Prenatal Exposure to Bisphenol A at Environmentally Relevant Doses Adversely Affects the Murine Female Reproductive Tract Later in Life
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.
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.
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.
These data suggest that BPA causes long-term adverse reproductive and carcinogenic effects if exposure occurs during critical periods of differentiation.
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
Effects of Diethylstilbestrol on the genital tract of male and female offspring
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.
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.
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.
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.
In utero DES-exposure associated with vaginal adenosis in DES Daughters
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 toclear 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.
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.