Bisphenol A can cause Long-Term Adverse Reproductive and Carcinogenic Effects

Abstract:

BPA can cause Long-Term Adverse Reproductive and Carcinogenic Effects, Data suggest

BACKGROUND:
Exposure to endocrine-disrupting chemicals during critical developmental periods causes adverse consequences later in life; an example is prenatal exposure to the pharmaceutical diethylstilbestrol (DES). Bisphenol A (BPA), an environmental estrogen used in the synthesis of plastics, is of concern because its chemical structure resembles that of DES, and it is a “high-volume production” chemical with widespread human exposure.

OBJECTIVES:
In this study we investigated whether prenatal BPA causes long-term adverse effects in female reproductive tissues in an experimental animal model previously shown useful in studying effects of prenatal DES.

METHODS:
Timed pregnant CD-1 mice were treated on days 9-16 of gestation with BPA (0.1, 1, 10, 100, or 1,000 mug/kg/day). After delivery, pups were held for 18 months; reproductive tissues were then evaluated.

RESULTS:
Ovarian cysts were significantly increased in the 1-mug/kg BPA group; ovarian cyst-adenomas were seen in the other three BPA-treated groups but not in corn-oil controls. We observed increased progressive proliferative lesions of the oviduct after BPA treatment, similar to those described in response to DES. Further, although not statistically different from the controls, prominent mesonephric (Wolffian) remnants and squamous metaplasia of the uterus, as well as vaginal adenosis, were present in BPA-treated mice, similar to lesions reported following DES treatment. More severe pathologies observed in some BPA-treated animals included atypical hyperplasia and stromal polyps of the uterus; sarcoma of the uterine cervix; and mammary adenocarcinoma. We did not observe these lesions in controls.

CONCLUSIONS:
These data suggest that BPA causes long-term adverse reproductive and carcinogenic effects if exposure occurs during critical periods of differentiation.

Sources:

• NCBI, PMID: 19590677
  doi: 10.1289/ehp.0800045. Epub 2009 Jan 15.
• Full sudy: PMCID: PMC2702400 2009 June. Prenatal Exposure to Bisphenol A at Environmentally Relevant Doses Adversely Affects the Murine Female Reproductive Tract Later in Life

Follow-up Study of Male and Female Offspring of DES-exposed Mothers

Abstract #1:

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

1975 – This is a follow-up study of male and female offspring of mothers who were part of a double-blind placebo controlled investigation during the years 1951-1952, originally aimed at determining the usefulness of Diethylstilbestrol (DES) administration in maintaining pregnancy.

• So far, 84 DES-exposed females, 43 female controls, 42 DES-exposed males and 37 male controls have been examined.
• Circumferential ridges of the vagina and cervix were seen in 39% of the DES-exposed females but in none of the controls.
• Colposcopy revealed vaginal epitheleal changes in 78% of the DES-exposed females 2% of the female controls.
• Cytology proved to be reliable as a screening test for vaginal epithelial changes in the DES-exposed female.
• Urine cytology was negative for tumor cells in all patients.
• The main abnormal finding in the DES-exposed males was that cysts in the epididymis were detected in 10%.
• No cases of cancer were observed in either the male or female offspring.

Abstract #2:

1977 – 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.

• 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.

NCBI Sources:

• Follow-up study of male and female offspring of DES-treated mothers a preliminary report
  J Reprod Med. 1975 Jul;15(1):29-32. PMID: 1171234.
• Follow-up study of male and female offspring of DES-exposed mothers, Obstet Gynecol. 1977 Jan;49(1):1-8. PMID: 318736.

More DES DiEthylStilbestrol Resources

• DES studies on cancers and screening.
• DES studies on epigenetics and transgenerational effects.
• DES studies on fertility and pregnancy.
• DES studies on gender identity and psychological health.
• DES studies on in-utero exposure to DES and side-effects.
• DES studies on the genital tract.
• Papers on DES lawsuits.
• DES videos and posts tagged DES, the DES-exposed, DES victims.

Vaginal Cancer Information Leaflet

It’s a tough one. We talk about sexual health these days in such open terms, but I feel that people just aren’t yet ready to talk about gynaecological cancers.

If you have any concerns about vaginal cancer please speak to your G.P.

