Cypermethrin induces endoplasmic reticulum stress and autophagy, leads to testicular dysfunction

Cypermethrin is a pyrethroid insecticide that is used to control insects and protect crops. However, pesticide residues and their possible toxicity to non-target animals such as mammals are concerning. Although cypermethrin reduces testosterone levels, the molecular mechanisms involved, particularly those regarding endoplasmic reticulum (ER) stress and autophagy regulation, have not yet been fully elucidated. In this study, we demonstrated testicular toxicity of cypermethrin in mouse Leydig (TM3) and Sertoli (TM4) cells. Cypermethrin suppresses TM3 and TM4 cell proliferation and induces apoptosis. Moreover, it interrupted calcium homeostasis in intracellular organelles and dissipated mitochondrial membrane polarization in mouse testicular cells. Moreover, we verified the accumulation of Sqstm1/p62 protein in the mitochondria of cypermethrin-treated TM3 and TM4 cells. Furthermore, we confirmed that cypermethrin activated autophagy and the ER stress pathway in a time-dependent manner in both cell types. Finally, we determined that cypermethrin downregulated testicular function-related genes, steroidogenesis, and spermatogenesis in mouse testis cells. Therefore, we conclude that cypermethrin regulates autophagy and ER stress, leading to testicular dysfunction.