Exposure of environmental estrogenic compound nonlyphenol to noble rats alters cell-cycle kinetics in the mammary gland.

p-Nonylphenol is an environmental estrogen-like chemical. Nonylphenol has previously been shown to mimic the actions of estrogen both in vivo and in vitro. In the present study, we have examined the effects of an environmental estrogenic chemical, nonlylphenol, on the proliferative activity, cell-cycle kinetics, and differentiation of the mammary gland of female Noble rats. The exposure of animals to two different doses of nonlylphenol (0.01 and 7.1 mg/24 h) significantly increased proliferation of the mammary epithelial cells. Both labeling index and growth fraction were increased by nonlylphenol treatment. Labeling index and growth fraction were 24 and 38%, respectively, for a low dose of nonylphenol; and 32 and 67%, respectively, for a high dose of nonlyphenol, compared to 18 and 35%, respectively, of controls. In addition, nonlylphenol exposure altered cell-cycle kinetics. Both low and high doses of nonylphenol significantly increased the conversion of mammary epithelial cells from G0 to G1 and S-phase cells by 2.2-and 2.6-fold, and by 11- and 4-fold, respectively, compared to that of controls. Differentiation measured by the degree of lobular maturation revealed that the conversion of immature structures to mature structures was significantly increased in response to nonylphenol exposure compared to that of control. Based on the previously reported estrogenic activity of an equivalent dose of nonylphenol to that of DES (0.01 mg/d), a calculated theoretical dose of the order of 10(5)- to 10(6)-fold higher of nonlylphenol will be required to produce the same biological effects as DES. However, the data of this study showed that exposure of 0.01 mg/d of nonlylphenol produced profound effect on cell proliferation in the mammary gland. The weak estrogenic activity of nonlylphenol does not explain its profound effect on cell proliferation observed in this study. Perturbation of cell cycle is considered as a risk factor for the development of cancer. Changes in proliferation and cell cycle have been shown to lead to genetic instability, ultimately resulting in cell transformation. Our results indicated an increase in labeling index and growth fraction, and a perturbation in cell-cycle kinetics from nonlylphenol exposure. Perturbation of cell cycle in response to nonlylphenol exposure may produce adverse effects in the mammary glands of the Noble rats.