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

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.