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  3. Folic acid alleviates fetal growth restriction induced by gestational Di (2-ethylhexyl) phthalate exposure in mice through activating the STAT3/HIF-1α/VEGFA signaling pathway

Folic acid alleviates fetal growth restriction induced by gestational Di (2-ethylhexyl) phthalate exposure in mice through activating the STAT3/HIF-1α/VEGFA signaling pathway

  • Reprod Toxicol. 2026 Jan:139:109109. doi: 10.1016/j.reprotox.2025.109109.
Fang Xie 1,  Mengzhen Hou 2,  Yingxia Wang 1,  Xutao Ling 1,  Yun Yu 3,  Qianqian Huang 3,  Lun Zhang 3,  Cheng Zhang 4,  Jun Yu 5,  Jianqing Wang 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center Hefei, 230032, China; School of Pharmaceutical Sciences, Anhui Medical University, Hefei 230012, China.
  • 2 Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center Hefei, 230032, China; School of Pharmaceutical Sciences, Anhui Medical University, Hefei 230012, China; Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
  • 3 Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center Hefei, 230032, China.
  • 4 Department of Toxicology, Anhui Medical University, Hefei, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China.
  • 5 Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center Hefei, 230032, China. Electronic address: [email protected].
  • 6 Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center Hefei, 230032, China; School of Pharmaceutical Sciences, Anhui Medical University, Hefei 230012, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China; Department of Pharmacy, Anhui No. 2 Provincial People's Hospital, Hefei, China. Electronic address: [email protected].
PMID: 41242435 DOI: 10.1016/j.reprotox.2025.109109
Abstract

Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous environmental pollutant, is extensively utilized in industrial, medical, and food-related applications. In our previous study, we successfully established an mice model of ICP induced by gestational di(2-ethylhexyl) phthalate (DEHP) exposure. Our findings suggested that DEHP-induced folic acid (FA) deficiency might contribute to the development of IUGR. However, the potential protective effects of FA supplementation against IUGR resulting from gestational DEHP exposure remain to be elucidated. Notably, administration of DEHP to pregnant mice resulted in a significant reduction in average placental weight and diameter, as well as fetal body weight and crown-rump length. Histological analysis using H&E staining and immunohistochemistry revealed a reduction in the area of placental blood sinuses and the density of CD34+ micro vessels. Gene expression analysis of placental nutrient transporters demonstrated significant downregulation of glucose transporter GLUT1, fatty acid transporters CD36 and Fatp1, as well as Amino acid Transporter Snat4. Molecular docking analysis indicated that FA exhibited strong binding affinity toward the target protein STAT3. Experimental findings confirmed that FA could enhance placental angiogenesis and alleviate placental hypoplasia and nutrient transport impairments by activating the STAT3/HIF-1α/VEGFA signaling pathway, thus preventing IUGR caused by maternal DEHP exposure. These results provide a theoretical foundation for the prevention and treatment of ICP-associated IUGR.

Keywords

Di (2-ethylhexyl) phthalate; Folic acid; Intrahepatic cholestasis in pregnancy; Intrauterine growth restriction; Placenta.

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