Excision repair of BPDE-adducts in human lymphocytes: diminished capacity associated with ERCC1 C8092A (rs3212986) polymorphism.

Abstract

Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), a metabolite of Benzo[a]pyrene (B[a]P), is a high-risk factor for development of a number of cancers. DNA damage caused by BPDE is normally repaired by Nucleotide Excision Repair system of which ERCC1 exerts an important role. We investigated whether two single nucleotide polymorphisms in ERCC1 (C19007T; rs11615 and C8092A; rs3213986) affected the repair efficacy of BPDE-DNA adducts. We collected peripheral blood of 780 healthy individuals from the northeast of China and detected the genotypes of rs11615 and rs3213986. The amount of induced BPDE-DNA adducts in lymphocytes from 117 randomly selected participants was assessed by HPLC. Presence of BPDE-DNA adducts in nucleus of lymphocytes was visualized using the modified comet assay. ERCC1 and CAST (3' adjacent gene of ERCC1) mRNA expression levels were quantified after in vitro exposure to BPDE. We found that the minor A allele in rs3212986 was related to higher levels of BPDE-DNA adducts and holistic marking DNA damage (P < 0.01). Haplotype CA (rs11615 and rs3213986) was also associated with an elevated risk of high BPDE-DNA adduct levels (OR = 1.801, 95 % CI of OR 1.191-2.724). Interestingly, in participants with AA genotype for rs3213986, CAST mRNA level was decreased compared to individuals with the homozygous CC genotype. Our findings suggests that ERCC1 C8092A (rs3213986) is associated with a diminished capacity of repairing BPDE-DNA adducts and may be used as a valid biomarker to predict an individual's risk to develop cancer upon exposure to environmental carcinogens.

• Authors: Tao Yu, Yanhua Liu, Xiaobo Lu, Sha Xiao, Yuan Cai, Cuihong Jin, Qiufang Liu, Jinghua Yang, Shengwen Wu, Xiaoyan Bao, Liang Pan, Tahar van der Straaten
• Journal: Archives of toxicology (Arch Toxicol) Vol. 87 Issue 4 Pg. 699-709 (Apr 2013) ISSN: 1432-0738 [Electronic] Germany
• PMID: 23203453 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens, Environmental
• DNA Adducts
• DNA-Binding Proteins
• 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
• DNA
• ERCC1 protein, human
• Endonucleases

Topics

• 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide (toxicity)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Carcinogens, Environmental (toxicity)
• Comet Assay
• DNA (drug effects)
• DNA Adducts
• DNA Damage
• DNA Repair (drug effects)
• DNA-Binding Proteins (genetics, metabolism)
• Endonucleases (genetics, metabolism)
• Female
• Humans
• Lymphocytes (drug effects, metabolism)
• Male
• Middle Aged
• Mutagenesis
• Polymorphism, Single Nucleotide
• Young Adult