Hu Liehai, Ren Ke, Li Yichang, Xia Yunhui, Chen Guijuan, Wang Xiaojian, Luo Chunyu, Sun Yun, Li Dongmei
State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.
Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China.
Arch Toxicol. 2025 Aug 19. doi: 10.1007/s00204-025-04157-2.
Developmental exposure to environmental pollutants is increasingly recognized as a significant risk factor for autism spectrum disorder (ASD), yet the specific mechanisms by which individual toxicants contribute to this neurodevelopmental disorder remain largely unknown. Methyl ester sulfonate (MES), a widely used anionic surfactant with widespread environmental detection, lacks comprehensive evaluation for developmental neurotoxicity. Here, we exposed pregnant mice to environmentally relevant MES doses (0.06-6 mg/L) from gestational day 8.5 (GD8.5) to postnatal day 21.5 (PND21.5) and assessed their offspring for neurodevelopmental changes. Results showed dose-dependent ASD-like behavioral deficits, including impaired social interactions, heightened anxiety-like behaviors, and increased repetitive/stereotypic patterns. These behavioral anomalies were accompanied by neuropathological alterations, including blood-brain barrier disruption, neuronal loss, and reduced dendritic spine density, indicative of impaired synaptogenesis. Integrative transcriptomic analysis of hippocampal tissue revealed significant dysregulation of key pathways involved in neurodevelopment, prominently featuring the Notch/Hes signaling pathway. Molecular docking simulations suggested that MES could directly interact with Notch receptors, potentially disrupting ligand-receptor interactions. Further in vitro experimental validation demonstrated that MES exposure suppressed neural stem cell differentiation. Collectively, these findings provided evidence that early-life MES exposure acts as a neurodevelopmental toxicant by disrupting Notch/Hes signaling, thereby impairing neuronal differentiation and synaptogenesis, which underlined the observed ASD-like behavioral deficits in mice. This study offers novel mechanistic insights into how environmental factors contribute to ASD pathogenesis and highlights the need for toxicological assessment of widely distributed surfactants.
越来越多的人认识到，发育过程中接触环境污染物是自闭症谱系障碍（ASD）的一个重要风险因素，然而，个体毒物导致这种神经发育障碍的具体机制在很大程度上仍然未知。甲基磺酸酯（MES）是一种广泛使用的阴离子表面活性剂，在环境中广泛检测到，但其对发育神经毒性缺乏全面评估。在这里，我们从妊娠第8.5天（GD8.5）到出生后第21.5天（PND21.5），将怀孕小鼠暴露于与环境相关的MES剂量（0.06 - 6毫克/升），并评估其后代的神经发育变化。结果显示出剂量依赖性的ASD样行为缺陷，包括社交互动受损、焦虑样行为加剧以及重复/刻板行为模式增加。这些行为异常伴随着神经病理学改变，包括血脑屏障破坏、神经元丢失和树突棘密度降低，表明突触发生受损。对海马组织的综合转录组分析揭示了神经发育相关关键通路的显著失调，其中Notch/Hes信号通路尤为突出。分子对接模拟表明，MES可以直接与Notch受体相互作用，可能破坏配体 - 受体相互作用。进一步的体外实验验证表明，MES暴露会抑制神经干细胞分化。总的来说，这些发现提供了证据，表明生命早期MES暴露通过破坏Notch/Hes信号传导，从而损害神经元分化和突触发生，进而导致小鼠出现观察到的ASD样行为缺陷，成为一种神经发育毒物。这项研究为环境因素如何导致ASD发病机制提供了新的机制见解，并强调了对广泛分布的表面活性剂进行毒理学评估的必要性。
