Am J Physiol Endocrinol Metab. 2021 Feb 15.
1,25(OH)2D3 have been demonstrated to exert direct actions on male reproductive system in humans or in animals. With age, renal synthesis of 1,25(OH)2D3 declines significantly, and vitamin D supplementation has been found to alleviate the manifestations of male reproductive aging. Therefore, the relationship between 1,25(OH)2D3 and male reproductive aging needs further study. Methods and results: To determine whether 1,25(OH)2D3 deficiency accelerates male reproductive senescence in aging mice, wild-type and 1α(OH)ase-/- male mice fed a rescue diet after weaning, and the reproductive phenotypes were evaluated at 12-18 month of age. We demonstrated that 1,25(OH)2D3 deficiency accelerated male reproductive senescence, representing lower fertility efficiency and gonadal hormone levels, reducing cell proliferation, increasing cell apoptosis, cellular senescence and the senescence-associated secretory phenotype (SASP). We confirmed that the increased oxidative stress and DNA damage detected in 1α(OH)ase-/- mice resulted in accelerated reproductive senescence in reproductive system, since exogenous antioxidant PQQ supplementation could largely rescue reproductive aging phenotype. We further validated the antioxidant effect of 1,25(OH)2D3 in aging wild-type mice and senescent Leydig cells by treated 18-month-old wild-type male mice or TM3 cells with 1,25(OH)2D3 or vehicle. We assessed the differential gene expression between grouped senescent TM3 cells using RNA-Seq, and verified 1,25(OH)2D3 exerted an antioxidant role by acting NF-kappaB/SOD. Conclusions: This study suggests that 1,25(OH)2D3 deficiency accelerates male reproductive senescence in aging mice by increasing oxidative stress and 1,25(OH)2D3 plays a role in alleviating oxidative stress via NF-kappaB/SOD signaling pathway.
Keywords: 1,25(OH)2D3; NF-kappaB/SOD signaling pathway; aging mice; male reproductive senescence; oxidative stress