Through their ability to alter gene expression and affect cell proliferation and differentiation, 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and related xenobiotics are potent immunogenic, reproductive, and developmental toxicants. They produce these effects by binding to a gene regulatory protein, the Ah receptor, (AhR), to inappropriately modulate gene expression. It is not yet known which tissues are most sensitive to these compounds and how this sensitivity varies during critical developmental periods. In addition, the normal function and endogenous ligand for the AhR have not been identified. Through a determination of the tissue- and cell-specific transcriptional activity of AhR in vivo it will be possible to determine 1) in which developing tissues and cells the AhR has some normal function, 2) in which tissues and cells the exposure to TCDD may disrupt this process. Thus, it will be possible to to determine the target tissues for TCDD toxicity, the critical periods of development that are most sensitive, and the gene alterations that are related to specific toxic events. The purpose of this project is to determine the tissue and cellular sites and time of AhR-stimulated transcriptional activity in developing animals. An additional purpose is to identify the critical biochemical pathways altered following TCDD exposure. A transgenic AhR-reporter mouse model has been established in which the tissue- and cell-specific AhR activation can be determined. Additional studies will establish an additional transgenic mouse line to determine if the induced expression of the transgene (TG) is dependent on the site of integration into the mouse genome. The cell-specific expression of the TG in developing brain, paws, ear, tooth bud and genital tubercle will be determined at various times of development and after treatment with various doses of TCDD. We will characterize the morphology of the toxic endpoints that are associated with AhR activation in these tissues. Using a combination of techniques, we will determine the genes altered in these tissues that may be responsible for initiating the cascade of events leading to toxicity. Finally, we will determine and characterize the expression of the TG in the absence o TCDD exposure. The latter results may indicate a normal function of the AhR during development, and will identify the tissues/cells and developmental periods in which this occurs. These data will provide for the first time information on the cell and gene targets associated with in vivo responses to TCDD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009430-05
Application #
6624068
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Heindel, Jerrold
Project Start
1999-02-01
Project End
2006-02-28
Budget Start
2003-03-14
Budget End
2004-02-29
Support Year
5
Fiscal Year
2003
Total Cost
$350,350
Indirect Cost
Name
University of Rochester
Department
Public Health & Prev Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Bemis, Jeffrey C; Nazarenko, Daniel A; Gasiewicz, Thomas A (2005) Coplanar polychlorinated biphenyls activate the aryl hydrocarbon receptor in developing tissues of two TCDD-responsive lacZ mouse lines. Toxicol Sci 87:529-36
Filbrandt, Carissa R; Wu, Zhenhua; Zlokovic, Berislav et al. (2004) Presence and functional activity of the aryl hydrocarbon receptor in isolated murine cerebral vascular endothelial cells and astrocytes. Neurotoxicology 25:605-16

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