Wang_2021_Chemosphere_275_129978

Triphenyl phosphate (TPP) is a frequently used aryl organophosphate flame retardant. Epidemiological studies have shown that TPP and its metabolite diphenyl phosphate (DPP) can accumulate in the placenta, and positively correlated with abnormal birth outcomes. TPP can disturb placental hormone secretion through the peroxisome proliferator-activated receptor gamma (PPARgamma) pathway. However, the extent and mechanism of placental toxicity mediation by TPP remains unknown. In this study, we used JEG-3 cells to investigate the role of PPARgamma-regulated lipid metabolism in TPP-mediated placental toxicity. The results of lipidomic analysis showed that TPP increased the production of triglycerides (TG), fatty acids (FAs), and phosphatidic acid (PA), but decreased the levels of phosphatidylethanol (PE), phosphatidylserine (PS), and sphingomyelin (SM). TG accumulation was accompanied by increased levels of sterol regulatory element binding transcription factor 1 (SREBP1), acetyl-coA carboxylase (ACC), and fatty acid transport protein (CD36). Although PPARgamma and its target CCAAT/enhancer binding proteins (C/EBPalpha) was decreased, the TG content and gene expression of SREBP1, ACC, and CD36 decreased when TPP was co-exposed to the PPARgamma antagonist GW9662. TPP also induced inflammatory responses, endoplasmic reticulum stress (ERS), and cell apoptosis. Expression of genes related to ERS and apoptosis were attenuated by GW9662. Together, these results show that TPP can disturb lipid metabolism and cause lipid accumulation through PPARgamma, induce ERS, and cell apoptosis. Our findings reveal that the developmental toxicity of TPP through placental toxicity should not be ignored.