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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 seventh edition of our electronic newsletter. Please take a moment to read over our recent activities.  

For more information on the MSU Superfund Research Program,
please visit: http://iit.msu.edu/superfund/index.html.

In This Newsletter:

Research Spotlight

Norbert Kaminski, Ph.D., Michigan State University
Dr. Timothy Zacharewski, Ph.D., MSU
Dr. Norbert Kaminski, Director for the Institute for Integrative Toxicology and professor in the Department of Pharmacology and Toxicology serves as the Principal Investigator for Project 1: TCDD Impedes the Minimal Activation Threshold Required for Initiation of B Cell Differentiation: An Integrated Experimental and Computational Modeling Approach.
 
Immune suppression and in particular suppression of antibody responses is a hallmark of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like compounds. TCDD is a high affinity ligand for the aryl hydrocarbon receptor (AHR) and the most toxic member of the family of environmental contaminants termed, halogenated aromatic hydrocarbons (HAH), which are ubiquitous. Previous studies in laboratory animals by this and many others laboratories have shown that B lymphocytes, a type of white blood cell responsible for producing protective antibodies against pathogens, is significantly impaired by TCDD treatment. Recent studies by the Kaminski lab have shown that in human blood-derived B lymphocytes (cells), suppression of antibody responses appears to be due to impaired antibody secretion but not production. In human B cells the antibody molecules can be readily detected inside the cells. Interestingly, human B cells are unable to transport the antibodies out of the cells. Mechanistically, this is very different from what occurs in mouse B cells, which have been the primary model used by most scientists to investigate how TCDD impairs antibody-mediated immune responses. The major assumption being that if TCDD suppresses antibody responses in rodents, like the mouse, and human B cells, it follows that the mechanism must be the same.

The above findings demonstrating distinct mechanisms for suppression of antibody response by TCDD across animal species is supported by a second line of investigations showing that the suite of gene altered by TCDD in activated B cells is very different between mouse, rat and human B cells. Collectively, our findings suggest that TCDD-mediated suppression of the antibody response in mouse B cells is due to suppression of the genes that code for the antibody. By contrast, in human B cells TCDD-mediated suppression of the antibody response is mediated by impairment of secretory processes that facilitate the movement of antibodies out of the cell.

Hui Li Receives 2017 Jackson Soil Chemistry & Mineralogy Award


Hui Li, co-investigator, Project 6, is the recipient of the 2017 Jackson Soil Chemistry and Mineralogy Award. The honor, presented by the Soil Science Society of America, is given to a midcareer scientist who has made outstanding contributions to soil chemistry and mineralogy. Li received his award at the 2017 International Annual Meeting of the American Society of Agronomy, the Crop Science Society of America and the Soil Science Society of America.

"This award further demonstrates Dr. Li's stature as a national and global leader in soil chemistry," said James Kells, chair of the MSU Department of Plant, Soil and Microbial Sciences. "It brings well-deserved recognition to his research program as well as to MSU, the department, the College of Agriculture and Natural Resources, and MSU AgBioResearch." Li was nominated for the Jackson award by Stephen Boyd, project leader, Project 6. Nominees are judged on four criteria: significance and originality of research, excellence in creative reasoning and skill in obtaining data, quality of teaching at the undergraduate or graduate level, and impact of the research on soil science and the larger society. Throughout his nearly 20 years in the field, Li has established himself as an expert in the environmental fate and transformation of chemicals of emerging concern, as well as organic contaminants and pesticides in soils and their impacts on ecosystems and human health.

Students Represent MSU SRP at Annual SRP Meeting
 

The MSU SRP was well represented by its students at the Annual SRP Meeting held in Philadelphia, Pennsylvania this past December. 

Kelly Fader (pictured left), graduate student, Project 3, was awarded first place in the Health Sciences category for her poster titled, "Dioxin increases bone density in male and female mouse femurs." Fader also presented two other posters, “Dioxin-mediated disruption of bile acid metabolism and circulation promotes fatty liver disease,” and “Dioxin-mediated loss of liver- and sex-specific gene expression in mice.”  

Peter Dornbos, graduate student, Project 2, was asked to give a presentation on, "Identification of Genetic Modulators of TCDD-induced B-cell Dysfunction using a Population-Based Approach."

