The direct effect of hepatic peroxisome proliferators on rat Leydig cell function in vitro

A review of the literature indicates that some compounds which produce hepatic peroxisome proliferation in rats also appear to produce Leydig cell adenomas, and some also affect the serum concentrations of testosterone and estradiol. Previous studies with the peroxisome proliferator ammonium perfluorooctanoate showed a direct effect on Leydig cells to alter steroidogenesis. It was therefore proposed that peroxisome proliferators in general may directly affect Leydig cell function to produce Leydig cell tumors by some undetermined mechanism. The present study investigated whether the following peroxisome proliferators directly affect Leydig cell function in vitro: 2,4-dichlorophenoxyacetic acid, ammonium perfluorooctanoate, acetylsalicylic acid, clofibric acid, ciprofibrate, gemfibrozil, tiadenol, tibric acid, trichloroacetic acid, trichloroethylene, and Wyeth 14,643. Leydig cells, isolated from adult Crl:CDBR rats (12-16 weeks old), were treated with peroxisome proliferator for 21 hr and the medium was assayed for estradiol. The function of the treated Leydig cell was evaluated by measuring the release of testosterone in response to human chorionic gonadotropin (hCG). In general, the peroxisome proliferators reduced the hCG-stimulated release of testosterone and either reduced or had no effect on the baseline release of testosterone. Of the 11 peroxisome proliferators, 8 increased the release of estradiol from Leydig cells treated for 1 day. Two more compounds were found to increase estradiol production when the treatment period was extended to 2 days. These effects were seen at noncytotoxic doses and at concentrations similar to those achieved in rat serum in dietary studies. The results suggest that peroxisome proliferators, as a class of compounds, directly modify the steroidogenic function of Leydig cells in vitro. Some of these compounds are known to produce Leydig cell tumors in rats, but this association has yet to be established for other peroxisome proliferators. This suggests that compounds which directly affect Leydig cell function in vitro may also induce Leydig cell tumors in vivo. Further investigations are necessary to address the mechanism for the in vitro effects on Leydig cells and to clarify the apparent relationship between peroxisome proliferator-induced changes in Leydig cell function and the development of Leydig cell tumors.