This proposal is directed at understanding the toxicology of halogenated dibenzo-p-dioxins (""""""""dioxins""""""""), as well as the biology of a basic-helix-loop-helix-PAS (bHLH-PAS) protein known as the Ah receptor (AHR). The goal is to better understand the biology of a number of modifiers of AHR signal transduction. The specific questions that will be answered are whether any of these modifiers play a role in dioxin toxicity or if their activity is limited to the induction of xenobiotic metabolizing enzymes (XMEs). The factors to be examined include the small immunophilin-like molecule we refer to as ARA9, a novel homologue of the Drosophila kelch protein, referred to as ARA3, and members of the nonreceptor tyrosine kinase superfamily, cYes and cSrc. The other modifiers to be included in these screens are members of the bHLH-PAS superfamily. These include the dominant negative """"""""Ah receptor related"""""""" protein (AHRR), the steroid receptor coactivator (SRC-1), and the AHR partners, ARNT and ARNT2. The final putative modifier we will examine is a cis-acting intragenic element we have recently identified within the AHR's structural gene. We propose that this element regulates AHR expression and thus may be a modulator of cellular sensitivity to receptor agonists. By monitoring toxic endpoints, in parallel with XME induction and liver development, we will be able to identify factors that are shared by these three processes and those which are specific to only a subset of pathways. Identification of pathway-specific factors will provide insight into the molecular mechanisms that underlie each of these biological processes. Information from these studies will have a significant impact on how we estimate risk from chemicals like dioxin, either by providing support for the use of XME induction as a surrogate for toxicity or an argument against such a paradigm.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES006883-10
Application #
6858596
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (02))
Program Officer
Heindel, Jerrold
Project Start
1994-09-01
Project End
2006-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
10
Fiscal Year
2005
Total Cost
$363,750
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Nukaya, Manabu; Walisser, Jacqueline A; Moran, Susan M et al. (2010) Aryl hydrocarbon receptor nuclear translocator in hepatocytes is required for aryl hydrocarbon receptor-mediated adaptive and toxic responses in liver. Toxicol Sci 118:554-63
Nukaya, Manabu; Lin, Bernice C; Glover, Edward et al. (2010) The aryl hydrocarbon receptor-interacting protein (AIP) is required for dioxin-induced hepatotoxicity but not for the induction of the Cyp1a1 and Cyp1a2 genes. J Biol Chem 285:35599-605
Lin, Bernice C; Nguyen, Linh P; Walisser, Jacqueline A et al. (2008) A hypomorphic allele of aryl hydrocarbon receptor-associated protein-9 produces a phenocopy of the AHR-null mouse. Mol Pharmacol 74:1367-71
Lin, Bernice C; Sullivan, Ruth; Lee, Youngsook et al. (2007) Deletion of the aryl hydrocarbon receptor-associated protein 9 leads to cardiac malformation and embryonic lethality. J Biol Chem 282:35924-32
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Walisser, Jacqueline A; Glover, Edward; Pande, Kalyan et al. (2005) Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types. Proc Natl Acad Sci U S A 102:17858-63
Bunger, Maureen K; Walisser, Jacqueline A; Sullivan, Ruth et al. (2005) Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus. Genesis 41:122-32
Thomae, Tami L; Stevens, Emily A; Bradfield, Christopher A (2005) Transforming growth factor-beta3 restores fusion in palatal shelves exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Biol Chem 280:12742-6
Walisser, Jacqueline A; Bunger, Maureen K; Glover, Edward et al. (2004) Gestational exposure of Ahr and Arnt hypomorphs to dioxin rescues vascular development. Proc Natl Acad Sci U S A 101:16677-82
Lahvis, G P; Lindell, S L; Thomas, R S et al. (2000) Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. Proc Natl Acad Sci U S A 97:10442-7

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