Oryzalin impairs maternal-fetal interaction during early pregnancy via ROS-mediated P38 MAPK/AKT and OXPHOS downregulation.

Oryzalin is a dinitroaniline pesticide for the control of weed growth via suppression of microtubule synthesis. There are studies about the deleterious effects of dinitroaniline pesticides on the reproductive system. Therefore, we attempted to demonstrate the toxic mechanisms of oryzalin on early pregnancy using porcine uterine epithelial cells (pLE) and trophectoderm (pTr) cells. According to our results, the viability and proliferation of pLE and pTr cells were suppressed in response to oryzalin exposure, and cell cycle progression was affected. Additionally, oryzalin induced apoptotic cell death and impaired mitochondrial membrane polarity in pLE and pTr cells. Moreover, we confirmed that oryzalin significantly downregulated adenosine triphosphate (ATP) production via the oxidative phosphorylation system and upregulated reactive oxygen species (ROS) generation in both pLE and pTr cells. The oryzalin-induced ROS generation was mitigated by N-acetylcysteine, a ROS scavenger, and further upregulation of phosphor-P38 MAPK/AKT/P70S6K protein expression was ameliorated in both pLE and pTr cells. We also confirmed that the suppression of migration and proliferation in oryzalin-treated pLE and pTr cells was restored upon oxidative stress mitigation. In summary, we revealed that the cytotoxic mechanisms of oryzalin-induced implantation failure were mediated by ROS-induced intracellular signaling regulation and migratory potential in pLE and pTr cells.