although this is an anecdotal case, the rarity of this disorder suggests that DES exposure could have a trans-generational effect.

An increased rate of hypospadias has recently been reported in third-generation men. A Dutch cohort study compared 205 sons of women who were exposed to DES in utero with 8934 men with no such history. Four (2%) of the exposed sons had hypospadias, compared with nine (0.01%) in the control group.

Differences between human and mice models in the effects of DES on the third generation suggest that the effect observed in mice is much greater than in humans. Nevertheless, some authors recommend that third-generation women should be examined carefully for presence of DES-associated changes.

A variety of theories have been proposed for the mechanism of action of multi-generational effects of DES. In mice, the carcinogenicity of DES can apparently be transmitted from prenatally exposed offspring to the next generation. Germ cell mutation has been implicated as the mode of transmission of the genotoxic effect. Imprinting might be another mode of transmission.

Sources:
  • Pregnant “DES daughters” and their offspringNCBI, PMCID: PMC1472948, Can Fam Physician. Apr 10, 2005; 51(4): 493–494.
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About One-Third of People with Autism also have Epilepsy

The connection between Autism and Epilepsy

Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood

Abstract

Jasper's Basic Mechanisms of the Epilepsies
The Connection between Autism And Epilepsy

PURPOSE:
Little is known about the long-term outcome of epilepsy in autism and the epilepsy characteristics of adults with autism. This prospective population-based study was conducted in an attempt to point out differences on a group basis between adults with autism with or without epilepsy, and to describe the occurrence, the seizure characteristics, and the outcome of epilepsy in autism.

METHODS:
One hundred eight of 120 individuals with autism diagnosed in childhood and followed up prospectively for a period of 13-22 years were reevaluated at ages 17-40 years. As adults, the majority had mental retardation and autistic disorder or autistic-like condition. Interviews were performed with the caretakers of 42 of 43 individuals with a history of epilepsy, and their medical records were reviewed.

RESULTS:
Adults with autism and mental retardation constituted a severely disabled group. On a group basis, both the cognitive level and the adaptive behavior level were lower in the epilepsy group than in the nonepilepsy group (p<0.05). In all, 38% had epilepsy. One third had epilepsy onset before age 2 years. Remission of epilepsy was seen in 16%. Partial seizures with or without secondarily generalized seizures were the dominating seizure type.

CONCLUSIONS:
In a community sample of individuals with autism followed up from childhood through to adult age, one of three had epilepsy since childhood/adolescence. Severe mental retardation and autism are significantly associated with epilepsy, especially in female patients. Seizure frequency has a great impact on the individuals’ lives. Specialist medical care is needed in this severely communication-disabled population.

Pathophysiology of Epilepsy in Autism Spectrum Disorders

Excerpt

Epilepsy occurs frequently in individuals with autism spectrum disorders (ASD). However, the mechanisms responsible for increased seizure susceptibility in ASD are largely unknown. Clues to neural hyperexcitability in the autistic brain might be derived from disorders in which single gene mutations cause both epilepsy and an autistic phenotype, such as fragile X syndrome and tuberous sclerosis complex. This chapter summarizes current understanding of epilepsy in individuals with ASD and explores potential links between the genetic disruption of neural circuits and cellular signaling pathways that contribute to both epilepsy and ASD.

Sources and Press Release
  • The Connection Between Autism And Epilepsy, LiveScience, 45951-autism-epilepsy-connection by Dr. Megdad Zaatreh,
    May 29, 2014.
  • Pathophysiology of Epilepsy in Autism Spectrum Disorders, NCBI, PMID: 22787637, National Center for Biotechnology Information (US); 2012. Full text NBK98169.
  • Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood, NCBI, PMID: 15946331, Epilepsia. 2005 Jun;46(6):918-23.
    Full text PDF.

Long-Term Effects of Fetal Exposure to Low Doses of Bisphenol-A in the Female Mouse Genital Tract

Developmental exposure to BPA induces morphological, functional, and behavioral anomalies associated with reproduction

Abstract

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Long-Term Effects of Fetal Exposure to Low Doses of Bisphenol-A in the Female Mouse Genital Tract.

Developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. Humans are routinely exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials and plastic food and beverage containers. The aim of the present study was to determine the effects of in utero exposure to low, environmentally relevant doses of BPA on the development of female reproductive tissues in CD-1 mice. In previous publications, we have shown that this treatment alters the morphology of the mammary gland and affects estrous cyclicity. Here we report that in utero exposure to 25 and 250 ng BPA/ kg of body weight per day via osmotic pumps implanted into pregnant dams at Gestational Day 9 induces alterations in the genital tract of female offspring that are revealed during adulthood. They include decreased wet weight of the vagina, decreased volume of the endometrial lamina propria, increased incorporation of bromodeoxyuridine into the DNA of endometrial gland epithelial cells, and increased expression of estrogen receptor-alpha (ERalpha) and progesterone receptor in the luminal epithelium of the endometrium and subepithelial stroma. Because ERalpha is known to be expressed in these estrogen-target organs at the time of BPA exposure, it is plausible that BPA may directly affect the expression of ER-controlled genes involved in the morphogenesis of these organs. In addition, BPA-induced alterations that specifically affect hypothalamic-pituitary-gonadal axis function may further contribute to the anomalies observed at 3 mo of age, long after the cessation of BPA exposure.

Sources:
  • Long-term effects of fetal exposure to low doses of the xenoestrogen bisphenol-A in the female mouse genital tract,
    NCBI, PMD: 15689538, Biol Reprod. 2005 Jun;72(6):1344-51. Epub 2005 Feb 2.
  • Full text, The Society for the Study of Reproduction, 72/6/1344, Biology of ReproductionJune 1, 2005 vol. 72 no. 61344-1351, biolreprod.104.036301v1.
DES Related Studies