High concentrations of bisphenol A induce cell growth and prolactin secretion in an estrogen-responsive pituitary tumor cell line

Abstract

PR1 cells are a prolactin (PRL)-secreting cell line derived from pituitary lactotroph tumors found in 17beta-estradiol (E(2))-treated female Fischer 344 rats. Recently, we reported that as little as 0. 01 pM E(2) could induce half-maximal cell proliferation, whereas the antiestrogen ICI 182,780 (ICI) inhibited proliferation. Interestingly, the cell proliferation response is 1000-fold more sensitive to E(2) than the PRL response (induction of prolactin protein synthesis), suggesting that there is a distinction between cell proliferation and the PRL response in PR1 cells. Bisphenol A (BPA) is a monomer of plastics and epoxy resins that is widely used in dentistry and the food packaging industry. Although it has low estrogenic activity in somatolactotrophs and breast cancer cell lines, its presence in the environment and its long biological half-life have raised concerns about potential effects in humans. We analyzed the effect of BPA and compared its activity with E(2) in the PR1 cell line. PR1 cells show half-maximal proliferation upon treatment with 10 nM BPA, which is 10,000- to 100,000-fold less active than E(2). BPA-induced PR1 cell proliferation is decreased by the pure antiestrogen ICI, suggesting that BPA-induced PR1 cell proliferation is mediated by the estrogen receptor (ER). The decreased affinity of BPA for the ER is illustrated by the fact that 1 nM of ICI inhibited 100 nM BPA-induced cell proliferation, whereas 100 nM ICI was required to block 1 nM E(2)-induced cell proliferation. The PRL response to BPA required 1000 nM BPA to match the PRL secretion induced by 0.01 nM E(2). A competitive binding assay showed that the K(i) of BPA for the ER in PR1 cells is approximately 30-60 nM, which is 1000- to 2000-fold lower than that of E(2). Our study suggests the PR1 cell line can be used as an in vitro assay system for analyzing the effects of weak estrogens on ER-mediated responses and the activities of various estrogenic compounds present in small amounts in the environment.