Exposure to fipronil induces cell cycle arrest, DNA damage, and apoptosis in porcine trophectoderm and endometrial epithelium, leading to implantation defects during early pregnancy

Fipronil, a phenyl-pyrazole insecticide, has a wide range of uses, from agriculture to veterinary medicine. Due to its large-scale applications, the risk of environmental and occupational exposure and bioaccumulation raises concerns. Moreover, relatively little is known about the intracellular mechanisms of fipronil in trophoblasts and the endometrium involved in implantation. Here, we demonstrated that fipronil reduced the viability of porcine trophectoderm and luminal epithelial cells. Fipronil induced cell cycle arrest at the sub-G1 phase and apoptotic cell death through DNA fragmentation and inhibition of DNA replication. These reactions were accompanied by homeostatic changes, including mitochondrial depolarization and cytosolic calcium depletion. In addition, we found that exposure to fipronil compromised the migration and implantation ability of pTr and pLE cells. Moreover, alterations in PI3K-AKT and MAPK-ERK1/2 signal transduction were observed in fipronil-treated pTr and pLE cells. Finally, the antiproliferative and apoptotic effects of fipronil were also demonstrated in 3D cell culture conditions. In summary, our results suggest that fipronil impairs implantation potentials in fetal trophectoderm and maternal endometrial cells during early pregnancy.