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Welcome to the MSU Superfund Research Program Newsletter
The MSU Superfund Research Program is pleased to send you the first edition of our electronic newsletter. Please take a moment to read over our latest successes and achievements!
For more information on the MSU Superfund Research Program, please visit: http://cit.msu.edu/superfund2013/index.html.
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Because of the dioxin contamination in the Tittabbassee River, local residents are very interested in the health risks associated with exposure. This photo shows the aerial view of the river and contamination levels. (Photo courtesy of Michigan DEQ)
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MSU Jumpstarts Community Engagement in the Michigan Tri-Cities Area
Michigan State University (MSU) Superfund Research Program (SRP) Director Norbert Kaminski, Ph.D., presented to the Saginaw-Tittabawassee Rivers Contamination Community Advisory Group (CAG) in November to explain the history and mission of the SRP and provide an overview of the MSU Program. The meeting, which took place in Saginaw, provided a starting point for MSU SRP’s community engagement work in the Michigan Tri-Cities area (Saginaw, Midland, and Bay City).
The CAG advises the U.S. Environmental Protection Agency (EPA) about issues related to the local Superfund site, which includes the Tittabawassee River, Saginaw River, and a portion of Saginaw Bay. Pollution at the site includes historic releases of dioxins, chemical by-products of various industrial processes, and other contamination from The Dow Chemical Co. in Midland.
The MSU SRP has a history of working to better understand how dioxin and dioxin-like compounds move through the environment, how the chemicals affect our health, and ways microbes may be used to degrade dioxins in the environment.
At the meeting, Kaminski familiarized the group with the SRP, which funds multidisciplinary research that addresses complex human and environmental health issues surrounding hazardous waste sites, and highlighted past successes of the program. He also explained results and ongoing research at MSU SRP related to dioxins and plans to engage communities in the Tri-Cities area to enhance the public's knowledge on the current state of environmental science and dioxin-associated health risks.
“The members of the CAG were all very interested in the Program and were very excited about the proposed community engagement activities,” said Kaminski. “They also provided excellent feedback to ensure that we aren’t reinventing the wheel and duplicating efforts that have already been done by groups in communities near the Superfund site.”
MSU SRP is currently developing a curriculum to explain the state of the science surrounding dioxins and provides problem solving activities for high school science classrooms. They are working with Midland High School to present the curriculum to students in the spring.
“The curriculum will provide Midland high school with the resources to teach students about the contamination along the river in their city and how to minimize exposure,” said Kaminski. “It may also provide an excellent opportunity for our SRP trainees to participate in the presentations and help improve the curriculum.”
- Article written by Sara Mishamandani
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Research Spotlight
Timothy R. Zacharewski, Ph.D., Michigan State University
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.
Metabolic syndrome (MetS) describes a set of risk factors known to contribute to diabetes, cardiovascular disease, hepatocellular carcinoma and non-alcoholic fatty liver disease (NAFLD). This multi-factorial disease involves the accumulation of lipids from adipose lipolysis and increased absorption of dietary fat, resulting in dyslipidemia, obesity, and increased hepatic triglycerides. Although fat accumulation in the liver (steatosis) is benign and reversible, chronic accumulation can progress to liver inflammation, diabetes and cancer. Coincidentally, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous environmental contaminant that is a potent aryl hydrocarbon receptor (AhR) agonsist, has been implicated in MetS, diabetes and dyslipidemia development. TCDD induces hepatic steatosis by increasing levels of fatty acids and triglycerides, inhibiting proliferation of adipocytes (fat cells), decreasing glucose transport, and disrupting lipid and carbohydrate metabolism and transport.
Dr. Zacharewski's group investigates comparative AhR-mediated systemic alterations in lipid metabolism and transport that contribute to the progression of liver disease in human, mouse and rat models. The hypothesis that AhR-mediated disruption of intestinal, circulatory and hepatic lipid uptake, metabolism, and transport contributes to hepatic steatosis using dioxin response element (DRE)-dependent and -independent mechanisms is currently being investigated. These studies have led to the development of a high-throughput quantitative histological analysis tool (QuHAnT) for the computational assessment of histological responses. Recent studies suggest repeated TCDD dosing leads to the progression of steatosis to steatohepatitis with fibrosis in mice. Furthermore, results indicate that the intestinal absorption of dietary fats plays a key role in the development of TCDD-mediated fat accumulation in the liver.
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Trainee Spotlight: Ashwini Phadnis-Moghe
Recent MSU doctoral graduate and trainee on Project 1, Ashwini Phadnis-Moghe, was invited to speak at the 2013 Superfund Annual Meeting in Baton Rouge, Louisiana this past fall. She spoke on, “The Role of B-cell Lymphoma-6 (BCL-6) in TCDD-Mediated Impaired Human B-cell Activation,” in the Scientific Session: Environmental and Health Effects of Halogenated Pollutants.
