The herbicide dinitramine affects the proliferation of murine testicular cells via endoplasmic reticulum stress-induced calcium dysregulation.

The hazardous effects of herbicides are well known; however, their effects on the reproductive system remain unclear. In this study, we demonstrated the anti-proliferative effects of dinitramine (DN) on immature murine testicular cell lines (Leydig and Sertoli cells) mediated via endoplasmic reticulum (ER) stress-induced calcium dysregulation in the cytosol and mitochondria. The results demonstrated that the viability and proliferation of DN-treated TM3 and TM4 cells decreased significantly, even in the spheroid state. DN induced the apoptosis of TM3 and TM4 cells and decreased the expression of genes related to cell cycle progression. Treatment with DN increased the cytosolic and intramitochondrial levels of calcium by activating ER stress signals. DN activated the Erk/P38/Jnk Mapk pathway and inactivated the Pi3k/Akt pathway in murine testicular cells. Co-treatment with 2-aminoethoxydiphenyl borate (2-APB) mitigated DN-induced calcium upregulation in both testicular cell lines. Although 2-APB did not antagonize the anti-proliferative effect of DN in TM3 cells, treatment with 2-APB and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid restored the proliferation of DN-treated TM4 cells.