The complex pathophysiology of autism spectrum disorder encompasses interactions between genetic and environmental factors. On the one hand, hundreds of genes, converging at the functional level on selective biological domains such as epigenetic regulation and synaptic function, have been identified to be either causative or risk factors of autism. On the other hand, exposure to chemicals that are widespread in the environment, such as endocrine disruptors, has been associated with adverse effects on human health, including neurodevelopmental disorders. Interestingly, experimental results suggest an overlap in the regulatory pathways perturbed by genetic mutations and environmental factors, depicting convergences and complex interplays between genetic susceptibility and toxic insults. The pervasive nature of chemical exposure poses pivotal challenges for neurotoxicological studies, regulatory agencies, and policy makers. This highlights an emerging need of developing new integrative models, including biomonitoring, epidemiology, experimental, and computational tools, able to capture real-life scenarios encompassing the interaction between chronic exposure to mixture of substances and individuals’ genetic backgrounds. In this review, we address the intertwined roles of genetic lesions and environmental insults. Specifically, we outline the transformative potential of stem cell models, coupled with omics analytical approaches at increasingly single cell resolution, as converging tools to experimentally dissect the pathogenic mechanisms underlying neurodevelopmental disorders, as well as to improve developmental neurotoxicology risk assessment.

中文翻译：

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自闭症谱系障碍处于基因和环境的十字路口：自闭症谱系障碍发育病理生理学的贡献、趋同和相互作用。

自闭症谱系障碍复杂的病理生理学包括遗传因素和环境因素之间的相互作用。一方面，数百个基因在功能水平上集中在选择性生物领域，例如表观遗传调控和突触功能，已被确定为自闭症的致病因素或危险因素。另一方面，接触环境中广泛存在的化学物质（例如内分泌干扰物）会对人类健康产生不利影响，包括神经发育障碍。有趣的是，实验结果表明，受基因突变和环境因素干扰的调控途径存在重叠，描绘了遗传易感性和毒性损伤之间的融合和复杂的相互作用。化学品暴露的普遍性给神经毒理学研究、监管机构和政策制定者带来了关键挑战。这凸显了开发新的综合模型的新需求，包括生物监测、流行病学、实验和计算工具，能够捕捉现实生活场景，包括长期接触物质混合物与个人遗传背景之间的相互作用。在这篇综述中，我们讨论了遗传损伤和环境侵害的相互交织的作用。具体来说，我们概述了干细胞模型的变革潜力，再加上单细胞分辨率不断提高的组学分析方法，作为实验剖析神经发育障碍致病机制以及改善发育神经毒理学风险评估的聚合工具。