Physical Activity attenuates Sperm DNA Damage induced by Sedentary Behavior via Testicular Thermoregulation

The contribution of male factors to infertility has been increasing progressively, with growing attention to non-genetic factors (lifestyle, environment). As a prevalent suboptimal lifestyle, the impact of sedentary behavior on male reproductive dysfunction remains to be fully elucidated. In this study, 6-week-old male C57BL/6 mice were randomly assigned to control (CT), sedentary (ST), and physical activity compensation (CS) groups for 10-week exposure. No observable differences in growth or behavior indicators were identified among groups. The ST group exhibited a pathological cascade: gonadal histopathological changes, sex hormone secretion disordered, and spermatogenic impairment, which were significantly alleviated in CS. Mechanistically, testicular RNA-seq revealed sedentary behavior disrupted thermoregulation, with DNA damage. Further analysis confirmed significant upregulation of Gpx4 (DNA damage marker) and Hsp70 (core temperature-sensing gene) in ST, along with increased testicular temperature and compromised sperm motility. Collectively, sedentary behavior may induce sperm DNA damage by disrupting testicular temperature homeostasis. Our findings provide a novel perspective for elucidating the mechanism underlying male infertility induced by sedentary behavior.