Superfund Research Program

The Aryl Hydrocarbon Receptor/Transcription Factor as a Regulator of Hydrocarbon Bioactivity

Project Leader: David H. Sherr
Grant Number: P42ES007381
Funding Period: 1995 - 2005

Project-Specific Links

Final Progress Reports

Year:   2004  1999 

The first goal of this project was to generate AhR transgenic mice in which high level AhR expression is directed to the B cell compartment. This goal was accomplished using a full length AhR cDNA plasmid linked to the immunoglobulin enhancer/promoter region. Prior to analysis of the response of these transgenic mice to AhR ligands, it was necessary to establish and characterize the baseline biologic responses of wildtype mice to AhR ligands. Using an in vitro model of B cell development, project investigators demonstrated that: 1) AhR ligands induce preB cell apoptosis, 2) apoptosis is dependent on bone marrow stromal cells or hepatic parenchymal cells which support preB cell growth, 3) AhR activity in the stromal/parenchymal cells is required for induction of a stromal cell-derived, preB cell-directed death signal, 4) AhR activation in stromal cells results in activation of the promiscuous transcription factor NF kappaB, 5) NF-kappaB induction in stromal cells is required for induction of the stromal cell-derived death signal, and 6) NF- kappaB down-regulation in preB cells is required for apoptosis. Similarly, in vivo injection of AhR ligands induced apoptosis in bone marrow hematopoietic cells, including CD45⁺ B cells. These results made it possible to develop important technologies and to detail the mechanism of AhR ligand-induced B cell toxicity. Additional studies in AhR transgenic mice demonstrated that the AhR transgene is highly expressed in both the T and B cell compartments. Results indicated that T cell development in AhR transgenic mice is significantly compromised. Thus, project investigators have developed a unique and important tool, i.e. AhR^TG mice, with which to study T cell development and function in the presence and absence of environmental AhR ligands. Finally, the possibility that the human AhR gene is polymorphic was evaluated. Of 150 human samples assayed, no polymorphism was observed in those AhR sequences which encode the ligand- or DNA-binding domains. Therefore, it is unlikely that inheritance of a particular AhR allele confers added susceptibility to AhR ligands present in Superfund hazardous waste sites.