Low expression of fatty acid transporter 1 in the placenta mediates the reduction in fetal birth weight caused by caffeine exposure during pregnancy

Fatty acids play extensive roles in fetal energy metabolism and various physiological processes. Insufficient maternal supply of fatty acids increases the risk of intrauterine growth retardation (IUGR). Our previous research found that prenatal caffeine exposure (PCE) can lead to IUGR, but it is unclear whether this is related to placental fatty acid transport disorder. This study systematically investigates the impact of caffeine intake during pregnancy on placental fatty acid transport function and its molecular mechanisms by establishing rat models, mice intervention models, and in vitro cell experiments. In this study, we found that PCE reduces fatty acid levels in fetal blood, accompanied by decreased expression of placental fatty acid transporter 1 (FATP1) in rats. Further studies indicate that caffeine can antagonize ADORA2A and inhibit the expression and activity of the ERK-ETS1-PXR/RXRɑ signaling pathway in placental trophoblast cells. Conversely, ADORA2AR agonists, ETS1 overexpression plasmids, or PXR agonists can reverse the ADORA2A receptor antagonism, the decrease in ERK-ETS1-PXR/RXRɑ-FATP1 expression, and the disorder of fatty acid uptake caused by caffeine. Lastly, we confirmed that PXR agonists can reverse the reduction in placental FATP1 expression, fetal fatty acid levels, and birth weight observed in mice caused by PCE. In summary, this study elucidates the placental fatty acid transport mechanism mediated by the ADORA2A-ERK-ETS1-PXR/RXRɑ pathway inhibition in PCE-induced IUGR model, providing crucial theoretical basis and experimental support for clinical prevention and treatment research from the perspective of placental fatty acid transport.