Sex-dependent regulation of hepatic peroxisome proliferation in mice by trichloroethylene via peroxisome proliferator-activated receptor alpha (PPAR alpha)

The mechanism of trichloroethylene-induced liver peroxisome proliferation a nd the sex difference in response was investigated using wild-type Sv/129 a nd peroxisome proliferator-activated receptor alpha (PPAR alpha)-null mice. Trichloroethylene treatment (0.75 g/kg for 2 weeks by gavage) resulted in liver peroxisome proliferation in wild-type mice, but not in PPAR alpha-nul l mice, suggesting that trichloroethylene-induced peroxisome proliferation is primarily mediated by PPAR alpha. No remarkable sex difference was obser ved in induction of peroxisome proliferation, as measured morphologically, but a markedly higher induction of several enzymes and PPAR alpha protein a nd mRNA was found in males. On the other hand, trichloroethylene induced li ver cytochrome P450 2E1, the principal enzyme responsible for metabolizing trichloroethylene to chloral hydrate, only in males, which resulted in simi lar expression levels in both sexes after the treatment. Trichloroethylene influenced neither the level of catalase, an enzyme involved in the reducti on of oxidative stress, nor aldehyde dehydrogenase, the main enzyme catalyz ing the conversion to trichloroacetic acid. These results suggest that tric hloroethylene treatment causes a male-specific PPAR alpha-dependent increas e in cellular oxidative stress.