The following students also presented posters at the meeting:
  • Lance Blevins, postdoctoral student, Project 1, presented, “Interferon Gamma-induced Stat3 SerinePhosphorylation Reverses TCDD-mediated Suppression of IgM Secretion in Primary Naïve Human B Cells.” 
  • Jeffrey Cox, postdoctoral student, Community Engagement Core, presented, “Remediation of Dioxins and Property Values.” 
  • Suha Eleya, graduate student, Project 5, presented, “Multiple Electron Transfer Components Participate in the First Step of Dioxin Metabolism.” 
  • Ryan Faisal, graduate student, Project 5, presented, “Characterization of a silent pathway for biphenyl degradation in Sphingomonas wittichii RW1.” 
  • Igor Ivanovski, graduate student, Project 5, presented, “Salicylate metabolism by the dioxin and dibenzofuran degrading organism Sphingomonas wittichii RW1.” 
  • Thamer Mutter, graduate student, Project 5, presented, “Growth of Sphingomonas wittichii RW1 on dibenzo-p-dioxin requires a chomosomally endcoded hydrolase.” 
  • Aakansha Roberts, graduate student, Project 5, presented, “Characterization of an Integrative and Conjugative Element Isolated from a Contaminated Passaic River Sediment.” 
  • Jiajun Zhou, graduate student, Project 1, presented, “2,3,7,8-tetracholradibenzo-p-dioxin (TCDD)-mediated activation of Aryl Hydrocarbon Receptor (AHR) in the Impairment of Immunoglobulin Secretion Involving the Increase of Lymphocyte Specific Tyrosine Kinase (LCK) by Human Primary B Cells.”

Short Course: Introduction to Physiologically Based Toxicokinetic (PBTK) / Pharmacokinetic (PBPK) Modeling 


The Training Core of the MSU SRP will offer an intensive three day short course, "Introduction to Physiologically Based Toxicokinetic (PBTK) / Pharmacokinetic (PBPK) Modeling," May 15-17, 2018. This short course will cover the principles of physiologically based pharmacokinetic (PBPK) modeling and introduce the application of this technique in chemical health risk assessment. Upon completion of this course, students will be able to: 
  • Understand the fundamental concepts underlying PBPK modeling
  • Describe the absorption, distribution, metabolism, and elimination of chemicals using mass balance dierential equations
  • Build PBPK models to simulate tissue dosimetry using Berkeley Madonna®
  • Appreciate the application of PBPK models in human health risk/safety assessment
Who should attend?
  • Students interested in computational approaches to predicting tissue concentrations of environmental, dietary, and pharmaceutical chemicals.
  • Risk and safety assessment professionals interested in tissue dosimetry and interpretation of biomarkers of exposures to toxicants.
  • Alternative toxicity testing professionals interested in in vitro concentration to in vivo dose extrapolation.
Course instructors are Sudin Bhattacharya, MSU, Wan-Yun Cheng, Boragen, Inc., Rory B. Conolly, US Environmental Protection Agency, and Qiang Zhang, Emory University. 

For course-specific questions, please contact Qiang Zhang, qiang.zhang@emory.edu, Sudin Bhattacharya, sbhattac@egr.msu.edu, or Rory B. Conolly, conolly.rory@epa.gov.

If you are interested in attending the course, please contact Kasey Baldwin, kbaldwin@msu.edu

Photo below: 2016 Short Course Class

Article Spotlight

 

The laboratory of Dr. Norbert Kaminski, Project 1, recently published a research article titled, "Application of gene specific mRNA level determinations in individual cells using flow cytometry-based PrimeFlow™ in Immunotoxicology," in Toxicology and Applied Pharmacology. 

Abstract: 
Determining changes in gene expression by measuring mRNA levels is an important capability in biological research. Real-Time Quantitative PCR (RT-qPCR) is the most ubiquitous technique for measuring changes in mRNA transcript levels, but heterogeneity of cell populations and low cell number are serious technical limitations. Recent advances in flow cytometric analytical techniques have enabled the quantification of mRNA levels in individual cells. Here, we present examples demonstrating the strength and challenges of concurrently measuring mRNA using PrimeFlow™ with other endpoints in immunotoxicological studies. Specifically, we demonstrate how measuring gene specific mRNA levels on a per cell basis was used to study: 1) markers of activation and differentiation; 2) cell signaling by measuring intracellular proteins in mature and developing cell types; and 3) a cell type that constitutes a minor population in peripheral blood. We also discuss cell type-specific modifications to the parent technique, which facilitated optimal performance in these cells. While the examples provided are focused on immunotoxicological questions and endpoints, this new strategy can be applied to a wide variety of toxicological research problems.
 
