An Overview of Adverse Outcome Pathway Links between PM_2.5 Exposure and Cardiac Developmental Toxicity

Fine particulate matter (PM_2.5) 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_2.5 has attracted growing concern. Despite several studies supporting the cardiac developmental toxicity of PM_2.5, 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_2.5-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_2.5.