Abstract
BackgroundBenzo[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.ResultsWe 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.ConclusionsOur 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.
Highlights
Benzo[a]pyrene(B[a]P) is a classic DNA damaging carcinogen which is one of a multitude of polycyclic aromatic hydrocarbons(PAHs) commonly found in tobacco smoke and in the ambient environment [1,2]
An efficient DNA repair system is crucial for eliminating BPDE-DNA adducts, and a reduced DNA repair efficiency is related to a higher risk of cancer development
Nucleotide Excision Repair (NER) is an important and versatile repair system that removes a wide variety of DNA damages and especially deals with bulky DNA damage that leads to a distortion of the DNA helix such as DNA adducts induced by chemical carcinogens [5]
Summary
Benzo[a]pyrene(B[a]P) is a classic DNA damaging carcinogen which is one of a multitude of polycyclic aromatic hydrocarbons(PAHs) commonly found in tobacco smoke and in the ambient environment [1,2]. Benzo[a]pyrene 7,8-diol 9,10-epoxide (BPDE), the ultimate metabolite of B[a]P, forms covalent BPDE-DNA adducts within a cell that damages the structure and function of biological macromolecules such as DNA and protein [3]. DNA repair is a complicated biological process consisting of several distinct pathways. ERCC1 (Excision repair cross complementation group 1) and ERCC2/XPD (Excision repair cross complementation group 2/xeroderma pigmentosum D) are both indispensable genes for a well functional NER. 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
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