Adverse outcome pathway of fine particulate matter leading to increased cardiovascular morbidity and mortality: An integrated perspective from toxicology and epidemiology.

Fine particulate matter (PM) exposure is a major threat to public health, and is listed as one of the leading factors associated with global premature mortality. Among the adverse health effects on multiple organs or tissues, the influence of PM exposure on cardiovascular system has drawn more and more attention. Although numerous studies have investigated the mechanisms responsible for the cardiovascular toxicity of PM, the various mechanisms have not been integrated due to the variety of the study models, different levels of toxicity assessment endpoints, etc. Adverse Outcome Pathway (AOP) framework is a useful tool to achieve this goal so as to facilitate comprehensive understanding of toxicity assessment of PM on cardiovascular system. This review aims to illustrate the causal mechanistic relationships of PM-triggered cardiovascular toxicity from different levels (from molecular/cellular/organ to individual/population) by using AOP framework. Based on the AOP Wiki and published literature, we propose an AOP framework focusing on the cardiovascular toxicity induced by PM exposure. The molecular initiating event (MIE) is identified as reactive oxygen species generation, followed by the key events (KEs) of oxidative damage and mitochondria dysfunction, which induces vascular endothelial dysfunction via vascular endothelial cell autophagy dysfunction, vascular fibrosis via vascular smooth muscle cell activation, cardiac dysregulation via myocardial apoptosis, and cardiac fibrosis via fibroblast proliferation and myofibroblast differentiation, respectively; all of the above cardiovascular injuries ultimately elevate cardiovascular morbidity and mortality in the general population. As far as we know, this is the first work on PM-related cardiovascular AOP construction. In the future, more work needs to be done to explore new markers in the safety assessment of cardiovascular toxicity induced by PM.