Profound effects of the weak environmental estrogen-like chemical bisphenol A on the growth of the mammary gland of Noble rats.

In the present study we have examined the effects of the environmental estrogenic chemical bisphenol A on proliferative activity, cell cycle kinetics and differentiation of the mammary gland of female Noble rats. Differentiation measured by the degree of lobular maturation revealed that the conversion of immature structures to mature structures was significantly increased in response to exposure to both low (0.1 mg/kg/day) and high (54 mg/kg/day) doses of bisphenol A compared to controls. The proliferative activity of epithelial cells was increased by 143% over controls by the exposure of animals to the low dose of bisphenol A, whereas a 220% increase over controls was observed for the high dose of bisphenol A. The labelling index and growth fraction were 19% and 27%, respectively, for a low dose of bisphenol A; and 27% and 45%, respectively, for a high dose of bisphenol A, compared to 18% and 31%, respectively, in controls. A significant increase in the conversion of mammary epithelial cells from G0, to G1, and S-phase cells by 1.8 and 4.5-fold, respectively, was observed in animals exposed to the high dose of bisphenol A compared to that of controls. Based on the previously reported estrogenic activity of an equivalent dose of bisphenol A to that of diethylstilbestrol (DES) (0.1 mg/kg/day), a calculated theoretical dose of the order of 10(6)-fold higher of bisphenol A will be required to produce the same biological effects as DES. A comparison of the proliferative activity of DES and that of an equivalent dose of bisphenol A observed in this study, however, revealed that its influence on proliferative activity in the epithelial cells of the mammary gland was profound. The weak estrogenic activity of bisphenol A does not explain its profound effect on cell proliferation observed in this study. Perturbation of the cell cycle is considered a risk factor for the development of cancer. Bisphenol-mediated perturbation of the cell cycle in epithelial cells may produce adverse effects in the mammary glands of Noble rats.