Spermatic circRNAs and Male Infertility: impact of environmental and metabolic stressors.

The obesity and the exposure to environmental toxicants have emerged as key risk factors for male reproductive health. In this context, circular RNAs (circRNAs) have recently been identified as promising epigenetic biomarkers of sperm quality. This study aimed to investigate the role of sperm circRNAs in the pathophysiology of male infertility induced by metabolic and environmental stressors, by assessing two distinct experimental models: i) the HFD mouse model, and ii) a human cohort of normozoospermic men living in the “Land of Fires” geographical area. In the HFD experimental model, the obesity condition induces testicular dysfunctions, sperm anomalies, and impaired sperm circRNA profile. Mechanistically, an enhanced FUS- dependent endogenous backsplicing occurs in sperm cells, while the disruption of the FUS– QKI protein complex impairs the epididymal circRNA biogenesis and their delivery to SPZ. In human, the toxicant exposure correlates with sperm morpho-functional defects, oxidative stress, acrosomal damage, and membrane lipid disorganization. At molecular level, the seminal Lead (Pb) bioaccumulation induces the p300-mediated FUS acetylation and its shuttling to the sperm tail, in turn promoting the biogenesis of sperm circRNAs related to poor quality parameters. Overall, this study reveals that metabolic and environmental stressors reshape the sperm epigenetic landscape through FUS dysregulation, highlighting the potential use of sperm circRNAs as sensitive and non-invasive biomarkers for male assessment.