Download The Eve Appeal Vaginal Cancer Information Leaflet.
By The Eve Appeal gynaecology cancer research fund, London UK – on Facebook and Twitter.

Watch the Diaporama, and the DES research photo set on flickr®  

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Our Posts about – Adenocarcinoma of the Vagina – Vaginal Adenosis – Vulvar cancer – Women’s Health.

DiEthylStilbestrol Resources: Cancer, Breast Cancer, CCAC, Vaginal Cancer, Screening

Cancer

NCBI PubMed DiEthylStilbestrol Resources: Cancer, Breast Cancer, CCAC, Vaginal Cancer, Screening.

• Aneuploidy Induction and Cell Transformation by Diethylstilbestrol: A Possible Chromosomal Mechanism in Carcinogenesis – 1983
• Animal models of prenatal exposure to diethylstilboestrol – 1989
• Cancer risk in DES daughters – 2010
• Cancer risk in diethylstilbestrol-exposed offspring – 1976
• Cancer Risk in Men exposed in Utero to DiEthylStilbestrol – 2001
• Cancer Risk in Women exposed to DiEthylStilbestrol in Utero – 1998
• Cancer Risk in Women Exposed to Diethylstilbestrol in Utero – 2015
• Cancer Risk in Women prenatally exposed to DiEthylStilbestrol – 2007
• Childhood cancer: overview of incidence trends and environmental carcinogens – 1995
• Critical windows of exposure for children’s health: cancer in human epidemiological studies and neoplasms in experimental animal models – 2000
• Diethylstilbestrol Genetics, Teratogenesis, and Tumor Spectrum in Humans – 1985
• Diethylstilboestrol: Pharmacology, Toxicology and Carcinogenicity in Experimental Animals – 1992
• Endocrine Disruptors in Female Reproductive Tract Development and Carcinogenesis – 2009
• Epidemiological studies of the effects of diethylstilboestrol – 1989
• Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol – 1998
• Introduction and overview. Perinatal carcinogenesis: growing a node for epidemiology, risk management, and animal studies – 2004
• Lessons learned from Perinatal Exposure to DiEthylStilbestrol – 2004
• Multi-generational Carcinogenesis from DiEthylStilbestrol investigated by Blastocyst Transfers in Mice – 1995
• Occurrence of tumours in the descendants of CBA male mice prenatally treated with diethylstilbestrol – 1992
• Offspring of women exposed in utero to diethylstilbestrol (DES): a preliminary report of benign and malignant pathology in the third generation – 2008
• Proliferative lesions and reproductive tract tumors in male descendants of mice exposed developmentally to diethylstilbestrol – 2000
• Risk of benign gynecologic tumors in relation to prenatal diethylstilbestrol exposure – 2005

– Breast Cancer

• 2015 Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo.
• 2014 Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters.
• 2013 Does cancer start in the womb? Altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors.
• 2013 Exposure to Synthetic Estrogens at different Times during the Life and their Side Effects on Breast Cancer Risk.
• 2013 Prenatal DES Exposure in Relation to Breast Size
• 2010 In Utero Exposure to Diethylstilbestrol (DES) or Bisphenol-A (BPA) Increases EZH2 Expression in the Mammary Gland: An Epigenetic Mechanism Linking Endocrine Disruptors to Breast Cancer
• 2006 Birth weight and breast cancer risk.
• 2006 Prenatal DiEthylStilbestrol Exposure and Risk of Breast Cancer.
• 2005 Breast cancer incidence in women prenatally exposed to maternal cigarette smoke.
• 2005 Management of breast cancer in patients prenatally exposed to diethylstilbestrol: are we prepared?.
• 2002 Risk of breast cancer in women exposed to diethylstilbestrol in utero: prelimiinary results (United States).
• 2001 Long-Term Cancer Risk in Women given DiEthylStilbestrol (DES) during Pregnancy.
• 1993 Breast cancer in mothers prescribed diethylstilbestrol in pregnancy. Further follow-up.
• 1978 A Twenty-Five-Year Follow-Up Study of Women exposed to DiEthylStilbestrol during Pregnancy.

