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Exposure of Hematopoietic Stem Cells to Benzene or 1,4-Benzoquinone Induces Gender-Specific Gene Expression

CIIT Centers for Health Research, Research Triangle Park, North Carolina, USA

Key Words. Hematopoietic stem cell • Benzene • Toxicity • In vitro culture • Leukemia Quantitative reverse transcription–polymerase chain reaction

Correspondence: Brenda Faiola, Ph.D.,GlaxoSmithKline, Research & Development, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398, USA. Telephone: 919-483-5075; Fax: 919-483-6858; e-mail: Brenda.x.Faiola{at}gsk.com

Chronic exposure to benzene results in progressive decline of hematopoietic function and may lead to the onset of various disorders, including aplastic anemia, myelodysplastic syndrome, and leukemia. Damage to macromolecules resulting from benzene metabolites and misrepair of DNA lesions may lead to changes in hematopoietic stem cells (HSCs) that give rise to leukemic clones. We have shown previously that male mice exposed to benzene by inhalation were significantly more susceptible to benzene-induced toxicities than females. Because HSCs are targets for benzene-induced cytotoxicity and genotoxicity, we investigated DNA damage responses in HSC from both genders of 129/SvJ mice after exposure to 1,4-benzoquinone (BQ) in vitro or benzene in vivo. 1,4-BQ is a highly reactive metabolite of benzene that can cause cellular damage by forming protein and DNA adducts and producing reactive oxygen species. HSCs cultured in the presence of 1,4-BQ for 24 hours showed a gender-independent, dose-dependent cytotoxic response. RNA isolated from 1,4-BQ–treated HSCs and HSCs from mice exposed to 100 ppm benzene by inhalation showed altered expression of apoptosis, DNA repair, cell cycle, and growth control genes compared with unexposed HSCs. Rad51, xpc, and mdm-2 transcript levels were increased in male but not female HSCs exposed to 1,4-BQ. Males exposed to benzene exhibited higher mRNA levels for xpc, ku80, ccng, and wig1. These gene expression differences may partially explain the gender disparity in benzene susceptibility. HSC culture systems such as the one used here will be useful for testing the hematotoxicity of various substances, including other benzene metabolites.

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