Liu Li, Zhou Xulan, Ma Zihan, Liu Ruming, Zhang Yuhan, Wang Yaqi, Liu Yiwen, Xia Xiaochun, Wang Juan
School of Public Health, Fujian Medical University, Fuzhou 350122, China.
Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen 361023, China.
Toxics. 2025 May 31;13(6):465. doi: 10.3390/toxics13060465.
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder, with lead (Pb) exposure increasingly linked to its risk. However, the molecular mechanisms linking Pb to ASD remain poorly understood. This study established a postnatal Pb-exposed mouse model and employed the three-chamber social test and the marble-burying test to assess ASD-like behavioral phenotypes. The Pb levels in both blood and the hippocampus were quantified, and hippocampal neurons were assessed for morphological alterations. Moreover, a Tandem Mass Tag (TMT)-based quantitative proteomics approach was applied to elucidate the underlying mechanisms. Neurobehavioral experiments revealed Pb-exposed C57BL/6 offspring exhibited reduced social interaction and novelty preference along with increased repetitive marble-burying behavior. The Pb levels in both the blood and hippocampus of Pb-treated mice were significantly elevated compared with those of control animals. Postnatal Pb exposure resulted in a reduction in the neuronal numbers and disorganized neuronal arrangement in the hippocampus. A total of 66 proteins were identified as being differentially expressed after postnatal Pb exposure. Among them, 34 differentially expressed proteins were common in both Pb exposure groups, with 33 downregulated and 1 upregulated. Bioinformatic analysis revealed multi-pathway regulation involved in Pb-induced neurodevelopmental disorders, including dysregulation of synaptic signaling, abnormal activation of neuron apoptosis, and neuroinflammation. Notably, the SYT10/IGF-1 signaling pathway may play a potential key role. These findings enhance understanding of Pb-induced autism-like behaviors, providing novel proteomic insights into the etiology of ASD.
自闭症谱系障碍（ASD）是一种多因素神经发育障碍，铅（Pb）暴露与其风险的关联日益增加。然而，将铅与ASD联系起来的分子机制仍知之甚少。本研究建立了出生后铅暴露小鼠模型，并采用三室社交试验和埋大理石试验来评估ASD样行为表型。对血液和海马中的铅水平进行了定量，并评估了海马神经元的形态改变。此外，应用基于串联质谱标签（TMT）的定量蛋白质组学方法来阐明潜在机制。神经行为实验表明，铅暴露的C57BL/6后代表现出社交互动减少、新奇偏好降低以及重复埋大理石行为增加。与对照动物相比，铅处理小鼠的血液和海马中的铅水平显著升高。出生后铅暴露导致海马中神经元数量减少和神经元排列紊乱。共鉴定出66种蛋白质在出生后铅暴露后差异表达。其中，34种差异表达蛋白质在两个铅暴露组中均常见，33种下调，1种上调。生物信息学分析揭示了铅诱导的神经发育障碍涉及多途径调节，包括突触信号失调、神经元凋亡异常激活和神经炎症。值得注意的是，SYT10/IGF-1信号通路可能起潜在关键作用。这些发现增进了对铅诱导的自闭症样行为的理解，为ASD的病因提供了新的蛋白质组学见解。