Dr. Phadnis-Moghe presented results showing that TCDD-treatment of activated human peripheral blood B cells leads to suppression of B cell activation. The mechanism responsible for suppressed B cell activation and ultimately imapairment of B cell differentiation into antibody secreting cells, involves, at least in part, the transcriptional repressor BCL-6. Specifically, her studies showed that TCDD treatment of B cells resulted in sustained high levels of BCL-6. Disregulation of BCL-6, which leads to high level expression, often through mutation of BCL-6, is well established to be involved Non-Hodgkin’s Lymphoma’s. Interestingly, epidemiological studies performed in areas of dioxin exposure have reported associations between TCDD exposure and an increased incidence of Non-Hodgkin’s Lymphoma. Dr. Phadnis-Moghe's studies showed an increase in the proportion of BCL-6 expressing cells (BCL-6hi) in the presence of TCDD. Likewise, a decrease in the expression of activation markers CD80 and CD69 was seen in the BCL-6hi cells, which was blocked by with a small molecule inhibitor of BCL-6. Collectively, Dr. Phadnis-Moghe’s studies suggest that TCDD treatment leads to an elevation of BCL-6 that impairs B cell activation and differentiation.
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Trainee News
Ashwini Phadnis-Moghe, trainee on Project 1 with Dr. Norbert Kaminski, successfully defended her dissertation, “Mechanisms Underlying 2,3,7,8-tetrachlorodibenzo-p-dioxin-Mediated Suppression of B Cell Activation and Differentiation,” on Friday, February 7, 2014.
Kelly Fader (pictured below), trainee on Project 3 with Dr. Timothy Zacharewski, received 1st place in the oral platform presentation competition at the Fall 2013 Michigan Chapter of Society of Toxicology meeting for her presentation titled, "Toxicogenomic Evaluation of Dose-Dependent TCDD-Elicited Effects in the Jejunal Epithelium of C57BL/6 Mice."
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Short Course: Introduction to Physiologically Based Pharmacokinetic (PBPK) Modeling
The MSU SRP will offer an intensive three day short course, “Introduction to Physiologically Based Pharmacokinetic (PBPK) Modeling,” May 20-22, 2014. Short course students will learn the principles of physiologically based pharmacokinetic (PBPK) modeling and the application of this technique in chemical health risk assessment and drug development. The course includes lectures and hands-on computer simulation exercises. Course instructors are Qiang Zhang, Ph.D., Sudin Bhattacharya, Ph.D., Miyoung Yoon, Ph.D. and Melvin E. Andersen, Ph.D., The Hamner Institutes for Health Sciences and Rory B. Conolly, Sc.D., US Environmental Protection Agency.
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Recent Publications
- Cole JR, Wang Q, Fish JA, Chai B, McGarrell DM, Sun Y, Brown CT, Porras-Alfaro A, Kuske CR and Tiedje JM. (2014) Ribosomal Database Project: data and tools for high throughput rRNA analysis. Nucl. Acids Res. 42(1):D633-42. PMID:24288368. PMCID:PMC Journal In Process.
- Angrish MM, Dominici CY and Zacharewski TR. (2013) TCDD-elicited effects on liver, serum, and adipose lipid composition in C57BL/6 mice. Toxicol Sci. 131(1):108-115. PMC3537129
- Fish JA, Chai B, Wang Q, Sun Y, Brown CT, Tiedje JM and Cole JR. (2013) FunGene: the functional gene pipeline and repository. Front. Microbiol. 4:291. PMC3787254
- Forgacs AL, Dere E, Angrish MM and Zacharewski TR. (2013) Comparative analysis of temporal and dose-dependent TCDD-elicited gene expression in human, mouse, and rat primary hepatocytes. Toxicol Sci. 133(1): 54-66. PMC3627554
- Kopec AK, Boverhof DR, Nault R, Harkema JR, Tashiro C, Potter D, Sharratt B, Chittim B and Zacharewski TR. (2013) Toxicogenomic evaluation of long-term hepatic effects of TCDD in immature, ovariectomized C57BL/6 mice. Toxicol Sci. 135(2):465-475. PMC3807621
- Nault R, Kim S, Zacharewski T. (2013) Comparison of TCDD-elicited genome-wide hepatic gene expression in Sprague-Dawley rats and C57BL/6 mice. Toxicol Appl Pharmacol, 267(2):184-191. PMID:23994337. PMCID:PMC Journal In Process.
- Nault R, Forgacs AL, Dere E, and Zacharewski TR. (2013) Comparisons of differential gene expression elicited by TCDD, PCB126, betaNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver. Toxicol Lett. 223(1):52-59. PMID:23238561. PMCID:PMC Journal In Process.
- Penton CR, Johnson TA, Quensen JF, Iwai S, Cole JR and Tiedje M. (2013) Functional genes to assess nitrogen cycling and aromatic hydrocarbon degradation: primers and processing matter. Front. Microbiol. 4:279. PMC3775264
- Zhang Q, Bhattacharya S and Andersen ME. (2013) Ultrasensitive Response Motifs: Basic Amplifiers in Molecular Signaling Networks. Open Biol 3(4):130031. PMC3718334
- Zhang Q, Kline DE, Bhattacharya S, Crawford RB, Conolly RB, Thomas RS, Andersen ME and Kaminski NE. (2013) All-or-None Suppression of B Cell Terminal Differentiation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol. 268(1):17-26. PMC3594464
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