Project #1: Superfund Chemicals, Nutrition, and Endothelial Cell Dysfunction
Atherosclerosis, a chronic inflammatory disease, is still the number one cause of death in the United States. Numerous risk factors for the development of atherosclerosis have been identified, including obesity and hypertriglyceridemia. Superfund chemicals, and especially persistent organic pollutants such as PHAs and PCBs, also have been shown to increase the risk and incidence of cardiovascular diseases. Most of all, we have evidence that both selected PCBs and fatty acids can induce endothelial cell dysfunction and inflammation, critical events in the early pathology of atherosclerosis. Our data suggest that diet, nutrition, and life-style changes can modify pathologies of chronic diseases, as well as diseases associated with environmental toxic insults.
Little is known about mechanisms and regulation of cellular uptake, trafficking and initiation of proinflammatory pathways by both PCBs and fatty acids. Membrane lipid rafts such as caveolae are particularly abundant in endothelial cells, where they are believed to play a major role in the regulation of endothelial vesicular trafficking. Thus, we hypothesize that caveolae are critical in the cellular uptake of selected fatty acids and lipophilic environmental contaminants such as PCBs. Caveolae have also been implicated in the regulation of cell signal transductions. We further hypothesize that PCBs and certain dietary lipids interact with caveolae and trigger distinct proatherogenic signaling pathways, leading to endothelial cell dysfunction. We also hypothesize that these signaling pathways can be down-regulated by antioxidant nutrients and related bioactive compounds (e.g., diet-derived flavonoids) as well as by ligands of antiatherogenic nuclear receptors (PPARs).
These hypotheses are being tested in vitro as well as in vivo by studying the interactions of PCBs with dietary compounds such as fatty acids and antioxidants. Importantly, we will use cell and mouse models lacking the caveolin gene to determine the involvement of caveolae in the PCB and fatty acid uptake and toxicity. We propose to explore mechanisms of nutrient-mediated modulation of PCB toxicity, and the outcome of our proposed study may lead to novel nutritional recommendations and therapeutic interventions in populations exposed to Superfund chemicals.
- Wahlang, B., Perkins, J.T., Petriello, M.C., Hoffman, J.B., Stromberg, A.J., Hennig, B. (2017). A compromised liver alters polychlorinated biphenyl-mediated toxicity. Toxicology, 380: 11-22. doi: 10.1016/j.tox.2017.02.001
- Hennig, B. (2017). Environmental challenges in Central and Eastern Europe. Reviews on Environmental Health, 32(1-2): 1. doi: 10.1515/reveh-2017-0004
- Perkins, J.T., Petriello, M.C., Xu, L., Stromberg, A., Hennig, B. (2017). An open sourced statistical application for identifying complex toxicological interactions of environmental pollutants. Reviews on Environmental Health, 32(1-2): 23-26. doi: 10.1515/reveh-2016-0044
- Petriello, M.C., Hoffman, J.B., Morris, A.J., Hennig, B. (2017). Emerging roles of xenobiotic detoxification enzymes in metabolic diseases. Reviews on Environmental Health, 32(1-2): 105-110. doi: 10.1515/reveh-2016-0050
- Hoffman, J.B., Petriello, M.C., Hennig, B. (2017). Impact of nutrition on pollutant toxicity: an update with new insights into epigenetic regulation. Reviews on Environmental Health, 32(1-2): 65-72. doi: 10.1515/reveh-2016-0041
- Hoffman, J.B., Hennig, B. (2017). Protective influence of healthful nutrition on mechanisms of environmental pollutant toxicity and disease risks. Annals of the New York Academy of Sciences, 1398(1):99-107. doi: 10.1111/nyas.13365
- Wahlang, B., Barney, J., Thompson, B., Wang, C., Hamad, O.M., Hoffman, J.B., Petriello, M.C., Morris, A.J., Hennig, B. (2017). Editor’s Highlight: PCB126 Exposure Increases Risk for Peripheral Vascular Diseases in a Liver Injury Mouse Model. Toxicological Sciences, 160(2): 256-267. doi: 10.1093/toxsci/kfx180
- Gupta, P., Thompson, B.L., Wahlang, B., Jordan, C.T., Hilt, J.Z., Hennig, B., Dziubla, T. (2017). The environmental pollutant, polychlorinated biphenyls, and cardiovascular disease: a potential target for antioxidant nanotherapeutics. Drug Delivery and Translational Research. [E-pub ahead of print]. DOI: 10.1007/s13346-017-0429-9
- Petriello, M.C., Brandon, J.A., Hoffman, J., Wang, C., Tripathi, H., Abdel-Latif, A., Ye, X., Li, X., Yang, L., Lee, E., Soman, S., Barney, J., Wahlang, B., Hennig, B., Morris, A.J. (2018). Dioxin-like PCB 126 increases systemic inflammation and accelerates atherosclerosis in lean LDL receptor deficient mice. Toxicological Sciences, 162(2): 548-558. doi: 10.1093/toxsci/kfx275
- Petriello, M.C., Charnigo, R., Sunkara, M., Soman, S., Pavuk, M., Birnbaum, L., Morris, A.J., Hennig, B. (2018). Relationship between serum Trimethylamine N-oxide and exposure to dioxin-like pollutants. Environmental Research, 162: 211-218. DOI: 10.1016/j.envres.2018.01.007
For a complete list of Dr. Hennig's publications, see PubMed.
Posters and Presentations
- Positive Associations Between Serum Levels of Dioxin-Like Pollutants and the Cardiometabolic Disease Risk Biomarker Trimethylamine-N-Oxide
- EGCG Prevents PCB-induced Endothelial Cell Inflammation via Epigenetic Modifications of NF-KB Target Genes
- Exposure to PCB126 Triggers Cellular Defense Through Cross-Talk of Caveolae and Nrf2 Signaling
- A New Role for Exercise: Examining the Effects of Physical Activity on Polychlorinated Biphenyl-Induced Cardiovascular Disease
- PCB77 Dechlorination Mixtures Alter Proinflammatory Events in Vascular Endothelial Cells
- Dietary DHA Promotes an Antioxidant Response in Mice Exposed to Environmental Pollutants
- Benzo[a]pyerne-Induced Vascular Endothelial Adhesion Molecule Expression Can Be Disrupted by Selective Flavonoid Treatment
- Caveolae Mediate Pro-Inflammatory Properties of Coplanar Polychlorinated Biphenyls
- Dietary Flavonoids Block PCB-Induced Proinflammatory Responses in Vascular Endothelial Cells
- Nutritional Intervention to Modify Pro-atherogenic Effects of Persistent Organic Pollutants
- PPARa Agonists Protect Against PCB-Induced Vascular Endothelial Cell Activation
- Role of Caveolin-1 in EGCG-Mediated Protection Against Linoleic Acid-Induced Endothelial Cell Activation
UK Superfund Postdoctoral Trainee Mike Petriello, PhD