Environmental pollutants and atherosclerosis: Epigenetic mechanisms linking genetic risk and disease

Abstract

Over the past half-century, significant strides have been made to identify key risk factors, genetic mechanisms, and treatments for atherosclerosis. Yet, coronary artery disease (CAD) remains a leading global public health challenge. While the heritability of CAD is well-documented, there is increasing focus on the role of environmental exposures, such as smoking, air pollution, and heavy metals, on global CAD risk. Recent research has shed light on the interplay between genetic variation and environmental factors, offering insights into gene-environment (GxE) interactions. Moreover, emerging evidence suggests that environmental toxicants can profoundly impact the epigenome, altering gene regulation beyond the genetic sequence itself, revealing novel mechanisms underlying disease. Epigenetic changes — such as modifications in DNA methylation, chromatin structure, and non-coding RNA function — are now recognized as key molecular determinants of atherosclerosis. These observations have created a foundational paradigm that environment, genetics, and epigenetic mechanisms influence risk through a highly complex interaction regulating cellular phenotype, pathology, and disease progression. In this review, we explore the mechanisms by which environmental exposures influence the epigenome and contribute to the regulation of atherosclerotic disease. Additionally, we examine the transgenerational epigenetic effects of these exposures on disease risk. Advancing our understanding of these mechanisms is essential for informing public health strategies aimed at mitigating harmful environmental exposures and reducing the global burden of cardiovascular disease.