""""""""There is increasing evidence that human exposure to bacterial endotoxin (lipopolysaccharide, LPS) is common and that LPS exposure may increase the susceptibility of individuals to tissue injury by a variety of chemical agents. In this proposal, the investigators seek to examine this paradigm by determining the mechanisms by which LPS and one class of immunotoxicants, the trichothecene mycotoxins, interact to cause depletion of lymphoid tissue. Trichothecenes are food and indoor air contaminants that include some of the most potent protein synthesis inhibitors known. The investigators have observed that, following co-exposure of mice to small doses of LPS and the trichothecene vomitoxin (VT), mRNA expression and serum concentrations of TNF-alpha are greatly elevated as compared to mice receiving LPS or VT alone. Subsequently, apoptosis in lymphoid tissue is observed as the earliest and most prominent histologic lesion. The investigators hypothesize that induction of lymphocyte apoptosis by LPS and trichothecene co-exposure is mediated by elevated TNF-alpha expression and TNF-alpha mediated sequelae. To test this hypothesis, the investigators propose to achieve three Specific Aims in a murine model.
In Aim 1, we will characterize and measure lymphocyte apoptosis following exposure to LPS and VT in vivo with respect to dose, timing and susceptible phenotypes.
In Aim 2, the investigators will relate elevated expression of TNF-alpha and TNF- alpha mediated sequelae (i.e. corticosterone, prostaglandin E2 [PG E2]) to lymphocyte apoptosis that occurs following exposure to LPS and VT in vivo.
In Aim 3, the investigators will determine the extent to which in vitro exposure to VT can directly induce apoptosis or augment the action of TNF-alpha, corticosterone, PGE2, and other apogenic signals in selected lymphocyte phenotypes. Structure-activity relationships among common trichothecenes encountered by humans will be examined using relevant Aim 1 and 3 endpoints. The immediate outcomes of this project will improve mechanistic understanding of how LPS and trichothecens interacts to cause lymphocyte death and the role of TNF-alpha in the process. Over the long term, this research will provide insight into adverse immunologic consequences that may occur in LPS-exposed individuals who are exposed to environmental toxicants.""""""""

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009521-03
Application #
6382262
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (01))
Program Officer
Mastin, Patrick
Project Start
1999-05-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
3
Fiscal Year
2001
Total Cost
$186,156
Indirect Cost
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
Mbandi, E; Pestka, J J (2006) Deoxynivalenol and satratoxin G potentiate proinflammatory cytokine and macrophage inhibitory protein 2 induction by Listeria and Salmonella in the macrophage. J Food Prot 69:1334-9
Pestka, James J; Smolinski, Alexa T (2005) Deoxynivalenol: toxicology and potential effects on humans. J Toxicol Environ Health B Crit Rev 8:39-69
Pestka, James J; Uzarski, Rebecca L; Islam, Zahidul (2005) Induction of apoptosis and cytokine production in the Jurkat human T cells by deoxynivalenol: role of mitogen-activated protein kinases and comparison to other 8-ketotrichothecenes. Toxicology 206:207-19
Kinser, Shawn; Li, Maioxing; Jia, Qunshan et al. (2005) Truncated deoxynivalenol-induced splenic immediate early gene response in mice consuming (n-3) polyunsaturated fatty acids. J Nutr Biochem 16:88-95
Clifford, Laura J; Jia, Qunshan; Pestka, James J (2003) An improved method for the purification of the trichothecene deoxynivalenol (vomitoxin) from Fusarium graminearum culture. J Agric Food Chem 51:521-3
Chung, Yong-Joo; Jarvis, Bruce; Pestka, James (2003) Modulation of lipopolysaccharide-induced proinflammatory cytokine production by satratoxins and other macrocyclic trichothecenes in the murine macrophage. J Toxicol Environ Health A 66:379-91
Uzarski, Rebecca L; Pestka, James J (2003) Comparative susceptibility of B cells with different lineages to cytotoxicity and apoptosis induction by translational inhibitors. J Toxicol Environ Health A 66:2105-18
Moon, Yuseok; Pestka, James J (2003) Cyclooxygenase-2 mediates interleukin-6 upregulation by vomitoxin (deoxynivalenol) in vitro and in vivo. Toxicol Appl Pharmacol 187:80-8
Chung, Yong-Joo; Yang, Gi-Hyeok; Islam, Zahidul et al. (2003) Up-regulation of macrophage inflammatory protein-2 and complement 3A receptor by the trichothecenes deoxynivalenol and satratoxin G. Toxicology 186:51-65
Uzarski, Rebecca L; Islam, Zahidul; Pestka, James J (2003) Potentiation of trichothecene-induced leukocyte cytotoxicity and apoptosis by TNF-alpha and Fas activation. Chem Biol Interact 146:105-19

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