Association of AHR gene-environment interactions with oxidative stress, sperm DNA fragmentation, and bull subfertility.

Declining male fertility poses significant challenges to both human health and livestock production. In this study, we investigated cases of bull subfertility that occurred despite normal semen quality and quantity metrics. Analysis of fertility records and genotype-based kinship among hundreds of inseminating bulls revealed familial clustering of subfertility, supporting a monogenic component. Whole-genome sequencing identified a polymorphism in the AHR gene present in affected bulls but absent in controls. Fluorometric assessments of sperm function demonstrated that bulls harboring the AHR polymorphism exhibit elevated reactive oxygen species production, altered mitochondrial membrane potential, and increased DNA fragmentation under oxidative stress conditions. Further experiments simulating environmental stressors, such as oxidative stress, indicated that these adverse effects on sperm function are exacerbated in the presence of the AHR variant. Our findings underscore the pivotal role of AHR in regulating mature sperm function through modulation of redox homeostasis and suggest that even bulls meeting standard quality-assurance criteria may harbor underlying molecular defects that compromise fertility. This study highlights a conserved mechanism by which genetic aberrations and environmental factors interact to impair reproductive performance, providing new insights into the molecular determinants of male subfertility. The results also support that targeted antioxidant interventions might mitigate oxidative damage and restore sperm function. These findings have broad implications for improving breeding strategies in livestock and advancing our understanding of oxidative stress-related infertility in humans.