Cumulative epidemiological and experimental data have shown that exposure to ambient particulate matter (PM) leads to increased cardiovascular morbidity and mortality. A causal association between PM exposure and atherosclerosis has been established. Unfortunately, the pathogenic mechanisms remain unknown preventing the development of effective therapeutic strategies. We have found that exposures to ultrafine particles (UFP, PM with an aerodynamic diameter < 0.2 m) and diesel exhaust lead to increased lipid peroxidation in the lungs and systemic tissues, accompanied by dyslipidemia and a proatherogenic plasma lipoprotein profile, consisting of LDL particles more susceptible to oxidation and dysfunctional HDL particles with loss of their vascular protective properties. However, the mechanisms by which inhalation of UFP lead to effects in the systemic vasculature remain unknown. We and others have shown that exposure to PM lead to marked changes in the gut microbiome, which is known to modulate host metabolism, immunity, and inflammatory responses resulting in pathological conditions, including cardiovascular diseases. This project will evaluate whether a novel microbome-mediated gastrointestinal (GI) pathway mediates PM-induced dyslipidemia and atherosclerosis. Our preliminary data indicate that oral administration of UFP or inhaled diesel exhaust induces changes in gut microbiota diversity, which associates with lipid oxidation in the intestines and blood, dyslipidemia, and liver steatosis together with decreased expression of hepatic PPAR?, which may mediate some of the UFP-mediated cardiometabolic actions. Our central hypothesis is that inhalation exposure to ambient UFP induces dyslipidemia and atherosclerosis partly due to changes in gut microbiota composition that lead to dysregulation of PPAR? in the liver. We will test this hypothesis via three specific aims: 1) To determine the changes in gut microbiota composition following pulmonary exposure to ultrafine PM. We will perform both UFP inhalation and oral gavage studies to characterize the relative changes in microbiota in Ldlr KO and C57BL/6 mice. 2) To examine whether UFP-induced dyslipidemia and atherosclerosis are mediated by the gut microbiome. The microbiota of UFP-exposed mice will be transferred into germ-free and antibiotic-treated Ldlr KO and C57BL/6 recipients to establish a causal link between UFP- induced gut microbiota effects, lipid metabolism, and atherosclerosis. 3) To determine whether UFP-mediated changes in gut microbiota promote lipid metabolic effects and atherosclerosis via modulation of PPAR? expression in the liver. We will determine if UFP-induced changes in hepatic PPAR? mediate effects induced by UFP exposure on lipid and atherosclerosis using PPAR? KO mice. The results are expected to enhance our understanding of a novel gut microbiome-mediated pathway by which UFP induce adverse systemic effects. If successful, results derived from this project are expected to have a significant impact in developing preventive and therapeutic efforts to ameliorate the health impact of air pollution.

Public Health Relevance

This project aims to understand how air pollution induces atherosclerosis, an inflammatory process within the blood vessels which is initiated and propagated by the deposition of lipids and inflammatory cells, and that is the main cause for cardiovascular ischemic diseases such as heart attacks and strokes, responsible for the largest number of deaths in the western world. Air pollution contains both gaseous and particulate matter, and it appears that the particles of the smallest size, the ultrafine particles, are most toxic in promoting systemic oxidative stress, proinflammatory effects and atherosclerosis. This proposal is designed to test whether ambient ultrafine particles cause cardiovascular disease by altering the composition of the gut microbiome, with the ultimate goal of helping to develop in the future, strategies that could allow inhibiting the toxic and harmful effects of air pollutants and/or stratify individual risk for toxicity.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Systemic Injury by Environmental Exposure (SIEE)
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Dzierlenga, Anika Lin
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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