Abstract
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental endocrine disruptors (EDCs) that enter the human body through respiratory, digestive, and dermal exposure. Prolonged exposure has been associated with adverse health outcomes, including carcinogenicity, mutagenicity, and reproductive toxicity. However, whether genetic variation in apoptosis-related pathways modifies the reproductive effects of PAH exposure remains unclear. To investigate gene-environment interactions between urinary PAH metabolites and polymorphisms in apoptosis-related genes in relation to sperm apoptosis, we conducted a cross-sectional study involving 176 male participants from an infertility clinic in Wuhan, China, who completed structured questionnaires and provided biological samples. Ten OH-PAH metabolites in repeated urine samples were measured, along with genotyping of single-nucleotide polymorphisms (SNPs) at apoptosis-related genes (Fas, FasL, and caspase-3) in whole blood DNA, and sperm apoptosis. Multivariable linear regression evaluated the interaction between urinary OH-PAH levels and apoptotic gene SNPs on apoptotic sperm, with genotype-stratified analyses. PAH exposure appeared to interact with SNPs in FasL rs763110, Fas rs2234767, and caspase-3 rs12108497 to jointly influence sperm cell apoptosis. Specifically, for the FasL rs763110, higher 9-OHFlu was associated with fewer viable sperm and more apoptotic sperm, and this association was more pronounced among CC genotype homozygotes. For the caspase-3 rs12108497, higher 2-OHFlu was associated with more dead sperm, and this association was significant among TC and TC/CC genotypes. These findings suggest that genetic variation in apoptosis-related genes may modify susceptibility to PAH-induced sperm apoptosis, highlighting the importance of gene-environment interactions in male reproductive toxicity.