Prenatal Triphenyl\nPhosphate Exposure and Hyperlipidemia\nin Offspring: Role of Trophoblast-Derived Extracellular Vesicle PPARγ

Triphenyl phosphate (TPhP) is a widely used organophosphate\nflame\nretardant, the health risks of TPhP are a global concern. In this\nstudy, we found that prenatal TPhP exposure at human relevant concentration\ninduced hyperlipidemia in male offspring, it increased serum levels\nof triglyceride, total cholesterol, and low-density lipoprotein cholesterol.\nPlacental trophoblast-derived extracellular vesicles (T-EVs) could\ntransport to the fetus through maternal-fetal circulation. TPhP significantly\nupregulated the protein level of peroxisome proliferator activated\nreceptor γ (PPARγ) in T-EVs. Similar to TPhP, gestational\nexposure to T-EVs isolated from TPhP exposed mice placentae induced\nthe same effects. While, gestational intervention with GW9662 (PPARγ\ninhibitor) or GW4869 (EVs secretion inhibitor) would alleviate the\ndisturbed lipid metabolism induced by TPhP. Meanwhile, in vitro experiments\nverified that TPhP upregulated PPARγ in HTR8/SVneo cells derived\nEVs, and these EVs promoted adipogenesis in preadipocyte 3T3-L1 cells.\nKnock down of PPARγ in HTR8/SVneo could alleviate the adipogenensis\neffects of EVs derived from TPhP exposed HTR8/SVneo cells. These results\ndemonstrate that TPhP exposure induces hyperlipidemia in male offspring\nby upregulating PPARγ in T-EVs. Our study provides new insights\ninto the metabolic disruptive effects of TPhP, and emphasizes the\nmediating effects of placental T-EVs on gestational environmental\nstress in fetal development.