Prenatal exposure to bisphenol a at environmentally relevant doses adversely affects the murine female reproductive tract later in life

Abstract

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.

Keywords: BPA; DES; carcinogenesis; development; diethylstilbestrol; endocrine disruptors; ovary; reproduction; toxicology; uterus.

Figure 1

Photomicrographs of representative examples of abnormalities (H&E-stained tissue sections) in mice prenatally treated with BPA. (A) Cystadenoma of the ovary (BPA-100) composed of anastomosing papillary fronds (arrow). (B) Adenomatous hyperplasia and CEH (arrow) in the uterus (BPA-1), characterized by hyperplastic endometrial glands and foci of cystic dilated glands lined by flattened epithelium; some secretory material is present in the lumen of some glands. (C) Higher magnification of (B) showing hyperplastic endometrial glands lined by cells with regularly shaped nuclei with little to no cellular pleomorphism or mitotic activity. (D) Atypical hyperplasia in the uterus (BPA-0.1) composed of foci of irregularly shaped glands with little intervening stroma (arrows). (E) Higher magnification of (D) shows “piling up” of cells (arrows) with hyperchromatic nuclei and many mitotic figures. (F) Endometrial polyps (P) extending into the uterine lumen (BPA-1).

Figure 2

Photomicrographs of abnormalities in H&E-stained tissue sections from mice prenatally treated with BPA. (A) Endometrial stromal polyp (P) extending into the uterine lumen (BPA-10); note areas of CEH (arrow) with secretory material in glands. (B) Endometrial stromal sarcoma that has infiltrated into the uterine cervix (BPA-100). The lesion is composed of cells with pleomorphic nuclei with a moderate amount of mitotic activity; foci of inflammatory cells are indicated by the arrow. (C) Vaginal adenosis in tissue (BPA-1000) shows foci of “glandular structures” (G) lined by simple cuboidal to columnar epithelium. In one area, these “glands” were lined by squamous epithelium with keratinizing cells in the lumen (arrow); some of these glandular structures connected with the vaginal lumen (L), which is lined by stratified squamous epithelium. (D) Higher magnification of of vaginal adenosis in (C) showing glandular structures that connect to the squamous epithelium lining the vaginal lumen. (E) Mammary adenocarcinoma (BPA-1000) is a large solid tumor that has invaded the entire mammary structure and underlying muscle. (F) Higher magnification of (E) showing mammary adenocarcinoma composed of irregular shaped glands and pleomorphic cells with hyperchromatic nuclei.