Assessing developmental neurotoxicity of emerging environmental chemicals using multiple in vitro models: A comparative analysis.

Newly synthesized chemicals are being introduced into the environment without undergoing proper toxicological evaluation, particularly in terms of their effects on the vulnerable neurodevelopment. Thus, it is important to carefully assess the developmental neurotoxicity of these novel environmental contaminants using methods that are closely relevant to human physiology. This study comparatively evaluated the potential developmental neurotoxicity of 19 prevalent environmental chemicals including neonicotinoids (NEOs), organophosphate esters (OPEs), and synthetic phenolic antioxidants (SPAs) at environment-relevant doses (100 nM and 1 μM), using three commonly employed in vitro neurotoxicity models: human neural stem cells (NSCs), as well as the SK-N-SH and PC12 cell lines. Our results showed that NSCs were more sensitive than SK-N-SH and PC12 cell lines. Among all the chemicals tested, the two NEOs imidaclothiz (IMZ) and cycloxaprid (CYC), as well as the OPE tris(1,3dichloro-2-propyl) phosphate (TDCIPP), generated the most noticeable perturbation by impairing NSC maintenance and neuronal differentiation, as well as promoting the epithelial-mesenchymal transition process, likely via activating NF-κB signaling. Our data indicate that novel NEOs and OPEs, particularly IMZ, CYC, and TDCIPP, may not be safe alternatives as they can affect NSC maintenance and differentiation, potentially leading to neural tube defects and neuronal differentiation dysplasia in fetuses.新型合成化学品未经全面毒理学评价便被排入环境，尤其未考量其对脆弱的神经发育过程的影响。因此，采用与人类生理学高度匹配的实验方法，精准评估这类新型环境污染物的发育神经毒性，具有重要意义。本研究采用三种常用的体外神经毒性模型——人神经干细胞（human neural stem cells, NSCs）、SK-N-SH细胞系与PC12细胞系，在环境相关剂量（100 nM与1 μM）下，对19种常见环境污染物的潜在发育神经毒性进行了比较评价，所涉污染物包括新烟碱类（neonicotinoids, NEOs）、有机磷酸酯类（organophosphate esters, OPEs）与合成酚类抗氧化剂（synthetic phenolic antioxidants, SPAs）。研究结果显示，人神经干细胞对污染物的敏感性高于SK-N-SH与PC12细胞系。在所测试的所有化学品中，两种新烟碱类物质咪虫噻嗪（imidaclothiz, IMZ）与环丙虫胺（cycloxaprid, CYC），以及有机磷酸酯类化合物三(1,3-二氯-2-丙基)磷酸酯（tris(1,3dichloro-2-propyl) phosphate, TDCIPP）所引发的扰动最为显著：它们会损伤人神经干细胞的维持与神经元分化过程，并促进上皮-间质转化进程，其作用机制可能与激活核因子κB（NF-κB）信号通路有关。本研究数据表明，新型新烟碱类与有机磷酸酯类化合物——尤其是IMZ、CYC与TDCIPP——并非安全的替代产品，因为它们会干扰人神经干细胞的维持与分化过程，有可能导致胎儿出现神经管缺陷以及神经元分化发育异常。