Sex-dependent regulation of hepatic peroxisome proliferation in mice by trichloroethylene via peroxisome proliferator-activated receptor alpha (PPAR alpha)
T. Nakajima et al., Sex-dependent regulation of hepatic peroxisome proliferation in mice by trichloroethylene via peroxisome proliferator-activated receptor alpha (PPAR alpha), CARCINOGENE, 21(4), 2000, pp. 677-682
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.