ERCC1 and ERCC2 haplotype modulates induced BPDE-DNA adducts in primary cultured lymphocytes

PLoS One. 2013 Apr 4;8(4):e60006. doi: 10.1371/journal.pone.0060006. Print 2013.

Abstract

Background: Benzo[a]pyrene(B[a]P), and its ultimate metabolite Benzo[a]pyrene 7,8-diol 9,10-epoxide (BPDE), are classic DNA damaging carcinogens. DNA damage caused by BPDE is normally repaired by Nucleotide Excision Repair (NER), of which ERCC1 and ERCC2/XPD exert an indispensable role. Genetic variations in ERCC1 and ERCC2 have been related to DNA repair efficiency. In this study we used lymphocytes from healthy individuals to show that polymorphisms in ERCC1 and ERCC2 are directly associated with decreased DNA repair efficiency.

Methods: ERCC1 (rs3212986 and rs11615) and ERCC2 (rs13181, rs1799793 and rs238406) were genotyped in 818 healthy Han individuals from the northeast of China. BPDE induced DNA adducts in lymphocytes were assessed by high performance liquid chromatography (HPLC) in 282 randomly selected participants. The effect of ERCC1 rs3212986 and ERCC2 rs238406 on DNA damage caused by B[a]P was assessed with a modified comet assay.

Results: We found that the variant genotypes of ERCC1 rs3212986 and ERCC2 rs238406 were associated with the high levels of BPDE-DNA adducts. Especially ERCC1 rs3212986 A-allele variant was significantly associated with the high BPDE-DNA adducts. Haplotype analysis showed that the ERCC1 haplotype AC (OR = 2.36, 95% CI = 1.84-2.97), ERCC2 haplotype AGA (OR = 1.51, 95% CI = 1.06-2.15) and haplotype block AGAAC (OR = 5.28, 95% CI = 2.95-9.43), AGCAC (OR = 1.35 95% CI = 1.13-1.60) were linked with high BPDE-DNA adducts. In addition, we found that the combined minor alleles of ERCC1 rs3212986 and ERCC2 rs238406 were associated with a reduced DNA repair capacity.

Conclusions: Our results suggest that the variant genotypes of ERCC1 rs3212986 and ERCC2 rs238406 are associated with decreased repair efficiency of BPDE induced DNA damage, and may be predictive for an individual's DNA repair capacity in response to environmental carcinogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / metabolism*
  • 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / pharmacology
  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Alleles
  • Benzo(a)pyrene / analogs & derivatives
  • Benzo(a)pyrene / pharmacology
  • Carcinogens / pharmacology
  • Cells, Cultured
  • DNA Adducts / metabolism*
  • DNA Damage / drug effects
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Endonucleases / genetics*
  • Endonucleases / metabolism
  • Female
  • Haplotypes*
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Smoking
  • Xeroderma Pigmentosum Group D Protein / genetics*
  • Xeroderma Pigmentosum Group D Protein / metabolism
  • Young Adult

Substances

  • Carcinogens
  • DNA Adducts
  • DNA-Binding Proteins
  • benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA
  • Benzo(a)pyrene
  • 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
  • ERCC1 protein, human
  • Endonucleases
  • Xeroderma Pigmentosum Group D Protein
  • ERCC2 protein, human

Grants and funding

This study was supported by National Natural Science Foundation of China (No. 30972506). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.