Microcystin-LR induces lactate production disruption via altering the m6A modification in Sertoli cells

We have previously reported the toxicity of microcystin-LR (MC-LR) to the male reproductive system, which results in functional changes in mouse testes. In this study, mice were orally exposed to MC-LR at 1, 7.5, 15, or 30 μg/L daily for 180 days. We found an increase in germ cell Apoptosis in the seminiferous tubules and low-quality sperm in the epididymis. A decrease in Lactate Dehydrogenase A (Ldha) expression in testes through high-throughput Sequencing was observed. We validated that MC-LR disrupted lactate production in Sertoli cells by suppressing the expression of Ldha. Further studies identified that methyltransferase 3 (METTL3) catalysed N⁶-methyladenosine (m⁶A) methylation of Ldha mRNA. METTL3 was downregulated in Sertoli cells following exposure to MC-LR, decreasing m⁶A levels of Ldha. The stability of Ldha mRNA decreased when m⁶A levels of Ldha were inhibited. In conclusion, these results showed that MC-LR inhibits the expression of Ldha in an m⁶A-dependent manner, which might result in the Apoptosis of spermatogenic cells and a decline in sperm quality. Our work provides a new perspective to understanding MC-LR-induced male infertility.