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.