A novel role for zinc transporter 8 in the facilitation of zinc accumulation and regulation of testosterone synthesis in Leydig cells of human and mouse testicles.

OBJECTIVE:Zinc is intimately involved in testosterone production. Zinc transporter 8 (ZnT8) is found to be localized in insulin secretory granules as a β-cell specific Zn transporter. The effect of ZnT8 and related zinc accumulation in steroidogenesis, however, is still unknown. The present study aimed to explore whether ZnT8 plays a role in the facilitation of zinc accumulation and regulation of testosterone synthesis in testicles. METHODS:Leydig cells were isolated from the testicles of human, CD-1 suckling and ZnT8-KO mice. Zn accumulation in mitochondria was induced by hCG stimulation. Transfection of hZnT8-EGFP and RNA interfere of mZnT8 were done in MLTC-1 cells. ZnT8 expression and its co-localization with steroidogenic acute regulatory (StAR) protein were analyzed with RT-PCR, Western blot and dual-fluorescent staining protocols. Serum testosterone levels in mice were determined with chemiluminescent enzyme immunoassay. RESULTS:ZnT8 was found to be presented in Leydig cells and up-regulated in suckling mouse Leydig cells and MLTC-1 cells after hCG administration, by which zinc accumulation occurred in mitochondria. ZnT8 gene silencing or knockout inhibited stimulated progesterone and testosterone production, reduced stimulated zinc accumulation and down-regulated phosphorylated steroidogenic acute regulatory (StAR) expression in Leydig cells. Furthermore, an inhibitor (H89) of blocked hCG-stimulated progesterone caused by ZnT8 over-expression and zinc treatment. CONCLUSION:The present study provided the first evidence that ZnT8 transports Zn into Leydig cell mitochondria with gonadotropin stimulation and suggests that ZnT8 may play a role in testosterone production via the duanyu1529 signaling pathway.

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