Prenatal triphenyl phosphate exposure impairs placentation and induces preeclampsia-like symptoms in mice

Qian Liu; Mengzhu Jiang; Xiaoxun Lu; Jiabin Hong; Yanqin Sun; Chun Yang; Yuting Chen; Xingxing Chai; Huanwen Tang; Xiaoshan Liu

doi:10.1016/j.envres.2024.119159

Prenatal triphenyl phosphate exposure impairs placentation and induces preeclampsia-like symptoms in mice

Environ Res. 2024 May 14:119159. doi: 10.1016/j.envres.2024.119159. Online ahead of print.

Authors

Qian Liu¹, Mengzhu Jiang¹, Xiaoxun Lu², Jiabin Hong³, Yanqin Sun⁴, Chun Yang⁵, Yuting Chen², Xingxing Chai⁶, Huanwen Tang², Xiaoshan Liu⁷

Affiliations

¹ The first Dongguan affiliated hospital, Guangdong Medical University, Dongguan, 523808, Guangdong, China; School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Dongguan, 523808, Guangdong, China.
² School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Dongguan, 523808, Guangdong, China.
³ The third People's Hospital of Zhuhai, Zhuhai, 519000, Guangdong, China.
⁴ Department of pathology, Guangdong Medical University, Dongguan, 523808, Guangdong, China.
⁵ Dongguan Key Laboratory of stem cell and regenerative tissue engineering, Guangdong Medical University, Dongguan, 523808, Guangdong, China.
⁶ Dongguan Key Laboratory for Development and Application of Experimental Animal Resources in Biomedical Industry, Laboratory Animal Center, Guangdong Medical University, Dongguan, 523808, Guangdong, China.
⁷ The first Dongguan affiliated hospital, Guangdong Medical University, Dongguan, 523808, Guangdong, China; School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Dongguan, 523808, Guangdong, China. Electronic address: liuxshan@gdmu.edu.cn.

PMID: 38754605
DOI: 10.1016/j.envres.2024.119159

Abstract

Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is widely used in many commercial products. The United States Environmental Protection Agency has listed TPhP as a priority compound that requires health risk assessment. We previously found that TPhP could accumulate in the placentae of mice and impair birth outcomes by activating peroxisome proliferator-activated receptor gamma (PPARγ) in the placental trophoblast. However, the underlying mechanism remains unknown. In this study, we used a mouse intrauterine exposure model and found that TPhP induced preeclampsia (PE)-like symptoms, including new on-set gestational hypertension and proteinuria. Immunofluorescence analysis showed that during placentation, PPARγ was mainly expressed in the labyrinth layer and decidua of the placenta. TPhP significantly decreased placental implantation depth and impeded uterine spiral artery remodeling by activating PPARγ. The results of the in vitro experiments confirmed that TPhP inhibited extravillous trophoblast (EVT) cell migration and invasion by activating PPARγ and inhibiting the PI3K-AKT signaling pathway. Overall, our data demonstrated that TPhP could activate PPARγ in EVT cells, inhibit cell migration and invasion, impede placental implantation and uterine spiral artery remodeling, then induce PE-like symptom and impair birth outcomes. Although the exposure doses used in this study was several orders of magnitude higher than human daily intake, our study highlights the placenta as a potential target organ of TPhP worthy of further research.

Keywords: peroxisome proliferator-activated receptor gamma; placentation; preeclampsia; triphenyl phosphate.