3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice.
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.
Wickliffe
J K
JK
Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas, USA. jkwickli@utmb.edu
Galbert
L A
LA
Ammenheuser
M M
MM
Herring
S M
SM
Xie
J
J
Masters
O E
OE
Friedberg
E C
EC
Lloyd
R S
RS
Ward
J B
JB
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
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