title: 3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice.
abstract: Xpc-null (Xpc-/-) mice, deficient in the global genome repair subpathway of nucleotide excision repair (NER-GGR), were exposed by intraperitoneal (i.p.) injection to a 300 mg/kg mutagenic dose of 3,4-epoxy-1-butene (EB), to investigate NER's potential role in repairing butadiene (BD) epoxide DNA lesions. Mutagenic sensitivity was assessed using the Hprt assay. Xpc-/- mice were significantly more sensitive to EB exposure, exhibiting an average 2.8-fold increase in Hprt mutant frequency (MF) relative to those of exposed Xpc+/+ (wild-type) mice. As a positive control for NER-GGR, additional mice were exposed by i.p. injection to a 150 mg/kg mutagenic dose of benzo[a]pyrene (B[a]P). The Xpc-/- mice had MFs 2.9-fold higher than those of exposed Xpc+/+ mice. These results suggest that NER-GGR plays a role in recognizing and repairing some of the DNA adducts formed following in vivo exposure to EB. Additional research is needed to examine the response of Xpc-/- mice, as well as other NER-deficient strains, to inhaled BD. Furthermore, it is likely that alternative DNA repair pathways also are involved in restoring genomic integrity compromised by BD-epoxide DNA damage. Collaborative studies are currently underway to address these critical issues.
authors.affiliation: Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas, USA. jkwickli@utmb.edu
authors.forename: J K
authors.initials: JK
authors.lastname: Wickliffe
authors.forename: L A
authors.initials: LA
authors.lastname: Galbert
authors.forename: M M
authors.initials: MM
authors.lastname: Ammenheuser
authors.forename: S M
authors.initials: SM
authors.lastname: Herring
authors.forename: J
authors.initials: J
authors.lastname: Xie
authors.forename: O E
authors.initials: OE
authors.lastname: Masters
authors.forename: E C
authors.initials: EC
authors.lastname: Friedberg
authors.forename: R S
authors.initials: RS
authors.lastname: Lloyd
authors.forename: J B
authors.initials: JB
authors.lastname: Ward
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity; D004247:DNA / Q000235:genetics; D018736:DNA Adducts; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004852:Epoxy Compounds / Q000633:toxicity*; D017930:Genes, Reporter / Q000235:genetics; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation
chemical_list: D018736:DNA Adducts; D004268:DNA-Binding Proteins; D004852:Epoxy Compounds; D009153:Mutagens; C501002:Xpc protein, mouse; D001564:Benzo(a)pyrene; C024370:3,4-epoxy-1-butene; D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase