The overall goal of this research proposal is to test the following hypothesis: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acts directly on B-cells to suppress immunoglobulin (Ig) secretion. This suppression is mediated by the aryl hydrocarbon receptor (AhR) which induces an incomplete Ig heavy chain class switch by directly binding DRE sites within the Ig 3' pie heavy chain enhancer (3' pie enhancer). To test this hypothesis, a molecular and cellular approach using a murine two cell line model system will be utilized in addressing the following specific aims.
In specific aim # 1, transfection of the AhR into an AhR-deficient B-cell line will determine if the AhR is essential for TCDD-induced inhibition of B-cell function. To determine if this inhibition is transcriptionally mediated, the effect of AhR expression on TCDD-induced protein binding to the dioxin responsive enhancer (DRE) and akB motif, both located within the 3'alpha enhancer, will be examined in specific aim #2.
Specific aim #3 will evaluate the effect of TCDD on Ig heavy chain class switch, along with the AhR-dependency for this effect. The results of this research will advance the current understandig of the mechanism by which TCDD, a potent and persistent environmental contaminant, alters B-cell function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32ES005914-02
Application #
6382117
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Shreffler, Carol K
Project Start
2001-05-01
Project End
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
2
Fiscal Year
2001
Total Cost
$34,832
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824