Zearalenone Induces Testicular Injury via METTL3-Mediated Dysregulation of m6A Modification.

Zearalenone (ZEA) is a typical environmental and food contaminant widely present in grains, feed, and animal-derived products, posing a serious threat to human and animal health. Studies indicate that the toxic mechanisms of mycotoxins are closely linked to the regulation of N6-methyladenosine (m6A) modification. However, whether the reproductive toxicity of ZEA involves m6A remains to be insufficiently elucidated. This study was used in the in vitro/in vivo models to investigate whether ZEA mediates testicular injury by regulating the m6A enzyme. The results showed that ZEA exposure disrupted the architecture of seminiferous tubules and damaged Spermatogonia and Sertoli cells. Mechanistically, ZEA induced inflammation and downregulated blood-testis barrier (BTB)-associated junction proteins, thereby compromising barrier integrity. Concurrently, ZEA decreased total m6A levels and downregulated the expression of the key m6A regulatory protein METTL3. Conversely, overexpression of METTL3 markedly alleviated ZEA-induced inflammation and restored BTB junctional proteins, suggesting that METTL3 is a key molecular target in ZEA-induced testicular injury. In summary, ZEA promotes inflammation and BTB disruption through a METTL3-dependent m6A regulatory mechanism. Targeting METTL3 may be a potential strategy to mitigate reproductive injury caused by ZEA exposure in humans and animals.