Abstract
We explored the effects of single nucleotide polymorphisms (SNP) of nucleotide excision repair (NER) genes on DNA damage caused by exposure to carcinogenic polycyclic aromatic hydrocarbons (PAH) in 475 Chinese workers. We quantified urinary 1-hydroxypyrene using high-performance liquid chromatography, and the DNA damage level of lymphocytes was examined by the comet assay and represented as the Olive tail moment (OTM) value. We genotyped 38 tagSNPs in 10 NER genes. The SNP function was further investigated using luciferase reporter assay in three cell lines. Our results showed that two promoter SNPs, XPA rs1800975 and XPC rs3731055, were associated with lower OTM values (P(trend) = 0.01 and 0.02 respectively). However, another missense SNP rs2228001 in the XPC gene was positively associated with OTM value (P(trend) = 0.01). A stratified analysis found that the association between this SNP and DNA damage was only observed among subjects with higher PAH exposure levels but not among those with lower exposure levels (P(interaction) = 0.018). A dose-response association was found between the combined risk alleles of the above three genetic variants and increased DNA damage levels (P(trend) = 0.004). This association was more pronounced in subjects with higher PAH exposure than those with lower exposure levels (P(interaction) = 0.046). Our functional study indicated that XPA rs1800975G and XPC rs3731055A alleles had a higher luciferase expression than their corresponding SNP alleles (P < 0.05). These results suggested that genetic variations in key NER genes, especially in XPA and XPC genes, may modulate DNA damage levels when exposed to PAHs.
Highlights
Polycyclic aromatic hydrocarbons (PAH) are the main products of coke oven emissions produced during incomplete combustion of natural or synthetic fuels
We found that the number of rs2228001G allele was associated with higher Olive tail moment (OTM) values in the intermediate- and high-exposure groups, but not in the low-exposure group, indicating an interaction between single nucleotide polymorphisms (SNP) rs2228001 and PAH exposure on OTM value (Pinteraction = 0.018; Supplementary Table S1)
We examined the single and joint effects of nucleotide excision repair (NER) genetic loci on the DNA damage levels in Chinese coke oven workers
Summary
Polycyclic aromatic hydrocarbons (PAH) are the main products of coke oven emissions produced during incomplete combustion of natural or synthetic fuels. Long-term exposure to PAHs had been reported to be associated with high incidence of lung cancer in coke oven workers [1]. Urinary 1-hydroxypyrene has been widely used as a biomarker of exogenous PAH exposure [2, 3]. PAHs can cause DNA damage that is mainly repaired through the nucleotide excision repair (NER) pathway. The NER pathway is a multiprotein process [6] including two related subpathways [7]: the general global genome repair and the transcription-coupled repair, which differ only in the recognition step of DNA lesions. XPA, XPC-hHR23B, and RPA recognize DNA lesions; the TFIIH helicases (including XPB and XPD) unwind the DNA duplex; and ERCC1-XPF and XPG make the dual incision at the 5′ and 3′ boundary, respectively, followed by DNA repair synthesis. CSA and CSB recognize DNA lesions instead
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