Yang Xiaomeng, Hayat Kashif, Chen Ruici, Liu Yingxue, Bai Xiaoxia, Liu Weiping
MOE Key Laboratory of Environmental Remediation and Ecosystem Health, Institute of Environmental Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058, China.
ZJP Key Laboratory of Pollution Exposure and Health Intervention, Interdisciplinary Research Academy (IRA), Zhejiang Shuren University, Hangzhou, 310015, China.
Arch Toxicol. 2025 Jun 7. doi: 10.1007/s00204-025-04108-x.
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.
外源性物质的胎盘转运，尤其是对映选择性转运，是发育毒理学中一个关键且不断发展的领域。孕妇作为一个高度脆弱的群体，经常接触能穿过胎盘的普遍存在的手性化学物质，胎盘起着对映选择性屏障的作用。尽管使用各种模型（体内、体外和离体）对外源性物质的对映选择性转运进行了大量研究，但仍缺乏对外源性物质与血浆蛋白结合潜在机制的全面理解。本综述对药物、农药和工业添加剂（对公众健康有重大影响的代表性手性外源性物质）对映选择性胎盘转运的特征和机制进行了最新综合阐述。我们强调外源性物质作为配体如何与蛋白质相互作用，通过血浆蛋白结合、转运体介导的生物转运和酶催化的生物转化等关键过程影响对映选择性转运。值得注意的是，外源性物质与人血清白蛋白（HSA）而非α1-酸性糖蛋白（AGP）的结合主要抑制小分子的跨膜转运。而有限的对接研究表明，Sudlow位点II是对映选择性结合的关键位点。此外，P-糖蛋白（通透性糖蛋白，P-gp）和细胞色素P450（CYP450）在决定母体和胎儿之间的对映体分布方面很重要。病理状况也可能改变胎盘转运效率（TTEs）。未来采用同位素示踪、亲和色谱、高分辨率筛选和机器学习等先进技术的研究，对于进一步阐明对映体转运机制及其对胎儿发育的影响至关重要。