Fig.1: Overview of the standard PrimeFlow™ assay protocol. Cells are first fixed with fixation buffer I, stained for surface markers, then permeabilized and treated with RNase inhibitors. Cells are then stained for intracellular markers and further fixed with fixation buffer II. To amplify the target mRNA, target probes are hybridized to the mRNA of interest. A preamplifier (PreAmp) oligonucleotide is then bound to the target probe/mRNA dimer followed by the binding of amplification (Amp) probes. Finally, fluorescent dye labeled probes are bound to the Amp probes and detected through flow cytometry.

Spring Virtual Lab Meetings

The Training Core of the MSU SRP will hold several virtual laboratory meetings this spring. The MSU SRP Virtual Lab meetings feature a presentation by one or two individuals (PI, graduate student, post doc) from a different project or core at each meeting. The Training Core's overall goal with these meetings is to help the graduate students and post docs working on the MSU SRP enhance their communication skills and acquaint themselves with each other's work. Another goal is to promote 'cross training' of our trainees across the many disciplines involved in our SRP program.

This spring virtual lab meetings will be held from noon to 1 p.m. eastern time at MSU in room 162 Food Safety and Toxicology Building. Purdue, Rutgers and Texas A&M are invited to join by Zoom. Virtual lab meeting dates this spring: March 22 (Kelly Fader, Project 3), and April 26 (Gerben Zylstra's Lab, Project 5). Please contact Jay Goodman, goodman3@msu.edu for more information.

Recent Publications


Boyd SA, Sallach JB, Zhang Y, Crawford R, Li H, Johnston CT, Teppen BJ, and Kaminski, NE. (2017) Sequestration of TCDD by activated carbon eliminates bioavailability and the suppression of immune function in mice. Environ Toxicol Chemistry. (In press)

Boyd SA, Sallach JB, Zhang Y, Crawford R, Li H, Johnston CT, Teppen BJ, Kaminski NE. Sequestration of 2,3,7,8-tetrachlorodibenzo-p-dioxin by activated carbon eliminates bioavailability and the suppression of immune function in mice. Environ Toxicol Chem. 2017 Oct;36(10):2671-2678. PubMed PMID: 28370362.

Stedtfeld RD, Brett Sallach J, Crawford RB, Stedtfeld TM, Williams MR, Waseem H, Johnston CT, Li H, Teppen BJ, Kaminski NE, Boyd SA, Tiedje JM, Hashsham SA. TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal. Appl Microbiol Biotechnol. 2017 Oct;101(19):7409-7415. PubMed PMID: 28812142.

Stedtfeld RD, Chai B, Crawford RB, Stedtfeld TM, Williams MR, Xiangwen S, Kuwahara T, Cole JR, Kaminski NE, Tiedje JM, Hashsham SA. Modulatory Influence of Segmented Filamentous Bacteria on Transcriptomic Response of Gnotobiotic Mice Exposed to TCDD. Front Microbiol. 2017 Sep 7;8:1708. PubMed PMID: 28936204.

Fader KA, Zacharewski TR. Beyond the Aryl Hydrocarbon Receptor: Pathway Interactions in the Hepatotoxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Related Compounds. Curr Opin Toxicol. 2017 Feb;2:36-41. PubMed PMID: 28948239.

Li J, Bhattacharya S, Zhou J, Phadnis-Moghe AS, Crawford RB, Kaminski NE. Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis. J Immunol. 2017 Nov 15;199(10):3504-3515. PubMed PMID: 28978690.

Henriquez J, Zhou J, Li J, Crawford R, Kaminski N. Application of gene specific mRNA level determinations in individual cells using flow cytometry-based PrimeFlow™ in immunotoxicology. Toxicol Appl Pharmacol. 2017 Dec 15;337:39-44. PubMed PMID: 29107001.

Dornbos P, LaPres JJ. Incorporating population-level genetic variability within laboratory models in toxicology: From the individual to the population. Toxicology. 2018 Feb 15;395:1-8. PubMed PMID: 29275117.
 
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