Dicyclohexyl phthalate derails trophoblast function and lipid metabolism through NDRG1 by targeting PPARα:RXRα

Phthalates (PAEs) can impair trophoblast cell and subsequent placental development, adversely affecting pregnancy. The effects of dicyclohexyl phthalate (DCHP), the main PAE homologue in urban household dust, on trophoblast function and placental development are unknown. In this study, we investigated the effects and potential mechanisms of DCHP on trophoblast function and placental development by constructing in vitro trophoblast (10, 20, 30 μM) and in vivo mouse pregnancy (25, 50, 100 mg/kg bw) exposure models. We found that exposure to DCHP during pregnancy led to the accumulation of placental lipid droplets and foetal weight gain. Consistently, DCHP induced the uptake of fatty acids by HTR-8/SVneo cells, leading to intracellular lipid droplet accumulation and mitochondrial dysfunction while inhibiting cell migration and invasion. This suggests that metabolic processes can serve as important links for environmental pollutants to interfere with bodily functions. Knocking down N-myc Downstream-Regulated Gene 1 (NDRG1) can alleviate lipid metabolism abnormalities caused by DCHP exposure while restoring cell migration and invasion abilities. Further research has found that the enhanced transcriptional activity of PPARα:RXRα is an important molecular initiating event for the role of DCHP, which promotes the transcription of downstream target gene NDRG1 by binding to PPARα:RXRα. These findings fill the research gap regarding the effects and related mechanisms of DCHP exposure on the placenta, help explore prevention and treatment strategies for DCHP reproductive toxicity, and provide new insights into toxicological research on environmental pollutants.