Protective role of m⁶A binding protein YTHDC2 on CCNB2 in manganese-induced spermatogenesis dysfunction

Human infertility has become the third largest serious disease in the world, seriously affecting the quality of human fertility. Studies have shown that manganese (Mn) can accumulate in the testis through the blood-testicular barrier and damage the male reproductive system. However, the mechanism has not been explored clearly. Recent studies have reported that YTH domain-containing 2 (YTHDC2) can regulate reproductive function. However, none has explored the role of YTHDC2 in Mn-induced reproductive toxicity. The present study investigated whether YTHDC2/CyclinB2 (CCNB2) pathway participates in Mn-induced reproductive toxicity using Kunming mice, spermatogonia, and the seminal plasma of male workers. The mice were received intraperitoneal (i.p.) injections of 0, 12.5, 25, and 50 mg/kg MnCl₂ once daily for 2 weeks. The cells were treated with 0, 100, 200 and 400 μM MnCl₂ for 24 h. Here, we found that occupational Mn exposure significantly increased Mn levels in the seminal plasma of male workers, while decreased sperm density, semen quality, and the levels of YTHDC2, CCNB1, and CCNB2. We found that Mn can inhibit the YTHDC2/CCNB2 signaling pathway and block the G2/M phase of the cell cycle. Moreover, the morphology of cells and the histomorphology of mice testis were injured. Notably, over-expression (OE) of YTHDC2 increased CCNB2 levels, reduced cell cycle arrest, and improved reproductive toxicity after Mn exposure. These findings suggest that the YTHDC2/CCNB2 signaling pathway participates in Mn-induced reproductive toxicity, and OE of YTHDC2 can mitigate the toxicity of Mn.