ToxSci Advance Access originally published online on March 7, 2003
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Toxicological Sciences 72, 201-209 (2003)
Copyright © 2003 by the Society of Toxicology
CARCINOGENICITY |
Male Mice Deficient in Microsomal Epoxide Hydrolase Are Not Susceptible to Benzene-Induced Toxicity
* CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709; and
National Cancer Institute, Bethesda, Maryland 20892
Enzymes involved in benzene metabolism are likely genetic determinants of benzene-induced toxicity. Polymorphisms in human microsomal epoxide hydrolase (mEH) are associated with an increased risk of developing leukemia, specifically those associated with benzene. This study was designed to investigate the importance of mEH in benzene-induced toxicity. Male and female mEH-deficient (mEH–/–) mice and background mice (129/Sv) were exposed to inhaled benzene (0, 10, 50, or 100 ppm) 5 days/week, 6 h/day, for a two-week duration. Total white blood cell counts and bone marrow cell counts were used to assess hematotoxicity and myelotoxicity. Micronucleated peripheral blood cells were counted to assess genotoxicity, and the p21 mRNA level in bone marrow cells was used as a determinant of the p53-regulated DNA damage response. Male mEH–/– mice did not have any significant hematotoxicity or myelotoxicity at the highest benzene exposure compared to the male 129/Sv mice. Significant hematotoxicity or myelotoxicity did not occur in the female mEH–/– or 129/Sv mice. Male mEH–/– mice were also unresponsive to benzene-induced genotoxicity compared to a significant induction in the male 129/Sv mice. The female mEH–/– and 129/Sv mice were virtually unresponsive to benzene-induced genotoxicity. While p21 mRNA expression was highly induced in male 129/Sv mice after exposure to 100-ppm benzene, no significant alteration was observed in male mEH–/– mice. Likewise, p21 mRNA expression in female mEH–/– mice was not significantly induced upon benzene exposure whereas a significant induction was observed in female 129/Sv mice. Thus mEH appears to be critical in benzene-induced toxicity in male, but not female, mice.
Key Words: benzene; bone marrow; genotoxicity; hematotoxicity; leukemia; mEH; micronuclei.
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