The trichothecenes, a group of sesquiterpenoid mycotoxins commonly encountered as food contaminants worldwide, have been etiologically linked to human and animal illnesses with the immune system being a major target. In experimental animals, these mycotoxins and other natural toxins that bind with high affinity to eukaryotic ribosomes (eg. ricin, Shiga toxin, anisomycin) induce proinflammatory gene expression and apoptosis in lymphoid tissues. Because of their potential for use in chemical terrorism, trichothecenes and other ribotoxins are now included on the CDC Select Agents list. Although ribosome-directed agents are known to exert toxicity by activating mitogen-activated protein kinases, the underlying mechanisms for this "ribotoxic stress response" (RSR) remain largely undefined. Thus, a critical gap exists in our knowledge of the signal transduction mechanisms by which ribotoxins modulate gene expression and apoptosis. The objective of this proposal is to test the guiding hypothesis that the ribosome plays a central role in the initiation and integration of protein kinase-mediated stress responses to trichothecenes and other ribotoxic agents. This hypothesis is based on observations in the macrophage that: 1)deoxynivalenol (DON), a common foodborne trichothecene, mediates cleavage of 18S and 28S ribosomal (r)RNA, 2) double-stranded RNA-activated protein kinase (PKR), a ribosome-associated serine-threonine kinase, is essential for DON-induced protein kinase activation and 3) DON induces mobilization of several protein kinases to the ribosome whereupon they are phosphorylated. To test our hypothesis, three Specific Aims are proposed.
In Aim 1, we will characterize DON-induced rRNA cleavage relative to targets, kinetics and mechanisms in the macrophage.
In Aim 2, we will use both macrophage and cell-free models to characterize the role of PKR as an early sensor of DON-induced rRNA damage.
In Aim 3, we will track DON-induced changes in ribosome-associated proteins in the macrophage relative to composition, kinetics and kinase activites. From these studies, we expect to understand how the ribosome mediates the induction and integration of multiple intracellular signaling cascades that drive altered gene expression and apoptosis in mononuclear phagocytes in response to ribotoxic agents. Anticipated outcomes include: 1) improved understanding of the molecular basis by which trichothecenes and other ribotoxins disrupt immunity, 2) enhanced capacity to assess and manage risks associated with exposure to trichothecenes and other ribotoxins, and 3) mechanism-based strategies for preventing and/or treating persons exposed to trichothecenes and ribotoxic chemicals via natural contamination or chemical terrorism. Collectively, these outcomes will positively impact public health by providing a scientific basis for generating sound recommendations relative to this important class of toxins and appropriate remedial actions should exposure occur.

Public Health Relevance

We propose to learn how a class of potent biological toxins interferes with the function and survival of cells that are essential to the immune system. This research will enhance our capacity to assess and manage risks associated with exposure to these toxins as well as yield mechanism-based strategies for preventing and/or treating persons exposed to these agents via inadvertent food contamination or deliberate chemical terrorism. Collectively, these outcomes will positively impact public health by providing a scientific basis for generating sound recommendations relative to these important toxins and appropriate remedial actions should exposures occur.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003358-26
Application #
8272657
Study Section
Special Emphasis Panel (ZRG1-DIG-C (90))
Program Officer
Humble, Michael C
Project Start
1984-03-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
26
Fiscal Year
2012
Total Cost
$301,674
Indirect Cost
$103,204
Name
Michigan State University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Wu, Wenda; He, Kaiyu; Zhou, Hui-Ren et al. (2014) Effects of oral exposure to naturally-occurring and synthetic deoxynivalenol congeners on proinflammatory cytokine and chemokine mRNA expression in the mouse. Toxicol Appl Pharmacol 278:107-15
Flannery, Brenna M; Amuzie, Chidozie J; Pestka, James J (2013) Evaluation of insulin-like growth factor acid-labile subunit as a potential biomarker of effect for deoxynivalenol-induced proinflammatory cytokine expression. Toxicology 304:192-8
Pan, Xiao; Whitten, Douglas A; Wu, Ming et al. (2013) Global protein phosphorylation dynamics during deoxynivalenol-induced ribotoxic stress response in the macrophage. Toxicol Appl Pharmacol 268:201-11
Wu, Wenda; Flannery, Brenna M; Sugita-Konishi, Yoshiko et al. (2012) Comparison of murine anorectic responses to the 8-ketotrichothecenes 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, fusarenon X and nivalenol. Food Chem Toxicol 50:2056-61
Amuzie, C J; Flannery, B M; Ulrich, A M et al. (2011) Effects of deoxynivalenol consumption on body weight and adiposity in the diet-induced obese mouse. J Toxicol Environ Health A 74:658-67
Flannery, Brenna M; Wu, Wenda; Pestka, James J (2011) Characterization of deoxynivalenol-induced anorexia using mouse bioassay. Food Chem Toxicol 49:1863-9
Shi, Yuhui; Pestka, James J (2009) Mechanisms for suppression of interleukin-6 expression in peritoneal macrophages from docosahexaenoic acid-fed mice. J Nutr Biochem 20:358-68
Pestka, J J (2008) Mechanisms of deoxynivalenol-induced gene expression and apoptosis. Food Addit Contam :1-13
Loniewski, Katie; Shi, Yuhui; Pestka, James et al. (2008) Toll-like receptors differentially regulate GPCR kinases and arrestins in primary macrophages. Mol Immunol 45:2312-22
Pestka, J J (2008) Mechanisms of deoxynivalenol-induced gene expression and apoptosis. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 25:1128-40

Showing the most recent 10 out of 12 publications