Microplastic exposure elicits sex-specific atherosclerosis development in lean low-density lipoprotein receptor-deficient mice

Microplastics (MPs) are small plastic particles emerging as significant environmental pollutants and humans are ubiquitously exposed to MPs. MPs can be detected in human atherosclerotic plaques and are associated with a higher risk of cardiovascular disease (CVD) and stroke in humans. However, the impact of MP exposure on the cardiovascular system remains elusive. In the current study, we investigated the effects of exposure to MPs at an environmentally relevant dose on atherosclerosis development in male and female low-density lipoprotein receptor-deficient (LDLR^-/-) mice. LDLR^-/- mice were fed a semisynthetic low-fat (4.3 %), low-cholesterol (0.02 %) diet and exposed to 10 mg/kg body weight MPs via daily oral gavage for 9 weeks. Male and female LDLR^-/- mice fed the low-fat diet did not develop obesity phenotype and exposure to MPs did not affect adiposity and circulating lipid profiles in those lean mice. Intriguingly, MP exposure increased atherosclerotic lesion areas in the aortic root by 63 % (p = 0.0185) and brachiocephalic artery by 624 % (p = 0.0541) in male LDLR^-/- mice but did not significantly affect atherosclerosis in female mice. Single-cell RNA sequencing analysis of the whole aorta revealed that exposure to MPs affected the proportions and cellular processes of key atherogenesis-related cell types, especially endothelia cells. Consistently, MP exposure induced pro-atherogenic gene expression in murine primary endothelia cells and human endothelial cells in vitro. Our findings reveal the sex-specific atherogenic effects of MPs in vivo and provide mechanistic insights and new understanding of the impact of MPs on atherosclerosis development and CVD risk in humans.