Reduced nucleotide excision repair and GSTM1-null genotypes influence anti-B[a]PDE-DNA adduct levels in mononuclear white blood cells of highly PAH-exposed coke oven workers

Abstract

It is important to identify the potential genetic-susceptible factors that are able to modulate individual responses to exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs). In the present study we evaluated the influence of four polymorphisms of nucleotide excision repair (NER) genes [xeroderma pigmentosum-C (XPC)-PAT +/-, xeroderma pigmentosum-A (XPA) 5' non-coding region-A23G, XPD-exon 23 A35931C Lys751Gln, xeroderma pigmentosum-D (XPD)-exon 10 G23591A Asp312Asn] and that of glutathione S-transferase mu1 (GSTM1-active or -null) on benzo[a]pyrene diol epoxide (B[a]PDE)-DNA adduct levels from the lympho-monocyte fraction (LMF) of highly PAH benzo[a]pyrene (B[a]P)-exposed Polish coke oven workers (n = 67, 67% current smokers) with individual urinary post-shift excretion of 1-pyrenol exceeding the proposed biological exposure index (BEI) (2.28 micromol/mol creatinine). The bulky (+/-)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-B[a]PDE)-DNA adduct levels were detected by high-performance liquid chromatography (HPLC)/fluorescence analysis and genotypes by polymerase chain reaction. We found that workers with the low DNA repair capacity of XPC-PAT+/+ and XPA-A23A genotypes had significantly increased anti-B[a]PDE-DNA adduct levels (Mann-Whitney U-test, z = 2.24, P = 0.02 and z = 2.65, P = 0.01). Moreover, DNA adducts were also raised in workers without GSTM1 activity (GSTM1-null genotype) (Mann-Whitney U-test, z = 2.25, P = 0.0246). Workers with unfavourable XPC-PAT+/+ and XPA-A23A NER genotypes, alone (approximately 65% of workers) or combined with GSTM1-null genotype (approximately 75% of workers) were in the tertile with the highest adduct level, i.e. >4.11 adducts/10(8) nt (chi2 = 5.85, P = 0.0156 and chi2 = 5.40, P = 0.01). The increase in anti-B[a]PDE-DNA adduct levels (ln values) was significantly related in a multiple linear regression analysis to PAH exposure (i.e. urinary post-shift excretion of 1-pyrenol) (t = 2.61, P = 0.0115), lack of GSTM1 activity (t = 2.41, P = 0.0192) and to low DNA repair capacity of the XPC-PAT+/+ genotype (t = 2.34, P = 0.0226). The influence of the XPA-A23A genotype was not evident in this statistical analysis, and no associations with XPD polymorphisms, dietary habits or tobacco smoking were found. The modulation of anti-B[a]PDE-DNA adducts in the LMF by GSTM1-null and some low-activity NER genotypes may be considered as a potential genetic susceptibility factor capable of modulating individual responses to PAH (B[a]P) genotoxic exposure and the consequent risk of cancer in coke oven workers.

XPC polymorphisms play a role in tissue-specific carcinogenesis: a meta-analysis

“…Both biological and biochemical evidence also indicate the importance of XPC Lys939Gln polymorphism associated with a differential repair capacity. 63 -66 Low repair capacity of benzo(a)pyrene DNA adducts was also observed in lymphocytes of individuals with this XPC variant, 67 although the protein levels of XPC were not measured in that study. Moreover, XPC has two other polymorphisms in linkage with the Gln allele -an insertion of an 83-bp ATs (PAT) in intron 9 and an exchange of C to A in splicing site of intron 11 -that might contribute to a decreased expression of XPC, due to abnormalities in RNA stability and splicing process.…”

Modulation of DNA damage/DNA repair capacity by XPC polymorphisms

“…Qiao et al [33] studied XPC genotype-related DRC using a host-cell reactivation assay and found that healthy subjects with the homozygous variant genotype of the PAT polymorphism (+/+) exhibited lower DRC as compared to wild-type carriers (-/-). In another study, the PAT +/+ genotype was associated with higher levels of anti-BPDE-DNA adducts than those with the -/-genotype in coke oven workers [36].…”

Global and gene‐specific promoter methylation changes are related to anti‐B[a]PDE‐DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon‐exposed individuals

“…25,30 At the Institute of Occupational Medicine and Environmental Health in Sosnowiec: (i) PBL cultures for MN detection were prepared and MN analyses performed; (ii) PBLs for adduct analyses were isolated in Ficoll separating solution (Seromed, Berlin, Germany) within 4 hr after blood collection and kept frozen at 280°C, until they were sent to the Department of Environmental Medicine and Public Health in Padova (Italy), where DNA was extracted. Data on other possible elevated nonoccupational PAH exposure (diet, environment) and consumption of fruit and vegetables were collected by means of a questionnaire, as previously described 23,24 (i.e., high dietary intake of PAHs was the consumption of charcoaled meat (PAH-rich meals) more than once a week; indoor and environmental exposure to PAHs was the use of wood or coal to heat the home, and an index of location of residence that included intense local traffic and presence of industries in the residential area). This study was reviewed by the appropriate Ethics Committee of the Institute of Occupational Medicine and Environmental Health in Sosnowiec.…”

“…[20][21][22] Finally, increased anti-B[a]PDE-DNA and MN levels have been related to occupational (cokeries) and environmental (smoking, diet) PAH exposure. [23][24][25][26] However, no studies have addressed whether PAH exposure alters epigenetic patterns in PBLs from occupationally exposed people, who are, therefore, at high risk of lung carcinogenesis.…”