Michigan State University Superfund Research Program
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MSU Superfund Research Program Newsletter

The MSU Superfund Research Program is pleased to send you the eighth edition of our electronic newsletter. Please take a moment to read over our recent activities.  

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In This Newsletter:

Research Spotlight

Timothy Zacharewski, Ph.D., Michigan State University
Dr. Timothy Zacharewski, Ph.D., MSU
Dr. Timothy Zacharewski, Professor in the Department of Biochemistry and Molecular Biology at MSU, is PI for Project 3 of the MSU Superfund Research Program: TCDD-Elicited Steatosis - The Role of Aryl Hydrocarbon Receptor Regulation in Lipid Uptake, Metabolism, and Transport
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders in which simple lipid accumulation (steatosis) progresses to steatohepatitis (steatosis with inflammation) and fibrosis (collagen deposition). Recently identified as the second leading cause for liver transplant, NAFLD is reaching pandemic proportions worldwide. Several factors contribute to NAFLD development including genetics, diet, sedentary lifestyle, and age. Recently, disruptions in circadian behaviors including shift work, jet lag, and binge eating have also been associated with metabolic disorders such as NAFLD. Moreover, accumulating evidence suggests that environmental contaminants including 2,3,7,8-tetarchlorodibenzo-p-dioxin (TCDD) and related compounds play an underappreciated role in NAFLD development. In mice, TCDD causes steatohepatitis with fibrosis, while chronic exposure increases the incidence of hepatocellular carcinoma (HCC).
Current research in the Zacharewski lab investigates the impact of aryl hydrocarbon receptor (AhR) activation by TCDD and related compounds on circadian-regulated metabolism in the liver. Hepatic gene expression analysis using RNA-Seq revealed that TCDD dampened the oscillating expression of several core clock transcriptional regulators including BMAL1 and CLOCK, despite no change in daily food consumption. Chromatin immunoprecipitation demonstrated that activated AhR co-binds with BMAL1 and CLOCK at E-box response elements, suggesting direct AhR interference of the transcriptional regulation of BMAL1-CLOCK target genes. As a result, the oscillating pattern of virtually all circadian-regulated genes and polar metabolites was abolished by TCDD, disrupting lipid metabolism, bile acid homeostasis, and glycogenesis. For example, TCDD flattened expression of the rate-limiting enzymes of both glucose and glycogen biosynthesis, consistent with depletion and loss of rhythmic storage of hepatic glycogen. Collectively, these results suggest TCDD decoupled hepatic metabolism from feeding/fasting cycles, impairing energy storage and metabolic efficiency. Moreover, TCDD dysregulated several cues responsible for entraining hepatic cycling including NADH/NADPH and heme. Biosynthesis of heme, a co-factor for several clock regulators, is transcriptionally controlled by nutrient availability, allowing altered feeding times to reset the phase of hepatic cycling. Loss of rhythmic expression across the heme biosynthesis pathway led to hepatic heme accumulation, rendering the hepatic clock less responsive to intestinal nutrient availability.
Beyond disruption of hepatic rhythmicity, our recent studies demonstrate TCDD also causes segment-specific transcriptional and functional changes along the intestinal tract. This includes: (i) continuous duodenal absorption of dietary iron, (ii) enhanced digestion and jejunal absorption of dietary lipids, (iii) increased bile acid reabsorption in the ileum, and (iv) increased microbial production of hepatotoxic secondary bile acids in the colon. In addition, AhR activation by TCDD increased intestinal paracellular permeability, decreased gut motility, and depleted intestinal antigen-presenting cells, which may promote hepatic inflammation. Interestingly, perturbations in circadian rhythm have been associated with several adverse effects along the intestine-liver axis including alterations in the gut microbiome, intestinal permeability, gut motility, and lipid absorption. Therefore, AhR-mediated dysregulation of circadian rhythm may represent a novel unifying mechanism responsible for TCDD-elicited NAFLD, wasting syndrome, HCC, and gut dysbiosis. Overall, we propose that the AhR is central regulator in a liver-gut axis which coordinates circadian rhythm, metabolism, and homeostasis.

MSU Superfund Program Helps Develop MI Safe Fish App with the State of Michigan

The Research Translation Core of the MSU Superfund Program has worked diligently with the Michigan Department of Health and Human Services (MDHHS) to develop an app based off the MI Eat Safe Fish Guide available on the State of Michigan website. The MDHHS test filets of fish taken from Michigan’s lakes and rivers to find the average amount of chemical contaminants in the fish species located there. They use this information to make recommendations on monthly fish consumption in their Eat Safe Fish Guide. The collaboration between MDHHS and the MSU Superfund Program will bring this information to more consumers in a user-friendly mobile app. The app is now available to download for Android devices in the Google Play Store by searching, “MI Safe Fish”. It will be in the Apple App Store for iPhone users to download in the coming weeks. 

The MI Safe Fish app has eight categories: 
  • MI Serving – Tool to help you determine the serving size of fish in relation to your body weight. 
  • Eat 8 – A visual guide to help you choose fish low in mercury from restaurants and grocery stores.
  • Three Cs – A visual guide to the three Cs of fish consumption – choose, clean and cook.
  • Fish ID – Upload a photo of your catch and the app will compare and identify your fish. Or browse the thirty Michigan fish in the gallery to make your own comparisons. 
  • Chemical Risks – Learn more about each of the chemicals identified in the Eat Safe Fish Guide. 
  • Eat Safe Fish Guide – Download the Eat Safe Fish Guide for the region of Michigan you are fishing. 
  • FAQs – Get the answers to the most commonly asked questions about the Eat Safe Fish Guide.
  • About – Learn about the app collaborators.  
Drs. Brad Upham and Syed Hashsham from the MSU Superfund Program worked alongside Michelle Bruneau, Laura Gossiaux and Tom Mata from the State of Michigan Fish Advisory Program to bring the MI Safe Fish app to life. Collin Nicaise, Umama Fakher, and Maggie Williams from the MSU Superfund Program also contributed to the development of this app. The MSU Superfund Research Translation Core is proud to be involved in this project and hopes to work with other SRP centers in the future to develop this type of app for their own regions across the country. 

