Identifying environmental pollutants detrimental to the cardiovascular system - Project Summary/Abstract The current proposal represents a combined clinical and basic/molecular investigation which seeks to examine mechanisms of vascular dysfunction associated with persistent organic pollutants (POPs) and environmental toxicants that contribute to the pathogenesis of cardiovascular diseases. Lipophilic pollutants that have contaminated our food chains and consumer products bio-accumulate in human adipose tissues, some frequently termed “forever chemicals”, and negatively impact our health including the cardiovascular system. Our application builds on our compelling preliminary data which, to our knowledge for the first time, demonstrate that specific pollutants are causally linked to vascular dysfunction, impaired angiogenesis, and inflammation, many at concentrations thought to be safe for people. In this proposal, we will seek to characterize the pathogenic effects of diverse toxicants upon the human vascular system by probing direct and indirect mechanisms owing to disruption of adipocyte biology. We will employ several complementary approaches harnessing physiological studies of vascular endothelial function and angiogenesis, cellular imaging, single molecule fluorescence in situ hybridization (smFISH), RNA-Seq., cellular cross-talk experiments, and secretome proteomics analyses to gain novel insights into molecular mechanisms linked to the pathogenesis of toxicant-mediated disease. In Aim 1, we will characterize the effects of environmental chemicals on human vascular function by examining endothelial vasodilator responses using videomicroscopy of live intact human arterioles and perform angiogenic assays from human fat biopsies collected during elective surgical procedures in 150 obese male and female subjects. In Aim 2, we will investigate the pathophysiological contribution of toxicants to adipocyte dysfunction and their role in negatively skewing the adipose milieu toward a pro-atherogenic secretome, and probe biological effects via adipocyte-endothelial crosstalk studies. In Aim 3, we will turn to mouse models to test the ability of specific chemicals, starting with the widely used pyrethroid pesticide permethrin, and also polyethylene nanoplastics to induce atherosclerosis in an intact organism following a chronic, human relevant, low-dose exposure scenario in susceptible ApoE-/- mice fed an American diet. Our approaches involve a diverse multidisciplinary team and combine studies of physiology, molecular toxicology, cellular imaging, and in vivo chronic exposure models to study perturbations in adipocytes and endothelial cells that synergistically promote dysfunctional vascular phenotypes. The overall project tackles an unmet and urgent clinical need for understanding how environmental pollutants, omnipresent in nearly every American household, play causal roles in mediating vascular diseases. Our findings may impact public health policy and actions to reduce exposure risk to many toxicants for which major health concerns are rapidly mounting.
