Journal Article

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

Tamie Nakajima, Yuji Kamijo, Nobuteru Usuda, Yan Liang, Yoshimitsu Fukushima, Kiyokazu Kametani, Frank J. Gonzalez and Toshifumi Aoyama

in Carcinogenesis

Volume 21, issue 4, pages 677-682
Published in print April 2000 | ISSN: 0143-3334
Published online April 2000 | e-ISSN: 1460-2180 | DOI:
Sex-dependent regulation of hepatic peroxisome proliferation in mice by trichloroethylene via peroxisome proliferator-activated receptor α (PPARα)

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The mechanism of trichloroethylene-induced liver peroxisome proliferation and the sex difference in response was investigated using wild-type Sv/129 and peroxisome proliferator-activated receptor α (PPARα)-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 PPARα-null mice, suggesting that trichloroethylene-induced peroxisome proliferation is primarily mediated by PPARα. No remarkable sex difference was observed in induction of peroxisome proliferation, as measured morphologically, but a markedly higher induction of several enzymes and PPARα protein and mRNA was found in males. On the other hand, trichloroethylene induced liver cytochrome P450 2E1, the principal enzyme responsible for metabolizing trichloroethylene to chloral hydrate, only in males, which resulted in similar expression levels in both sexes after the treatment. Trichloroethylene influenced neither the level of catalase, an enzyme involved in the reduction of oxidative stress, nor aldehyde dehydrogenase, the main enzyme catalyzing the conversion to trichloroacetic acid. These results suggest that trichloroethylene treatment causes a male-specific PPARα-dependent increase in cellular oxidative stress.

Keywords: ALDH, aldehyde dehydrogenase; AOX, acyl-CoA oxidase; CTEII, cytosolic thioesterase II; CYP, cytochrome P450; DAB, 3,3′-diaminobenzidine; DBF, D-type (peroxisomal) bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase), key enzyme of bile acid synthesis from cholesterol; PH, peroxisome bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase); PPARα, peroxisome proliferator-activated receptor α; PT, peroxisomal thiolase; RXRα, retinoid X receptor α; TPα, trifunctional protein α subunit (long chain-specific hydratase + long chain-specific 3-hydroxyacyl-CoA dehydrogenase); TPβ, long chain-specific 3-ketoacyl-CoA thiolase; VLACS, very long chain acyl-CoA synthetase.

Journal Article.  4042 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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