DNA damage, DNA repair gene expression, and topoisomerase IIα activity in CD-1 mice following in utero benzene exposure. (1st September 2022)

• Record Type: Journal Article
• Authors: Holmes, Trent H.; Winn, Louise M.
• Is Part Of: Toxicology letters. Volume 368(2022)
• Page Start: 47
• Page End: 55
• Publication Date: 2022-09-01
• Subjects: BQ Benzoquinone -- dsDNA double-stranded DNA -- GD gestational day -- HR Homologous recombination -- NER Nucleotide excision repair -- NHEJ Non-homologous end joining -- γH2AX phosphorylated histone variant 2AX; Benzene -- Fetal -- DNA Damage -- DNA repair -- Topoisomerase IIα; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2022.08.002
• Languages: English
• ISSNs: 0378-4274

Abstract

Abstract: Benzene is an environmental toxicant and known human carcinogen. Recent epidemiological studies show a relationship between exposure to benzene in pregnant women and increased incidence of childhood leukemias. Studies in murine models demonstrate a relationship between carcinogenicity and in utero benzene exposure which was sex dependent, thus the cellular mechanisms of benzene toxicity by sex require further studies. A hypothesized mechanism of benzene-induced in utero carcinogenicity is through increased DNA damage and reduced fetal DNA repair capacity. This includes the potential inhibition of topoisomerase IIα (topo IIα), in part, to generate double stranded DNA (dsDNA) breaks and induction of error-prone DNA repair. Using a mouse model of transplacental benzene carcinogenicity, gestational day (GD) 14 fetal livers were harvested 2, 6, and 24 h following maternal exposure to 200 mg/kg benzene and used to assess DNA damage, DNA repair gene expression and topo IIα activity. DNA damage, measured by levels of modified histone H2AX (γH2AX), is significantly increased in benzene exposed pups, with sex-dependent significance seen only in female pups. Comet assay results confirmed that benzene exposure in utero induces dsDNA damage in the GD14 fetal liver. Genes involved in DNA repair were assessed, and DNA repair gene expression changes were observed after 24 h in genes related to nucleotide excision repair, homologous recombination, and non-homologous end-joining. There were no significant differences in topo IIα activity in GD14 fetal livers at any timepoint, or between sexes. Overall, this study shows that 200 mg/kg benzene exposure induces dsDNA damage and alters fetal DNA repair gene expression in utero, without perturbing fetal topo IIα in CD-1 mice. Highlights: DNA damage is increased in fetal mouse livers following benzene exposure. Comet assay results confirmed that benzene induces dsDNA damage in fetal liver. Fetal DNA repair gene expression changes were observed following benzene exposure. No changes in topo IIα activity in fetal livers were seen after benzene exposure.