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

• Published in: PloS one Vol. 8; no. 4; p. e60006
• Main Authors: Lu, Xiaobo, Liu, Yanhua, Yu, Tao, Xiao, Sha, Bao, Xiaoyan, Pan, Liang, Zhu, Guolian, Cai, Yuan, Liu, Qiufang, Jin, Cuihong, Yang, Jinghua, Wu, Shengwen, An, Li, van der Straaten, Tahar
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04-04-2013; Public Library of Science (PLoS)
• Subjects: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide - metabolism; 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide - pharmacology; Adducts; Adult; Age Factors; Aged; Aged, 80 and over; Alleles; Benzo(a)pyrene; Benzo(a)pyrene - analogs & derivatives; Benzo(a)pyrene - pharmacology; Benzo(a)pyrene-diol epoxide; Bioassay; Bioassays; Biology; Bladder cancer; Breast cancer; Carcinogens; Carcinogens - pharmacology; Cells, Cultured; Chromatography; Colorectal cancer; Comet assay; Damage assessment; Damage detection; Deoxyribonucleic acid; DNA; DNA adducts; DNA Adducts - metabolism; DNA damage; DNA Damage - drug effects; DNA repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Efficiency; Endonucleases - genetics; Endonucleases - metabolism; Environmental health; ERCC1 protein; Esophagus; Female; Gene expression; Genetic aspects; Genetic diversity; Genotypes; Haplotypes; Health risk assessment; High performance liquid chromatography; Humans; Liquid chromatography; Lung cancer; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - metabolism; Male; Medicine; Middle Aged; Nucleotide excision repair; Physiological aspects; Polymorphism, Single Nucleotide; Population; Proteins; Public health; Pyrene; Repair; Risk Factors; Smoking; Toxicity; Toxicology; Xeroderma Pigmentosum Group D Protein - genetics; Xeroderma Pigmentosum Group D Protein - metabolism; XPD protein; Young Adult; Netherlands; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060006

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.
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.
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.
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.