Irreversible male infertility from sleep restriction: A dual hit on testicular steroidogenesis and Keap1-Nrf2-mediated antioxidant defense.

BACKGROUND

Chronic sleep restriction (SR) threatens male reproductive health, yet the mechanisms underlying the partial reversibility of the induced damage remain unclear. We hypothesized that this persistent infertility stems from a "dual-hit" mechanism, involving the simultaneous suppression of testicular steroidogenesis and disruption of the Keap1-Nrf2-mediated antioxidant defense system. This study aimed to investigate the interplay between testicular steroidogenesis and antioxidant defense in SR-induced, persistent male infertility.

METHODS

Male ICR mice were subjected to SR for 7, 14, or 21 days, followed by a 35-day recovery. We assessed sperm quality (CASA), testicular histology (H&E), apoptosis (TUNEL), serum hormones (ELISA), and the expression of key molecules in testosterone synthesis and Keap1-Nrf2 pathways (qPCR, Western Blot, IF, IHC).

RESULTS

SR caused a time-dependent decline in sperm quality and testicular function, which did not fully recover after a prolonged rest period. Mechanistically, SR induced a dual-pronged assault: it comprehensively inhibited the testosterone synthesis pathway, evidenced by reduced StAR and HSD17B3 expression, and simultaneously disrupted the primary antioxidant defense by impairing the Keap1-Nrf2 pathway. This resulted in sustained oxidative stress, extensive germ cell apoptosis, and a failure to restore testicular homeostasis.

CONCLUSION

Our findings demonstrate for the first time that the partial irreversibility of SR-induced male infertility arises from a self-perpetuating vicious cycle of steroidogenic impairment and oxidative damage. The persistent dysfunction of both testosterone synthesis and Keap1-Nrf2 signaling pathways provides the molecular basis for this prolonged testicular injury, identifying them as potential therapeutic targets for related reproductive health issues.