EFFECT OF THE PEROXISOME PROLIFERATOR, AMMONIUM PERFLUOROOCTANOATE (C8), ON HEPATIC AROMATASE-ACTIVITY IN ADULT MALE CRL-CD BR (CD) RATS

The incidence of Leydig cell adenomas increases in CD rats fed for 2 y ears with the hepatic peroxisome proliferator, ammonium perfluorooctan oate (C8). Treatment with C8 increased the serum concentration of estr adiol in 2-week gavage studies, and feeding studies at various time po ints up to 2 years, and was also accompanied by increases in liver wei ght and hepatic beta-oxidation activity, Since peroxisome proliferator s induce both hepatic beta-oxidation and specific cytochrome P450 enzy mes, C8 may also induce aromatase (cytochrome P450-19A1), the cytochro me P450 monooxygenase which converts androgens to estrogens. This hypo thesis 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 b ody wt. An additional group, the pair-fed control, was fed at a rate m atched to the daily consumption by the 40 mg C8/kg group. Treatment wi th C8 produced a dose-dependent decrease in body weight, and increases in absolute and relative liver weights, and in the protein yield of h epatic microsomes. These C8-induced changes were associated with a 2-f old increase in the serum concentration of estradiol and up to a 16-fo ld 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 beta-oxidatio n activity and the microsomal concentration of total cytochrome P450 w ere also increased by C8, A comparison of estimated EC50 values sugges ted that these parameters may be less sensitive to induction by C8 tha n hepatic aromatase activity. Co-incubation of control liver microsome s with C8 in the aromatase assay for 2 hr dose dependently reduced the apparent aromatase activity. This inhibition of aromatase in vitro bu t increase in vivo was further investigated using cultured rat hepatoc ytes. 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 ser um concentration of estradiol produced by C8 in rats is at least partl y due to a direct effect on the liver to increase synthesis of estradi ol through induction of aromatase cytochrome P450 in the endoplasmic r eticulum. (C) 1996 Society of Toxicology