Fine particulate matter (PM2.5) 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 PM2.5 has attracted growing concern. Despite several
studies supporting the cardiac developmental toxicity of PM2.5, 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 PM2.5-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 PM2.5.</sub