Bisphenol A-Induced Increase in Uterine Weight and Alterations in Uterine Morphology in Ovariectomized B6C3F1 Mice: Role of the Estrogen Receptor

Abstract

The ability of the environmental xenoestrogen bisphenol A (BPA) to increase uterine wet weight in the rodent remains controversial, and few studies have previously examined the effects of BPA on uterine morphology. Furthermore, it is not known whether BPA-induced uterotrophic effects are, similarly to beta-estradiol (E(2)), mediated through the estrogen receptor (ER). In this study, we compared the effects of BPA on uterine wet weight and morphology to those of E(2) in the B6C3F1 ovariectomized mouse. To examine whether these effects were mediated through the ER, the antiestrogen ICI 182, 780 (ICI) was co-administered with BPA or E(2). We report that subcutaneous administration of BPA at doses between 0.8 and 8 mg/day over 4 days significantly increased mean uterine wet weights above those of vehicle (corn oil)-treated mice. The uterine weight data suggest that BPA acts as a partial agonist with an EC(50) of 0.72 mg/day compared to 19.4 ng/day for E(2). BPA (2 mg/day) and E(2) (40 ng/day) induced a significant increase in luminal epithelial height and in the thickness of both the stromal and myometrial layers of the uterus. The effects of 40 ng E(2)/day on all endpoints studied were reversed by 20 microg ICI/day. ICI at 200, but not 20 microg/day, was able to reverse the BPA (2 mg/day)-induced increase in both uterine wet weight and luminal epithelial height. ICI alone at 200 microg/day stimulated an increase in thickness of both the stroma and myometrium and did not reverse the effects of BPA (2 mg/day) on these layers. These results suggest that the BPA-induced increase in uterine wet weight and in luminal epithelial height in the ovariectomized B6C3F1 mouse are mediated by the ER.

Effects of the Environmental Oestrogens Bisphenol A, Tetrachlorobisphenol A, Tetrabromobisphenol A, 4‐Hydroxybiphenyl and 4,4′‐Dihydroxybiphenyl on Oestrogen Receptor Binding, Cell Proliferation and Regulation of Oestrogen Sensitive Proteins in the Human Breast Cancer Cell Line MCF‐7

“…* (PϽ0.05), ** (PϽ0.01) different from control, (Mann-Whitney rank sum test on raw data). nent (Papaconstantinou et al 2000). Keeping this in mind, cell growth in MCF-7 cells can be used to distinguish between agonists (maximal stimulation of cell growth), and partial agonists (partial stimulation of cell growth) with regard to oestrogen-like properties (Soto et al 1997).…”

Bisphenol-A (BPA) Affects Reproductive Formation across Generations in Mice

“…Furthermore, our histology in F2 mice showed at some sites abnormal morphology inducing expansion or emphraxis of the uterine lumen and partial loss of the uterine epithelium, suggesting that the constituents of F2 uterus were out of harmony in growth. Although there is a report that hyperplasia of the uterine endometrium was induced by BPA exposure [9], the report analyzed the uterus of adult F1 mice or fetal F2 mice that were different from materials in the present study. Nevertheless, we cannot rule out the possibility that abnormal morphology of the adult F2 uterus in the present study resulted from BPA exposure to F0 mice.…”

“…was paid to HOXA10 gene that could be involved with all developmental stages in reproductive organs [2,9,12]. HOX genes can control the development of the oviduct, uterus, cervix, and upper vagina [15].…”

Organizational and activational effects of estrogenic endocrine disrupting chemicals

“…There are many studies of EDCs in terms of effects on ER binding and gene expression and on their effects in specific organs, such as the vagina (Papaconstantinou et al, 2000), and some studies on organism-level effects (NRC, 1999). However, there are few, if any, investigations integrating these effects from the molecular through the functional level.…”