Halogenated persistent organic pollutants (POPs) like perfluorinated alkylated substances (PFASs), brominated flame retardants (BFRs), organochlorine pesticides and polychlorinated biphenyls (PCBs) are known to cause cancer, immunotoxicity, neurotoxicity and interfere with reproduction and development. Concerns have been raised about the impact of POPs upon brain development and possibly neurodevelopmental disorders. The developing brain is a particularly vulnerable organ due to dynamic and complex neurodevelopmental processes occurring early in life. However, very few studies have reported on the effects of POP mixtures at human relevant exposures, and their impact on key neurodevelopmental processes using human in vitro test systems. Aiming to reduce this knowledge gap, we exposed mixed neuronal/glial cultures differentiated from neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) to reconstructed mixtures of 29 different POPs using concentrations comparable to Scandinavian human blood levels. Effects of the POP mixtures on neuronal proliferation, differentiation and synaptogenesis were evaluated using in vitro assays anchored to common key events identified in the existing developmental neurotoxicity (DNT) adverse outcome pathways (AOPs). The present study showed that mixtures of POPs (in particular brominated and chlorinated compounds) at human relevant concentrations increased proliferation of NSCs and decreased synapse number. Based on a mathematical modelling, synaptogenesis and neurite outgrowth seem to be the most sensitive DNT in vitro endpoints. Our results indicate that prenatal exposure to POPs may affect human brain development, potentially contributing to recently observed learning and memory deficits in children.

已知全氟烷基化物质 (PFAS)、溴化阻燃剂 (BFR)、有机氯农药和多氯联苯 (PCB) 等卤化持久性有机污染物 (POP) 会导致癌症、免疫毒性、神经毒性并干扰生殖和发育。人们担心持久性有机污染物对大脑发育和可能的神经发育障碍的影响。由于生命早期发生的动态和复杂的神经发育过程，发育中的大脑是一个特别脆弱的器官。然而，很少有研究报道 POP 混合物对人类相关暴露的影响，以及使用人体体外测试系统对关键神经发育过程的影响。为了缩小这一知识差距，我们将源自人类诱导多能干细胞 (hiPSC) 的神经干细胞 (NSC) 分化的混合神经元/神经胶质培养物暴露于 29 种不同 POP 的重建混合物中，使用的浓度与斯堪的纳维亚人类血液水平相当。使用基于现有发育神经毒性 (DNT) 不良结果途径 (AOP) 中确定的常见关键事件的体外测定来评估 POP 混合物对神经元增殖、分化和突触发生的影响。本研究表明，人类相关浓度的持久性有机污染物（特别是溴化和氯化化合物）混合物会增加 NSC 的增殖并减少突触数量。根据数学模型，突触发生和神经突生长似乎是最敏感的 DNT体外终点。 我们的研究结果表明，产前接触持久性有机污染物可能会影响人类大脑发育，可能导致最近观察到的儿童学习和记忆缺陷。