细颗粒物(PM2.5)会导致脑损伤和疾病。值得注意的是,空气动力学直径小于或等于100nm的超细颗粒(UFP)日益受到关注。有证据表明PM2.5和UFP对大脑有毒性作用,和神经疾病的联系。然而,由于研究模型的多样性,潜在的机制尚未得到充分说明,和不同的端点,等。不良结果途径(AOP)框架是一种基于途径的方法,可以将机械知识系统化以协助污染物的健康风险评估。这里,我们通过收集PM诱导的神经毒性评估中的分子机制构建了AOP。我们在比较毒性基因组学数据库(CTD)中选择了颗粒物(PM)作为压力源,并基于创造性途径分析(IPA)确定了关键毒性途径。我们发现65项研究调查了将PM2.5和UFP与神经毒性联系起来的潜在机制,总共包含2,675个基因。IPA分析显示神经炎症信号和糖皮质激素受体信号是常见的毒性通路。PM2.5和UFP的上游调节因子分析(URA)表明,神经炎症信号是最初触发的上游事件。因此,神经炎症被认为是MIE。引人注目的是,有一个明确的序列激活下游信号通路与UFP,但不是PM2.5。此外,我们发现炎症反应和稳态失衡是PM2.5的关键细胞事件,强调脂质代谢和线粒体功能障碍,UFP的血脑屏障(BBB)损伤。以前的AOPs,只关注PM暴露后神经毒性的表型变化,我们首次提出了AOP框架,其中PM2.5和UFP可以激活途径级联反应,导致与神经毒性相关的不良结局。我们的基于毒性途径的方法并未提高PM诱导的神经毒性的风险评估,但在构建新化学品的AOP框架方面引起了人们的关注。
Fine particulate matter (PM2.5) can cause brain damage and diseases. Of note, ultrafine particles (UFPs) with an aerodynamic diameter less than or equal to 100 nm are a growing concern. Evidence has suggested toxic effects of PM2.5 and UFPs on the brain and links to neurological diseases. However, the underlying mechanism has not yet been fully illustrated due to the variety of the study models, different endpoints, etc. The adverse outcome pathway (AOP) framework is a pathway-based approach that could systematize mechanistic knowledge to assist health risk assessment of pollutants. Here, we constructed AOPs by collecting molecular mechanisms in PM-induced
neurotoxicity assessments. We chose particulate matter (PM) as a stressor in the Comparative Toxicogenomics Database (CTD) and identified the critical toxicity pathways based on Ingenuity Pathway Analysis (IPA). We found 65 studies investigating the potential mechanisms linking PM2.5 and UFPs to
neurotoxicity, which contained 2, 675 genes in all. IPA analysis showed that neuroinflammation signaling and glucocorticoid receptor signaling were the common toxicity pathways. The upstream regulator analysis (URA) of PM2.5 and UFPs demonstrated that the neuroinflammation signaling was the most initially triggered upstream event. Therefore, neuroinflammation was recognized as the MIE. Strikingly, there is a clear sequence of activation of downstream signaling pathways with UFPs, but not with PM2.5. Moreover, we found that inflammation response and homeostasis imbalance were key cellular events in PM2.5 and emphasized lipid metabolism and mitochondrial dysfunction, and blood-brain barrier (BBB) impairment in UFPs. Previous AOPs, which only focused on phenotypic changes in
neurotoxicity upon PM exposure, we for the first time propose AOP framework in which PM2.5 and UFPs may activate pathway cascade reactions, resulting in adverse outcomes associated with
neurotoxicity. Our toxicity pathway-based approach not only advances risk assessment for PM-induced
neurotoxicity but shines a spotlight on constructing AOP frameworks for new chemicals.