In the previous project period we have found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds cause a reduction in epidermal growth factor (EGF) binding to its receptor with a concurrent rise in activities of several protein kinases, particularly protein tyrosine kinases in the hepatic plasma membrane of several experimental species. The major objective of this project is to ask what the toxicological consequences of elevated protein tyrosine kinase activities (Project 1-3) are and why TCDD causes such an effect on EGF receptor (Project 4 and 5). In more specific terms we plan to study (1) the consequence of TCDD-caused down-regulation of EGF receptor (EGF-R) in skin cells to test the possibility that TCDD-caused activation of EGF-R is the major cause for their subsequent proliferation and differentiation response; (2) TCDD-caused EGF-R and other protein tyrosine kinase changes in thymus, particularly with regard to their implication on thymocyte maturation and thymic involution; (3) effects of activation of EGF-R insulin-R and other tyrosine kinases and protein kinase C on pancreas, especially changes in several specific protein substrates known to regulate insulin secretion; (4) the possibility that TCDD's action is mediated through c-erbA, a member of a family of genes known to mediate steroid and thyroid hormones; and (5) to test the hypothesis that c-erbA eventually activates c-erbB, a family of genes producing protein tyrosine kinases including EGF-R. The rationale of such an approach is that TCDD given in vivo causes marked increases in protein tyrosine kinase activities at an early stage of poisoning (24 to 48 hrs) and that in the past few years a tremendous advance has been made in the understanding of the vital roles of some of the protein tyrosine kinases. We will, therefore, examine several highly TCDD-sensitive tissues where certain protein tyrosine kinases have been already shown to play key roles. We plan to test our hypothesis that TCDD first stimulates the expression of one of c-erbA genes (as in the case of steroid/thyroid hormones) which in turn signals a rise in expression of the c-erbB family of genes, endcoding proteins with tyrosine kinase activities. For this purpose several gene transfection/deletion experiments on otherwise TCDD nonresponsive cells will be carried out using c-erbA and c-erbB (EGF-R) to analyze each step of TCDD-triggered cascade of events leading to elevation of the level of target receptors such as EGF-R and other protein tyrosine kinases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES003575-06A1
Application #
3250986
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1987-12-01
Project End
1995-07-31
Budget Start
1990-08-09
Budget End
1991-07-31
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
Schools of Earth Sciences/Natur
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Hwang, Seong Gu; Sasagawa, Hiromi; Matsumura, Fumio (2007) Effect of in vitro administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on DNA-binding activities of nuclear transcription factors in NIH-3T3 mouse fibroblasts. J Environ Sci Health B 42:115-23
Liu, Phillip C C; Moreno-Aliaga, Maria J; Dunlap, Debra Y et al. (2002) Correlation between the high expression of C/EBPbeta protein in F442A cells and their relative resistance to antiadipogenic action of TCDD in comparison to 3T3-L1 cells. J Biochem Mol Toxicol 16:70-83
Moreno-Aliaga, Maria J; Matsumura, Fumio (2002) Effects of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane (p,p'-DDT) on 3T3-L1 and 3T3-F442A adipocyte differentiation. Biochem Pharmacol 63:997-1007
Nagashima, Hitoshi; Matsumura, Fumio (2002) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced down-regulation of glucose transporting activities in mouse 3T3-L1 preadipocyte. J Environ Sci Health B 37:1-14
Dunlap, D Y; Matsumura, F (2000) Analysis of difference in vivo effects of TCDD between c-src +/+ mice, c-src deficient, -/+ and -/- B6, 129-Src(tm 1 sor) mice and their wild-type littermates. Chemosphere 40:1241-6
Datta, S; Ohyama, K; Dunlap, D Y et al. (1999) Evidence for organochlorine contamination in tissues of salmonids in Lake Tahoe. Ecotoxicol Environ Saf 42:94-101
Moreno-Aliaga, M J; Matsumura, F (1999) Endrin inhibits adipocyte differentiation by selectively altering expression pattern of CCAAT/enhancer binding protein-alpha in 3T3-L1 cells. Mol Pharmacol 56:91-101
Ashida, H; Matsumura, F (1998) Effect of in vivo administered 2,3,7,8-tetrachlorodibenzo-p-dioxin on DNA-binding activities of nuclear transcription factors in liver of guinea pigs. J Biochem Mol Toxicol 12:191-204
Enan, E; Dunlap, D Y; Matsumura, F (1998) Use of c-Src and c-Fos knockout mice for the studies on the role of c-Src kinase signaling in the expression of toxicity of TCDD. J Biochem Mol Toxicol 12:263-74
Enan, E; Matsumura, F (1998) Activation of c-Neu tyrosine kinase by o,p'-DDT and beta-HCH in cell-free and intact cell preparations from MCF-7 human breast cancer cells. J Biochem Mol Toxicol 12:83-92

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