DNA repair gene polymorphisms and expression in sulfur mustard-exposed veterans: Associations with toxicity severity

Introduction Sulfur mustard (SM) as a potent alkylating chemical warfare agent, results in long-lasting health issues. This study aims to evaluate the associations among polymorphisms, the expression levels of DNA repair-related genes, oxidative stress, and the severity of sulfur mustard toxicity. Methods XPC (Xeroderma pigmentosum group C) rs2228001 and XRCC1 (X-ray repair cross-complementing protein 1) rs25487 were genotyped in three subgroups of 545 SM-exposed participants (asymptomatic, mild, and moderate-severe). Also, their transcriptional changes were evaluated. Results In the codominant model (AA reference), the GG genotype showed a negative association with the moderate-severe subgroup when compared to the mild subgroup. The AG genotype showed negative associations with the moderate-severe subgroup compared to both the asymptomatic and mild subgroups. In the recessive model (AA reference), the combined GG + AG genotypes only showed a negative association for the moderate-severe subgroup compared to the mild subgroup, suggesting that these genotypes may be associated with a lower risk of severe clinical signs. The XPC transcript decreased in the SM-exposed group and moderate-severe subgroup compared to the non-exposed group, while the XRCC1 transcript increased, especially in the mild and moderate-severe subgroups. This increase in XRCC1 transcript was only in the individuals with GG and AG genotypes. There was a negative correlation between XPC transcript and malondialdehyde (indicator of lipid peroxidation) levels. Discussion Variations in XRCC1 genotypes and expression of XRCC1/XPC gene are associated with responses to SM exposure and the risk of developing moderate-severe clinical signs, highlighting the complex interplay between oxidative stress and DNA repair.