Liang Chen, Ding Ruiyang, Sun Qinglin, Liu Shiqian, Sun Zhiwei, Duan Junchao
Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China.
Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
Environ Health (Wash). 2024 Jan 18;2(3):105-113. doi: 10.1021/envhealth.3c00143. eCollection 2024 Mar 15.
Fine particulate matter (PM) is a significant risk factor for birth defects. As the first and most important organ to develop during embryogenesis, the heart's potential susceptibility to PM has attracted growing concern. Despite several studies supporting the cardiac developmental toxicity of PM, the diverse study types, models, and end points have prevented the integration of mechanisms. In this Review, we present an adverse outcome pathway framework to elucidate the association between PM-induced molecular initiating events and adverse cardiac developmental outcomes. Activation of the aryl hydrocarbon receptor (AhR) and excessive generation of reactive oxygen species (ROS) were considered as molecular initiating events. The excessive production of ROS induced oxidative stress, endoplasmic reticulum stress, DNA damage, and inflammation, resulting in apoptosis. The activation of the AhR inhibited the Wnt/β-catenin pathway and then suppressed cardiomyocyte differentiation. Impaired cardiomyocyte differentiation and persistent apoptosis resulted in abnormalities in the cardiac structure and function. All of the aforementioned events have been identified as key events (KEs). The culmination of these KEs ultimately led to the adverse outcome, an increased morbidity of congenital heart defects (CHDs). This work contributes to understanding the causes of CHDs and promotes the safety evaluation of PM
细颗粒物（PM）是出生缺陷的一个重要风险因素。作为胚胎发育过程中首先发育且最为重要的器官，心脏对PM的潜在易感性已引起越来越多的关注。尽管有多项研究支持PM对心脏发育的毒性作用，但研究类型、模型和终点的多样性阻碍了作用机制的整合。在本综述中，我们提出了一个不良结局途径框架，以阐明PM诱导的分子起始事件与心脏发育不良结局之间的关联。芳烃受体（AhR）的激活和活性氧（ROS）的过度产生被视为分子起始事件。ROS的过度产生诱导氧化应激、内质网应激、DNA损伤和炎症，从而导致细胞凋亡。AhR的激活抑制Wnt/β-连环蛋白信号通路，进而抑制心肌细胞分化。心肌细胞分化受损和持续的细胞凋亡导致心脏结构和功能异常。上述所有事件均被确定为关键事件（KEs）。这些关键事件的最终结果导致不良结局，即先天性心脏病（CHD）发病率增加。这项工作有助于理解CHD的病因，并促进对PM的安全性评估
