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3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice

J K Wickliffe1, L A Galbert, M M Ammenheuser

  • 1Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas, USA. jkwickli@utmb.edu

Environmental and Molecular Mutagenesis
|August 12, 2005
PubMed

Insights

Nucleotide excision repair global genome repair (NER-GGR) helps fix DNA damage from 3,4-epoxy-1-butene. Mice lacking NER-GGR showed higher sensitivity to this mutagen, indicating NER-GGR

Area of Science:

  • Toxicology
  • Molecular Biology
  • Genetics

Background:

  • Butadiene (BD) is an industrial chemical with known mutagenic properties.
  • The epoxide metabolites of BD can form DNA adducts, potentially leading to mutations.
  • Nucleotide excision repair (NER) is a major DNA repair pathway crucial for removing bulky DNA adducts.

Purpose of the Study:

  • To investigate the role of the global genome repair (GGR) subpathway of NER in repairing DNA lesions induced by 3,4-epoxy-1-butene (EB), a metabolite of BD.
  • To assess the mutagenic sensitivity of mice deficient in NER-GGR following exposure to EB.

Main Methods:

  • Xpc-null (Xpc-/-) mice, deficient in NER-GGR, and wild-type (Xpc+/+) mice were exposed via intraperitoneal injection to mutagenic doses of EB.
  • Mutagenic sensitivity was evaluated using the Hprt gene mutation assay.
  • Benzo[a]pyrene (B[a]P) was used as a positive control to validate NER-GGR functionality.

Main Results:

  • Xpc-/- mice exhibited a 2.8-fold higher Hprt mutant frequency compared to exposed Xpc+/+ mice, indicating increased sensitivity to EB.
  • A similar 2.9-fold increase in mutant frequency was observed in Xpc-/- mice exposed to B[a]P, confirming the deficiency in NER-GGR.
  • These findings suggest that NER-GGR actively participates in the repair of EB-induced DNA adducts in vivo.

Conclusions:

  • NER-GGR plays a significant role in the repair of DNA damage caused by 3,4-epoxy-1-butene.
  • Further studies are warranted to explore the effects of inhaled butadiene and the involvement of other DNA repair pathways in mitigating BD-epoxide genotoxicity.
  • Collaborative research is ongoing to fully elucidate the mechanisms of DNA repair for butadiene-induced damage.

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