Syncytin-1 deficiency impairs placental nutrient transport via PI3K/Akt/mTOR signaling

The placenta, a vital organ bridging the fetus and mother, governs nutrient exchange. Syncytin-1, an endogenous retroviral envelope protein specifically expressed in placental trophoblasts, is diminished in preeclampsia and fetal growth restriction. This study aimed to investigate the effects of low syncytin-1 expression on placental transport of amino acids, fatty acids and cholesterol, and its implications for fetal and placental development, contributing to fetal growth restriction pathogenesis. Pregnant C57BL/6J mice received tamoxifen-induced conditional syncytin-a gene knockout at embryonic day 11.5, with controls receiving sunflower oil. Placentas and fetuses were collected and analyzed for transport efficiency. Parallelly, siRNA-mediated syncytin-1 knockdown in BeWo cells assessed trophoblast dysfunction. Nutritional content and the expression of relevant transporters for amino acids, fatty acids and cholesterol, were all evaluated in vivo and in vitro. Using conditionally induced syncytin-a gene knockout mouse models, we found that syncytin-A deficiency resulted in decreased fetal and placental weights, reduced placental labyrinthine layer area and syncytiotrophoblast layer structural defects. Placental amino acid (SNAT2, LAT1), fatty acid (CD36, FABP4, FATP4), and cholesterol (LDLR, SR-B1) transporters were dysregulated, aligning with altered nutrient levels in knockout mice. Similar dysfunction in amino acid and fatty acid transport was observed in syncytin-1-silenced BeWo cells. Mechanistically, syncytin-1 deficiency suppressed the PI3K/Akt/mTOR signaling, a key pathway modulating nutrient sensing and transporter activity. Our experiments demonstrate that syncytin-1 regulates the transport of amino acids, fatty acids and cholesterol in placental trophoblastic cells, providing new insights into the pathological role of decreased syncytin-1 in pregnancy-related disorders, particularly in fetal growth restriction.