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2017 Cardiovascular Research Day Abstract Book

31 PCB 126 Disrupts Gut

31 PCB 126 Disrupts Gut Microbiota and Increases Intestinal Inflammation in a Mouse Model of Atherosclerosis Jessie Hoffman, MS 1 • Michael Petriello, PhD 2 • Olga Vsevolozhskaya, PhD 3 • Richard Charningo, PhD 3 • Andrew Morris, PhD 2 • Bernhard Hennig, PhD 4 1Pharmacology and Nutritional Sciences, University of Kentucky • 2 Division of Cardiovascular Medicine, University of Kentucky • 3 Biostatistics, University of Kentucky • 4 Animal and Food Sciences, University of Kentucky Graduate Student The gut microbiome is sensitive to diet and environmental factors and is involved in the regulation of many host metabolic responses. Dioxin-like pollutants contaminate many food sources, and thus human exposure begins within the gut, which may play a role in pollutant-induced systemic toxicity. Additionally, gut dysbiosis and inflammation pose risk factors for the development of cardiovascular diseases, specifically atherosclerosis. We hypothesize that the dioxin-like pollutant PCB 126 will perturb gut microbial populations and impair gut health, which may contribute to pollutant-induced systemic toxicity in an atherosclerotic mouse model. LDLr -/- mice were fed a low fat atherogenic diet (10% fat, 0.15% cholesterol) for 14 weeks and exposed to PCB 126 at week 2 and 4. Exposure to PCB 126 reduced gut microbial diversity and shifted populations at the phylum and genus levels in ways that mimic observations in chronic inflammatory diseases. Furthermore, PCB exposed mice exhibited increased markers of inflammation in intestinal and plasma samples. Interestingly, Cyp1a1 gene expression was increased in intestinal samples even 10 weeks after PCB exposure, indicating a slow continual passage of pollutants through the enterohepatic circulation. These data imply that PCB toxicity is already initiated in the gut through disruption of healthy microbiota, and increases in gut inflammation. These observations highlight a unique opportunity for dietary interventions that are beneficial for both gut and overall health. Further research should examine how nutritional components can combat pollutant induced toxicity initiated at the gut level. 47

32 PCB 126 Exposure Increases Peripheral Vascular Disease Risk in Mice with Fatty Liver Jazmyne Barney 1 • Banrida Wahlang, PhD 2 • Brendan Thompson 1 • Chunyan Wang, PhD 3 • Omer Hamad 3 • Jessie Hoffman, MS 4 • Michael Petriello, PhD 2 • Andrew Morris, PhD 2 • Bernhard Hennig, PhD 3 1Toxicology and Cancer Biology, University of Kentucky • 2 UK Superfund Research Center, University of Kentucky • 3 Animal and Food Sciences, University of Kentucky • 4 Pharmacology and Nutritional Sciences, University of Kentucky Graduate Student Xenobiotic and energy metabolism is dependent on a functional liver. Exposure to environmental pollutants like polychlorinated biphenyls (PCBs) is associated with inflammatory diseases, including non-alcoholic fatty liver disease and atherosclerosis. A compromised liver may play a critical role in modifying the induction of PCB toxicity and inflammation of the peripheral vasculature. Over a 14 week study, male C57Bl/6 mice (n=10) were fed an amino acid control diet or a methionine-choline deficient diet (MCD) with or without oral gavage of PCB 126 (0.5mg/kg). Post euthanasia, tissue and blood were collected for histological, toxicological, and inflammatory evaluation. Regardless of diet, PCB 126 induced hepatic steatosis. The MCD+PCB126 group exhibited fibrosis and increased liver to body weight ratio, suggesting liver injury and toxicity. Mice fed MCD-diet and exposed to PCB 126 demonstrated altered expression of hepatic genes involved in carbohydrate and lipid metabolism, indicating metabolic dysfunction. With regard to effects of PCB 126 on extra-hepatic organs, all mice fed MCD diet had decreased expression of plasma leptin and resistin, and PCB 126 exposed groups appeared to have crown like structures in their epididymal adipose tissue, indicating the presence of inflammatory cells. In addition, MCD+PCB 126 mice displayed increased plasma inflammatory markers including Icam-1, Mcp-1, and Tnf-α. Interestingly, in the MCD+PCB 126 group, plasma ALT and AST levels were increased as well as proatherogenic trimethylamine-N-oxide (TMAO), implying simultaneous liver damage and increased peripheral vasculature disease risk. Together these results provide a novel linkage of a compromised liver to PCB-induced hepatic and vascular inflammation. These finding also a have translational component, suggesting environmental pollutants can cause inflammatory disease pathologies by stimulating cross-talk between individual organ systems. (Supported in part by NIEHS/NIH grant P42ES007380). 48

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