Both selenium deficiency and excess impair male reproductive system via inducing oxidative stress-activated PI3K/AKT-mediated apoptosis and cell proliferation signaling in testis of mice

Abstract

Selenium (Se) deficiency or excess impairs testicular development and spermatogenesis, while the underlying mechanisms in this regard remain unclear. This study was designed to explore the molecular biology of Se deficiency or excess in spermatogenesis in mice. Three-week-old male mice (n = 10 mice/diet) were fed with Se-deficient diet (SeD, 0.02 mg Se/kg), adequate-Se diet (SeA, 0.2 mg Se/kg), or excess-Se diet (SeE, 2.0 mg Se/kg) for 5 months. Compared with SeA, SeD reduced (P < 0.05) the body weight (10.4%) and sperm density (84.3%) but increased (P < 0.05) sperm deformity (32.8%); SeE decreased (P < 0.05) the sperm density (78.5%) and sperm motility (35.9%) of the mice. Meanwhile, both SeD and SeE increased (P < 0.05) serum FSH concentrations (10.4-25.6%) and induced testicular damage in mice in comparison with the SeA. Compared with SeA, SeD increased (P < 0.05) the 8-OHdG concentration by 25.5%; SeE increased (P < 0.05) both MDA and 8-OHdG concentrations by 118.8-180.3% in testis. Furthermore, transcriptome analysis showed that there 1325 and 858 transcripts were altered (P < 0.05) in the testis by SeD and SeE, respectively, compared with SeA. KEGG pathway analysis revealed that these differentially expressed genes were mainly enriched in the PI3K-AKT signaling pathway, which is regulated by oxidative stress. Moreover, western blotting analysis revealed that SeD and SeE dysregulated PI3K-AKT-mediated apoptosis and cell proliferation signaling, including upregulating (P < 0.05) caspase 3, cleaved-caspase 3, BCL-2 and (or) P53 and downregulating (P < 0.05) PI3K, p-AKT, p-mTOR, 4E-BP1, p-4E-BP1 and (or) p-p70S6K in the testis of mice compared with SeA. Additionally, compared with SeA, both SeD and SeE increased (P < 0.05) GPX3 and SELENOO; SeD decreased (P < 0.05) GPX1, TXRND3 and SELENOW, but SeE increased (P < 0.05) production of three selenoproteins in the testis. Conclusively, both Se deficiency and excess impairs male reproductive system in mice, potentially with the induction of oxidative stress and activation of PI3K/AKT-mediated apoptosis and cell proliferation signaling in the testis.

Keywords: Dietary selenium; Mice; Oxidative stress; Sperm quality; Testis.