– Clear Cell AdenoCarcinoma and Vaginal Cancer

• A case of vaginal adenocarcinoma after uterine exposure to diethylstilbestrol – 1985
• Age-incidence and risk of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix – 1977
• Atypical vaginal adenosis and cervical ectropion. Association with clear cell adenocarcinoma in diethylstilbestrol-exposed offspring – 1984
• Adenocarcinoma of the Vagina — Association of Maternal Stilbestrol Therapy with Tumor Appearance in Young Women – 1971
• Clear Cell AdenoCarcinoma and the current Status of DES-exposed Females – 1981
• Clear Cell Adenocarcinoma of the Ovary Associated With In Utero Diethylstilbestrol Exposure: Case Report and Clinical Overview – 2009.
• Clear cell adenocarcinoma of the vagina and cervix. An update of the central Netherlands registry showing twin age incidence peaks – 1997.
• Clear cell adenocarcinoma of the vagina and cervix: incidence, undetected disease, and diethylstilbestrol – 1988
• Clear cell adenocarcinoma of the vagina and cervix secondary to intrauterine diethylstilbestrol exposure – 1990
• Clear cell carcinoma of the cervix: a multi-institutional review in the post-DES era – 2008
• Colposcopic evaluation of DES-exposed progeny at two large medical centers: the squamous neoplasia problem – 1978
• Development of cervical and vaginal squamous cell neoplasia as a late consequence of in utero exposure to diethylstilbestrol – 2008
• Diethylstilbestrol (DES)-induced clear cell adenocarcinoma of the vagina metastasizing to the brain – 2007
• Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) project – 1981
• Epidemiologic aspects and factors related to survival in 384 Registry cases of clear cell adenocarcinoma of the vagina and cervix – 1979
• Epidemiology of vaginal adenosis and adenocarcinoma associated with exposure to stilbestrol in utero – 1977
• Follow-up of Patients with Clear-Cell Adenocarcinoma of the Vagina and Cervix – 2018.
• Genital clear cell adenocarcinoma – 1983
• Incidence of squamous neoplasia of the cervix and vagina in DES-exposed daughters – 2000
• Incidence of squamous neoplasia of the cervix and vagina in women exposed prenatally to diethylstilbestrol (United States) – 2001
• Increased incidence of cervical and vaginal dysplasia in 3,980 diethylstilbestrol-exposed young women. Experience of the National Collaborative Diethylstilbestrol Adenosis Project – 1984
• Ovarian Carcinoma in an Adolescent with TransGenerational Exposure to DiEthylStilbestrol – 2003
• Prenatal diethylstilbestrol exposure and high-grade squamous cell neoplasia of the lower genital tract – 2016
• Primary Vaginal Mucinous Adenocarcinoma of Intestinal Type, Associated With Intestinal Metaplasia of Skene Ducts in a Diethylstilbestrol-Exposed Woman – 2015
• Rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix. An update – 1987
• Risk of cervical intra-epithelial neoplasia and invasive cancer of the cervix in DES daughters – 2016
• Roles of p63 in the DiEthylStilbestrol-induced CervicoVaginal Adenosis – 2004
• Squamous cell dysplasia and carcinoma in situ of the cervix and vagina after prenatal exposure to diethylstilbestrol – 1978
• Squamous cell carcinoma in situ of the vagina and cervix after intrauterine DES exposure – 1978
• The Development of Cervical and Vaginal Adenosis as a Result of Diethylstilbestrol Exposure In Utero – 2012
• Vaginal Adenosis and AdenoCarcinoma in Mice exposed PreNatally or NeoNatally to DiEthylStilbestrol – 1982
• Vaginal adenosis and diethylstilboestrol – 1984
• Vaginal and Cervical Abnormalities, including CCA, related to PreNatal Exposure to Stilbestrol – 1974
• Vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones – 1977
• Vaginal and cervical cancer due to diethylstilbestrol (DES); end epidemic – 2009.
• Vaginal and cervical squamous cell dysplasia in women exposed to diethylstilbestrol in utero – 1978
• Very late recurrence of Diethylstilbestrol – related clear cell carcinoma of the cervix: case report – 2015

