Abstract
In vitro benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts in cultured peripheral lymphocytes have been shown to be a phenotypic biomarker of individual’s DNA repair phenotype that is associated with cancer risk. In this study, we explored associations between genotypes of base-excision repair genes (PARP1 Val762Ala, APEX1 Asp148Glu, and XRCC1 Arg399Gln) and in vitro BPDE-induced DNA adducts in cultured peripheral blood lymphocytes in 706 cancer-free non-Hispanic white subjects. We found that levels of BPDE-induced DNA adducts were significantly higher in ever smokers than in never smokers and that individuals with the Glu variant genotypes (i.e., Asp/Glu and Glu/Glu) exhibited lower levels of BPDE-induced DNA adducts than did individuals with the common Asp/Asp homozygous genotype (median RAL levels: 32.0 for Asp/Asp, 27.0 for Asp/Glu, and 17.0 for Glu/Glu, respectively; P trend = 0.030). Further stratified analysis showed that compared with individuals with the common APEX1-148 homozygous Asp/Asp genotype, individuals with the APEX1-148Asp/Glu genotype or the Glu/Glu genotype had a lower risk of having higher-level adducts (adjusted OR = 0.60, 95% CI: 0.36–0.98 and adjusted OR = 0.47, 95% CI: 0.26–0.86, respectively; P trend = 0.012) among smokers. Such an effect was not observed in non-smokers. However, there was no significant interaction between the APEX1 Asp148Glu polymorphism and smoking exposure in this study population (P = 0.512). Additional genotype-phenotype analysis found that the APEX1-148Glu allele had significantly increased expression of APEX1 mRNA in 270 Epstein-Barr virus-transformed lymphoblastoid cell lines, which is likely associated with more active repair activity. Our findings suggest that the functional APEX1-148Glu allele is associated with reduced risk of having high levels of BPDE-induced DNA adducts mediated with high levels of mRNA expression.
Highlights
Genomic instability plays an important role in the development of cancer, as DNA is frequently damaged by both endogenous metabolites and exogenous carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) occurring in many combustion products. benzo[a]pyrene (B[a]P) is one of the major PAHs and considered the most carcinogenic, which is metabolized in humans to its ultimate carcinogenic form of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE)
The genotype frequencies of the three single nucleotide polymorphisms (SNP) among these subjects were all in agreement with the Hardy– Weinberg equilibrium
To understand the underlying molecular mechanism of the observed association of the APEX1-148 variant genotypes (Glu/ Glu and Asp/Glu) with lower levels of BPDE-induced DNA adducts and decreased risk of cancer, we further assessed the effect of the APEX1 Asp148 Glu polymorphism on APEX1 mRNA levels using the APEX1 mRNA expression data in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines derived from 270 HapMap individuals and available genotyping data from the same individuals
Summary
Genomic instability plays an important role in the development of cancer, as DNA is frequently damaged by both endogenous metabolites and exogenous carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) occurring in many combustion products. benzo[a]pyrene (B[a]P) is one of the major PAHs and considered the most carcinogenic, which is metabolized in humans to its ultimate carcinogenic form of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). It is known that BPDE can damage DNA by forming DNA adducts through covalent binding to DNA bases [1]. If not repaired, such BPDE-DNA adducts can lead to mutagenesis, carcinogenesis, or possibly cell death. Nucleotide- and base-excision repair (NER and BER) are two major cellular responses to DNA damage to correct genomic lesions in mammalian cells. NER is one of the most versatile and important pathways, by which mammalian cells remove a variety of DNA lesions, such as bulky chemical adducts, ultra violet induced pyrimidine dimers [2], and interstrand cross-links [3,4,5], whereas BER is critically involved in the repair of damaged bases induced by reactive oxygen species, alkylation or ionizing radiation as well as a variety of other lesions, including deaminated base and DNA single strand breaks [6]. Inactivation of BER core proteins in mice leads to embryonic lethality, highlighting the vital importance of BER [7]
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