Below, a screenshot of the Fish ID portion of the app. 

Dr. Sudin Bhattacharya Wins Edward Carney Award for Predictive Toxicology at ASCCT 2018 Annual Meeting

Dr. Sudin Bhattacharya, co-investigator on the Computational Biology Core, won the Edward Carney Award for Predictive Toxicology at the 2018 Annual Meeting of the American Society for Celllular and Computational Toxicology (ASCCT) held in Bethesda, Maryland. The annual award is given to recognize excellence in predictive toxicology and 2018 marks the fourth year the award has been bestowed. Bhattacharya received the award for his presentation, "Integrating Genomics and Epigenomics into Predictive Toxicology of the Aryl Hydrocarbon Receptor." Congratulations Dr. Bhattacharya!

Dr. Brad Upham Receives Distinguished Service Award at SIVB 2018 Annual Meeting

Dr. Brad Upham, leader of the Research Translation Core, recently received the Distinguished Service Award from the Society for In Vitro Biology (SIVB) at their 2018 Annual Meeting. This award recognizes those, specially selected by the SIVB President, who have demonstrated and given extra effort in support of the SIVB programs and endeavors. 

Article Spotlight


Researchers from Project 6: Geochemical Controls on the Sorption, Bioavailability, Formation and Long-term Environmental Fate of Polychlorinated Dibenzo-p-Dioxins (PCDDs), recently published a research article titled, "Activated carbons of varying pore structure eliminate the bioavailability of 2,3,7,8-tetrachlorodibenzo-p-dioxin to a mammalian (mouse) model," in The Science of the Total Environment. 

The use of activated carbon (AC) as an in situ sorbent amendment to sequester polychlorinated-dibenzo-p-dioxins and furans (PCDD/Fs) present in contaminated soils and sediments has recently gained attention as a novel remedial approach. This remedy could be implemented at much lower cost while minimizing habitat destruction as compared to traditional remediation technologies that rely on dredging/excavation and landfilling. Several prior studies have demonstrated the ability of AC amendments to reduce pore water concentrations and hence bioaccumulation of PCDD/Fs in invertebrate species. However, our recent study was the first to show that AC had the ability to sequester 2,3,7,8‑tetrachlorodibenzo‑p‑dioxin (TCDD) in a form that eliminated bioavailability to a mammalian (mouse) model. Here we show that three commercially available ACs, representing a wide range of pore size distributions, were equally effective in eliminating the bioavailability of TCDD based upon two sensitive bioassays, hepatic induction of cyp1A1 mRNA and immunoglobulin M antibody-forming cell response. These results provide direct evidence that a wide range of structurally diverse commercially available ACs may be suitable for use as in situ sorbent amendments to provide a cost-effective remedy for PCDD/F contaminated soils and sediments. Potentially, adaption of this technology would minimize habitat destruction and be protective of ecosystem and human health. 

MSU SRP Virtual Lab Meetings

The next MSU SRP Virtual Lab Meeting will be held Tuesday, December 4 from noon to 1:00 p.m. Eastern Time. Project 1: TCDD Impedes the Minimal Activation Threshold Required for Initiation of B Cell Differentiation: An Integrated Experimental and Computational Modeling Approach will be presenting. The meeting will take place in 162 Food Safety and Toxicology Building, MSU and can be joined by affiliates at Purdue and Rutgers by using Zoom. Join from PC, Mac, iOS or Android: Or join by phone: 1-646-876-9923 or 1-669-900-6833 US Toll, meeting ID: 694 997 442. 

Recent Publications

Dornbos P, Warren M, Crawford RB, Kaminski NE, Threadgill DW, LaPres JJ. Characterizing Serpinb2 as a Modulator of TCDD-Induced Suppression of the B Cell. Chem Res Toxicol. 2018 Oct 30. PubMed PMID: 30339366.

Zhang Q, Li J, Middleton A, Bhattacharya S, Conolly RB. Bridging the Data Gap From in vitro Toxicity Testing to Chemical Safety Assessment Through Computational Modeling. Front Public Health. 2018 Sep 11;6:261. PubMed PMID: 30255008.

Konganti K, Ehrlich A, Rusyn I, Threadgill DW. gQTL: A Web Application for QTL Analysis Using the Collaborative Cross Mouse Genetic Reference Population. G3 (Bethesda). 2018 Jul 31;8(8):2559-2562. PubMed PMID: 29880557.

Fader KA, Nault R, Raehtz S, McCabe LR, Zacharewski TR. 2,3,7,8-Tetrachlorodibenzo-p-dioxin dose-dependently increases bone mass and decreases marrow adiposity in juvenile mice. Toxicol Appl Pharmacol. 2018 Jun 1;348:85-98. PubMed PMID:29673856.

Nault R, Doskey CM, Fader KA, Rockwell CE, Zacharewski T. Comparison of Hepatic NRF2 and Aryl Hydrocarbon Receptor Binding in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Treated Mice Demonstrates NRF2-Independent PKM2 Induction. Mol Pharmacol. 2018 Aug;94(2):876-884. PubMed PMID: 29752288.
Copyright © *|2018|* *|Michigan State University Superfund Research Program|*, All rights reserved.

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