Effect of the Peroxisome Proliferator, Ammonium Perfluorooctanoate (C8), on Hepatic Aromatase Activity in Adult Male Crl:CD BR (CD) Rats

Abstract

The incidence of Leydig cell adenomas increases in CD rats fed for 2 years with the hepatic peroxisome proliferator, ammonium perfluorooctanoate (C8). Treatment with C8 increased the serum concentration of estradiol in 2-week gavage studies, and feeding studies at various time points up to 2 years, and was also accompanied by increases in liver weight and hepatic β-oxidation activity. Since peroxisome proliferators induce both hepatic β-oxidation and specific cytochrome P450 enzymes, C8 may also induce aromatase (cytochrome P450-19A1), the cytochrome P450 monooxygenase which converts androgens to estrogens. This hypothesis was investigated in the present study. Adult male CD rats were dosed daily by gavage for 14 days with 0, 0.2, 2, 20, or 40 mg C8/kg body wt. An additional group, the pair-fed control, was fed at a rate matched to the daily consumption by the 40 mg C8/kg group. Treatment with C8 produced a dose-dependent decrease in body weight, and increases in absolute and relative liver weights, and in the protein yield of hepatic microsomes. These C8-induced changes were associated with a 2-fold increase in the serum concentration of estradiol and up to a 16-fold increase in total hepatic aromatase activity. A significant linear correlation was established between serum estradiol and total hepatic aromatase activity. The absolute weights and the aromatase activity of the testes were not affected by C8. Hepatic peroxisomal β-oxidation activity and the microsomal concentration of total cytochrome P450 were also increased by C8. A comparison of estimated EC50 values suggested that these parameters may be less sensitive to induction by C8 than hepatic aromatase activity. Co-incubation of control liver microsomes with C8 in the aromatase assay for 2 hr dose dependently reduced the apparent aromatase activity. This inhibition of aromatasein vitrobut increasein vivowas further investigated using cultured rat hepatocytes. Decreases in aromatase activity were found after up to 42 hr of treatment with C8, but the enzyme activity was increased almost 2-fold after 66 hr. The results of this study suggest that the increased serum concentration of estradiol produced by C8 in rats is at least partly due to a direct effect on the liver to increase synthesis of estradiol through induction of aromatase cytochrome P450 in the endoplasmic reticulum.