2. Academic Validation
  3. Activation of LXRα attenuates 2-Ethylhexyl diphenyl phosphate (EHDPP) induced placental dysfunction

Activation of LXRα attenuates 2-Ethylhexyl diphenyl phosphate (EHDPP) induced placental dysfunction

  • Ecotoxicol Environ Saf. 2023 Oct 19:266:115605. doi: 10.1016/j.ecoenv.2023.115605.
Yue Zhang 1,  Jie Liang 2,  Hao Gu 3,  Ting Du 1,  Pengfei Xu 4,  Ting Yu 1,  Qing He 1,  Zhenyao Huang 1,  Saifei Lei 5,  Jing Li 6
Affiliations

Affiliations

  • 1 School of Public Health, Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu 221002, China; Key Laboratory of Human Genetics and Environmental Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Key Laboratory of Environment and Health, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
  • 2 Yangzhou Center for Disease Control and Prevention, Yangzhou, Jiangsu 225007, China.
  • 3 Department of Central Laboratory, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an 223300, China.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.
  • 5 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: [email protected].
  • 6 School of Public Health, Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu 221002, China; Key Laboratory of Human Genetics and Environmental Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Key Laboratory of Environment and Health, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: [email protected].
PMID: 37864966 DOI: 10.1016/j.ecoenv.2023.115605
Abstract

2-Ethylhexyl diphenyl phosphate (EHDPP) is one of the typical organophosphate flame retardants (OPFRs) and has been widely detected in environmental media. Exposure to EHDPP during pregnancy affects placental development and fetal growth. Liver X receptor α (LXRα) is essential to placental development. However, finite information is available regarding the function of LXRα in placenta damages caused by EHDPP. In present study we investigated to figure out whether LXRα is playing roles in EHDPP-induced placenta toxicity. While EHDPP restrained cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells, overexpression or activation by agonist T0901317 of LXRα alleviated the above phenomenon, knockdown or inhibition by antagonist GSK2033 had the opposite effects in vitro. Further study indicated EHDPP decreased LXRα expression and transcriptional activity leading to mRNA, protein expression levels downregulation of viability, migration, angiogenesis-related genes Forkhead box M1 (Foxm1), endothelial nitric oxide synthase (eNos), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor-A (VEGF-A) and upregulation of inflammatory genes interleukin-6 (IL-6), interleukin-1β (Il-1β) and tumor necrosis factor-α (Tnf-α) in vitro and in vivo. Moreover, EHDPP caused decreased placental volume and fetal weight in mice, treatment with LXRα agonist T0901317 restored these adverse effects. Taken together, our study unveiled EHDPP-induced placenta toxicity and the protective role of LXRα in combating EHDPP-induced placental dysfunction. Activating LXRα could serve as a therapeutic strategy to reverse EHDPP-induced placental toxicity.

Keywords

2-Ethylhexyl diphenyl phosphate; Angiogenesis; Cell migration; Inflammation; LXRα; Placenta toxicity.

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