Wasting syndrome is one of the most consistently observed effects of TCDD in many animal species. In the past period we have found that TCDD causes suppression of not only lipoprotein lipase (LPL) but glucose transporters (GLUT), fatty acid binding proteins and many other gene expressions involved in lipogenesis and adipogenesis. The combined effect of these effects are serum hyperlipidemia, hypoinsulinemia and cellular starvation. In this project period we will address the question on the basic mechanism of TCDD's antiIipogenic action and toxicological significance of such actions. The main question we raise first is how TCDD induces simultaneously these many changes in a coordinated manner to turn adipocytes to a lipolytic mode. Our hypothesis is that one of the major Causes for the above changes is the activation of mitotic nuclear transcription factors such as AP-1 through TCDD-induced increases in growth factor signaling, and that such a stimulation of mitotic program works antagonistically to lipogenic and adipogenic cellular program through """"""""cross-talking"""""""" among nuclear transcription factors. To this end we propose to study, using mainly guinea pig adipose tissue and mouse 3T3- L1 preadipocytes as in vivo and in vitro models, respectively: (1) TCDD's effects on the DNA binding activities of growth factor-activated and lipogenesis-related transcription factors in guinea pig adipose tissue using gel mobility assay, (2) repeat the same in 3T3-L1 preadipocytes in vitro and assess TCDD's effects on adipocyte differentiation processes, (3) the role of CCAAT enhancer binding protein (C/EBPalpha), a nuclear factor known to regulate many adipogenic gene expressions in toxic action of TCDD both in vivo and in vitro, (4) the changes in 125I-TNF-alpha binding and its nuclear signal transducer, NFkappaB at various stages of 3T3-L1 differentiation to determine the role of TNFalpha in TCDD's action, and (5) TCDD's effects on nuclear modulators of the GLUT4 gene expression in 3T3-L1 cells. Our strategy is to closely follow the experimental design and approaches of successful studies demonstrating """"""""cross-talking"""""""" among key factors. Furthermore, we plan to study: (6) toxicological significance of TCDD-induced reduction in GLUTs by studying vitamin C uptake, which has been recently shown to be transported by GLUTs [15S], and relate the finding to lipid peroxidation in the guinea pig adipose tissue. Finally (7) we will integrate the data, carry out critical tests to determine the roles, the scope and the limit of this route of action mechanism of TCDD that is mediated by growth factor signaling and """"""""cross-talking"""""""" among nuclear transcription factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES005233-07
Application #
2414955
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1990-08-09
Project End
2000-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California Davis
Department
Public Health & Prev Medicine
Type
Schools of Earth Sciences/Natur
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Li, Wen; Vogel, Christoph F A; Wu, Dalei et al. (2010) Non-genomic action of TCDD to induce inflammatory responses in HepG2 human hepatoma cells and in liver of C57BL/6J mice. Biol Chem 391:1205-19
Sciullo, Eric M; Vogel, Christoph F; Wu, Dalei et al. (2010) Effects of selected food phytochemicals in reducing the toxic actions of TCDD and p,p'-DDT in U937 macrophages. Arch Toxicol 84:957-66
Dong, Bin; Nishimura, Noriko; Vogel, Christoph F et al. (2010) TCDD-induced cyclooxygenase-2 expression is mediated by the nongenomic pathway in mouse MMDD1 macula densa cells and kidneys. Biochem Pharmacol 79:487-97
Dong, Bin; Matsumura, Fumio (2009) The conversion of rapid TCCD nongenomic signals to persistent inflammatory effects via select protein kinases in MCF10A cells. Mol Endocrinol 23:549-58
Wong, Patrick S; Li, Wen; Vogel, Christoph F et al. (2009) Characterization of MCF mammary epithelial cells overexpressing the Arylhydrocarbon receptor (AhR). BMC Cancer 9:234
Vogel, Christoph F A; Matsumura, Fumio (2009) A new cross-talk between the aryl hydrocarbon receptor and RelB, a member of the NF-kappaB family. Biochem Pharmacol 77:734-45
Sciullo, Eric M; Dong, Bin; Vogel, Chris F A et al. (2009) Characterization of the pattern of the nongenomic signaling pathway through which TCDD-induces early inflammatory responses in U937 human macrophages. Chemosphere 74:1531-7
Matsumura, Fumio (2009) The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects. Biochem Pharmacol 77:608-26
Vogel, Christoph F A; Goth, Samuel R; Dong, Bin et al. (2008) Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem Biophys Res Commun 375:331-5
Li, Wen; Matsumura, Fumio (2008) Significance of the nongenomic, inflammatory pathway in mediating the toxic action of TCDD to induce rapid and long-term cellular responses in 3T3-L1 adipocytes. Biochemistry 47:13997-4008

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