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Investigating Steatosis Susceptibility in Pancreas Tissue of Mouse in Response to Vinyl Chloride Exposure
Citation:
Ge, Y., M. Bruno, B. Chorley, M. Cave, AND J. Biere. Investigating Steatosis Susceptibility in Pancreas Tissue of Mouse in Response to Vinyl Chloride Exposure. 2020 SOT, Anaheim, California, March 15 - 19, 2020. https://doi.org/10.23645/epacomptox.12685769
Impact/Purpose:
Vinyl chloride (VC) is a chemical toxicant and an important occupational/environmental pollutant relevant to human health. Most studies on the risks of VOC exposure to human health have focused exclusively on the effect of the compound alone (high conc.) and have not taken into consideration interactions (low conc.) with risk-modifying factors such as diet. Indeed, recent studies by our group and others suggest that obesity and hepatic steatosis increase susceptibility to environmental hepatotoxicants. The major goal of this project is to explore the molecular mechanism(s) by which the interaction of fat diet and VC exposure causes enhanced steatosis and other fatty diseases. The present study was undertaken to examine the proteomic effects of exposure to VC in pancreas tissues of C57BL/6J mice fed a HFD, with focus on the investigation of the changes at expression and/or phosphorylation levels of some protein biomarkers of fat metabolism, and key regulators of critical steatotic pathways. Considering all the proteomic results obtained from this study, we proposed a core toxicity pathway map to describe the interplay of these proteins and pathways associated with the steatosis susceptibility mouse in response to environmental vinyl chloride exposure. Importantly, our data raise concerns about the potential for overlap between fatty diets (i.e., Western diet) and exposure to VC and the health implications of this co‐exposure for humans. It also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity, steatosis and other fatty diseases.
Description:
Abnormal pancreatic function can result from environmental exposures, such as chemicals and diet, which can impact susceptibility to metabolic problems and fatty diseases. It has been reported that environmental vinyl chloride (VC) exposure significantly increased steatosis in mice fed a high‐fat diet (HFD) but not low-fat diet (LFD). However, little is known about toxicity pathways, key pathway regulators, and molecular mechanisms underlying the VC- increased steatosis and environmental susceptibility. The present study was undertaken to examine the protein responses to VC exposure at a targeted concentration of 0.1 ppm for 12 weeks in pancreas tissues of six-week-old C57BL/6J mice (Jackson Laboratory) fed LFD or HFD (Envigo Teklad Diets) using a combination of 200 Mouse cytokine array (QAM-CAA-4000)) and Western blot, with focus on the investigation of the changes at expression and/or phosphorylation levels of some protein biomarkers of fat metabolism, and key regulators of critical steatotic pathways. A small group of proteins were altered at expression and phosphorylation in pancreas of mice treated with VC and HFD as compared to control groups treated with LFD, HFD, or LFD and VC. For instance, the expression levels of chemokine 6 (CCL6) and angiotensin converting enzyme (ACE) were increased, and expression of CD48, NOV homolog (NOV), Mannose binding protein (MBL2), thymus-expressed chemokine 1 (TCK-1), glutathione-s-transferases (GSTµ), and phosphorylation of pAKT, and glycogen synthase kinase 3β (GSK3β) were decreased in pancreas of mice treated with VC and HFD as compared to those treated with VC or HFD alone. In addition, GSTµ, pAKT, and pGSK3β was decreased in expression levels in pancreas of mice treated with HFD and VC as compared to those treated with LFD and VC. These and other identified proteins were mainly involved in four predominant toxicity pathways such as pGSK3β mediated fatty acid oxidation and lipid metabolism, TCK-1, MBL2, ACE, CCL6, and CD48 mediate inflammation responses, GSTµ mediated oxidative stress, and NOV and CCL6 mediated cell fibrosis, and the protein alterations may modify the susceptibility of mouse to VC exposures in context of the existing steatotic pathways of inflammation, fatty acid oxidation, and fibrotic processes in the pancreas. (Approval of this abstract does not signify that the contents reflect the views of the Agency)
URLs/Downloads:
DOI: Investigating Steatosis Susceptibility in Pancreas Tissue of Mouse in Response to Vinyl Chloride Exposure
GE_SOT2020_ POSTER ON ENVIRONMENTAL SUSCEPTIBILITY.PDF (PDF, NA pp, 934.964 KB, about PDF)