Enantioselective transplacental transfer of xenobiotics: mechanisms, plasma protein binding, and health implications for fetal development.

The transplacental transfer of xenobiotics, particularly in an enantioselective manner, is a critical and evolving area of developmental toxicology. Pregnant women, as a highly vulnerable population, are frequently exposed to pervasive chiral chemicals that can cross the placenta, with the placenta serving as an enantioselective barrier. Despite significant research on enantioselective transfer of xenobiotics using various models (in vivo, ex vivo, and in vitro), a comprehensive understanding of the underlying mechanisms of xenobiotics-plasma protein binding remains lacking. This review provides a state-of-the-art synthesis of the characteristics and mechanisms governing the enantioselective transplacental transfer of pharmaceuticals, pesticides, and industrial additives-representative chiral xenobiotics of significant public health concern. We highlight how xenobiotics, acting as ligands, interact with proteins, influencing enantioselective transfer through key processes such as plasma protein binding, transporter-mediated biotransport, and enzyme-catalyzed biotransformation. Notably, the binding of xenobiotics to human serum albumin (HSA) rather than α1-acid glycoprotein (AGP) is shown to primarily inhibit the transmembrane transport of small molecules. Whereas limited docking studies suggest Sudlow site II as a pivotal site for enantioselective binding. Additionally, P-glycoprotein (permeability glycoprotein, P-gp) and cytochrome P450 (CYP450) are important in determining the enantiomeric distribution between maternal and fetus. Pathological conditions may also modify transplacental transfer efficiencies (TTEs). Future research employing advanced techniques, such as isotopic tracing, affinity chromatography, high-resolution screening, and machine learning, will be essential to further elucidate enantiomeric transport mechanisms and their implications for fetal development.