SR‐B1‐Mediated Transplacental Transfer of Hydrophobic Toxicants Disrupts Fetal Development During Barriergenesis

Gestation represents a critical developmental window of fetal vulnerability to xenobiotic-induced disruptions of biological homeostasis. While xenobiotic transfer is primarily studied through maternal-fetal comparisons at delivery, its spatiotemporal distribution across gestation stages, particularly the transport mechanisms in early pregnancy, remains poorly understood. In this study, we reveal spatiotemporal heterogeneity of hydrophobic toxicants (including persistent organic pollutants such as medium-chain chlorinated paraffins [MCCPs] and hexabromocyclododecane) and endogenous metabolites in the developing placenta and fetus by mass spectrometry imaging (MSI). The stage of transition to hemotrophic nutrition is found as a critical window with fetal-to-maternal distribution ratios of xenobiotics approximately 8.4-38.2-times higher than those estimated at birth. At this critical stage, Scavenger Receptor Class B Member 1 (SR-B1) is identified as the key, stage-specific, and predominate transporter mediating fetal delivery of hydrophobic toxicants and lipids in early gestation through integration of spatial metabolomics and single-nucleus RNA sequencing of placental tissue. Finally, our findings demonstrate that early gestational exposure to MCCPs is associated with fetal neuro-lipotoxicity. The results highlight the urgent need to reduce early-pregnancy xenobiotic exposure for preventing toxicant-associated fetal lipid metabolic disruption.