Chronic low-dose deltamethrin exposure impairs placental development through endoplasmic reticulum stress-associated trophoblast dysfunction in mice

Deltamethrin (DLM) is a widely used pyrethroid insecticide with potential reproductive and developmental toxicity. Here, we investigated whether chronic low-dose maternal DLM exposure impairs fetal and placental development through endoplasmic reticulum (ER) stress-associated trophoblast dysfunction. Female C57BL/6 mice were exposed to DLM before and during pregnancy, while HTR-8/SVneo cells were used for in vitro validation. DLM exposure reduced fetal size and weight and impaired placental development, accompanied by decreased placental MMP2 and MMP9 expression. In HTR-8/SVneo cells, DLM inhibited proliferation, clonogenic capacity, viability, migration, and wound closure, while inducing cell-cycle disturbance and apoptosis. Placental RNA sequencing revealed alterations in inflammatory response, apoptosis, protein processing, and unfolded protein response-related pathways. Consistently, ATF6 and GRP78 expression was increased in DLM-exposed placentas. The ER stress inhibitor 4-phenylbutyric acid partially restored trophoblast function, reduced apoptosis, suppressed placental ER stress markers, and restored MMP2/MMP9 expression. Moreover, offspring from DLM-exposed dams exhibited increased intestinal ATF6 and IRE1α expression. These findings indicate that chronic low-dose DLM exposure induces fetal growth restriction, at least partly through placental ER stress-associated trophoblast dysfunction.