– Screening

• Breast Cancer Screening in Women exposed in Utero to DiEthylStilbestrol – 2009
• Cervical and vaginal cancer detection at a regional diethylstilbestrol (DES) screening clinic – 1988
• Cervical intraepithelial neoplasia associated with exposure to diethylstilbestrol in utero: a clinical and pathologic study – 1981
• Cervical screening and general physical examination behaviors of women exposed in utero to diethylstilbestrol – 2008
• Colposcopic evaluation of DES-exposed progeny at two large medical centers: the squamous neoplasia problem – 1978
• Colposcopic findings and intraepithelial neoplasia in diethylstilbestrol-exposed offspring. The Dutch experience – 1990
• Development of DES-associated clear-cell carcinoma: the importance of regular screening – 1979
• Diethylstilbestrol (DES) update: recommendations for the identification and management of DES-exposed individuals – 2003
• Factors associated with a lack of pap smear utilisation in women exposed in utero to diethylstilbestrol – 2015
• Identification and management of DES-exposed women – 1988
• Magnetic resonance imaging of Müllerian duct anomalies in children – 2016
• Mammography Screening Behaviors of Women exposed prenatally to DiEthylStilbestrol – 2012
• Six years’ experience with screening of a diethylstilbestrol-exposed population – 1979
• The management of DES-exposed women: one physician’s approach – 1976
• Value of screening procedures for the detection of vaginal adenosis –  1976

More DES DiEthylStilbestrol Resources

• DES studies on cancers and screening.
• DES studies on epigenetics and transgenerational effects.
• DES studies on fertility and pregnancy.
• DES studies on gender identity and psychological health.
• DES studies on in-utero exposure to DES and side-effects.
• DES studies on the genital tract.
• Papers on DES lawsuits.
• DES videos and posts tagged DES, the DES-exposed, DES victims.

Vaginal Adenosis, Detection and Value of Screening Procedures

In utero exposure to Stilbestrol associated with vaginal adenosis in DES Daughters

Description:
Vaginal Adenosis (submucosal glands lined by mullerian-type epithelium) was rarely described in the past. It has been seen frequently in young women whose mothers took diethylstilbestrol and similar compounds during pregnancy. The adenosis can appear as a red granular lesion. Biopsy of these red areas as well as those that initially appear normal but fail to stain with Schiller’s iodine can usually be accomplished in the office. Although these glands appear to be benign, they
have been observed in close proximity to clear cell adenocarcinomas that have also occurred in young females whose mothers took stilbestrol during pregnancy. Present estimates suggest that the carcinomas are rare among the exposed population while adenosis occurs frequently. Although adenosis has been treated by surgical excision and local destruction (cauterization), the natural history of stilbestrol-associated adenosis is unknown. Close follow-up of patients with vaginal adenosis is certainly indicated and in many instances might prove to be the most prudent approach.

Study:
This study describes the use of routine vaginal iodine staining and other screening procedures for the detection of vaginal adenosis in 3871 postpubertal female patients. Iodine staining identified 65 patients with nonstaining areas in the vagina. Colposcopy verified the presence of vaginal adenosis in 11 of the 65 patients. Directed biopsies confirmed the diagnosis in 10 patients. The iodine staining procedure detected vaginal adenosis in only 1 patient who did not have a positive history of DES exposure or coexisting physical findings. Iodine staining of the vagina has little value as a screening procedure for the detection of vaginal adenosis. Based on these findings, a careful medical history and vaginal examination are recommended as the most productive routine screening procedures for vaginal adenosis. Evaluation and followup of those patients with a history of DES exposure in utero or physical findings suggestive of vaginal adenosis should include vaginal Papanicolaou smears supplemented by colposcopy at 6-month to 1-year intervals. Colposcopically directed biopsies of all abnormal areas should be obtained.

Sources: Value of screening procedures for the detection of vaginal adenosis, NCBI, Dr Herbst A, Mar 1976

Screening for DES Daughters

• Screening for DES Daughters – Exposed to DES? Get a Pap Smear!
• Are you a probable DES Daughter? See this Chart and establishhow much Risk you face!
• Pap smears – Letter of the Day, March 2012

More DES DiEthylStilbestrol Resources

• DES studies on cancers and screening.
• DES studies on epigenetics and transgenerational effects.
• DES studies on fertility and pregnancy.
• DES studies on gender identity and psychological health.
• DES studies on in-utero exposure to DES and side-effects.
• DES studies on the genital tract.
• Papers on DES lawsuits.
• DES videos and posts tagged DES, the DES-exposed, DES victims.