title: ERCC1 and ERCC2 haplotype modulates induced BPDE-DNA adducts in primary cultured lymphocytes.
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.
authors.affiliation: Department of Toxicology, School of Public Health, China Medical University, Shenyang, People's Republic of China. xiaobolu69@163.com
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Lu
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.forename: Sha
authors.initials: S
authors.lastname: Xiao
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Bao
authors.forename: Liang
authors.initials: L
authors.lastname: Pan
authors.forename: Guolian
authors.initials: G
authors.lastname: Zhu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cai
authors.forename: Qiufang
authors.initials: Q
authors.lastname: Liu
authors.forename: Cuihong
authors.initials: C
authors.lastname: Jin
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yang
authors.forename: Shengwen
authors.initials: S
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: An
authors.forename: Tahar
authors.initials: T
authors.lastname: van der Straaten
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism* / Q000494:pharmacology; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001564:Benzo(a)pyrene / Q000031:analogs & derivatives / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006239:Haplotypes; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human