Toxicological Sciences 69, 117-124 (2002)
Copyright © 2002 by the Society of Toxicology
IMMUNOTOXICOLOGY |
2,3,7,8-Tetrachlorodibenzo-p-dioxin Causes Alterations in Lymphocyte Development and Thymic Atrophy in Hemopoietic Chimeras Generated from Mice Deficient in ARNT2
* Department of Microbiology and Immunology, State University of New York, Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210;
Environmental Health Science Center, Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642; and
Department of Biochemistry and Cell Biology and the Institute for Cell and Developmental Biology, State University of New York at Stony Brook, Stony Brook, New York 11794
It is well established that dioxins cause a variety of toxic effects and syndromes including alterations of lymphocyte development. Exposure to the prototypical dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to severe thymic atrophy in all species studied. It has been shown that most of this toxicity is due to TCDD binding to and activating the aryl hydrocarbon receptor (AHR). Upon activation, the AHR enters the nucleus, dimerizes with the AHR nuclear translocator (ARNT), and this heterodimer modulates a number of genes that mediate toxicity. The AHR and ARNT are members of the basic-helix-loop-helix-Per, ARNT, and Sim homology (bHLH-PAS) family of transcription factors. In this study, we wanted to determine if another bHLH-PAS transcription factor, ARNT2, which has high amino acid sequence identity to ARNT and has been shown to dimerize with the TCDD-activated AHR, is involved in mediating TCDD's effect on lymphocyte development. We determined by RT-PCR that ARNT2 is expressed at a low level in whole thymus, thymocytes, and bone marrow lymphocytes. We created hemopoietic chimeras by lethally irradiating C57BL/6 mice and reconstituting them with fetal liver stem cells that either have or are deficient in a portion of chromosome 7 that contains ARNT2. Regardless of whether chimeras possessed or lacked this chromosome fragment, equal sensitivity to TCDD-induced thymic atrophy was observed despite expression of ARNT2 in the thymus. Furthermore, the absence of ARNT2 (or any other genes found on this portion of chromosome 7) did not confer any protection against TCDD-induced alterations in bone marrow B-cell subsets. These data indicate that in this model system the effects of TCDD-induced thymic atrophy and alterations in B-cell maturation are not dependent on an AHR-ARNT2 heterodimer.
Key Words: TCDD; dioxin; ARNT2; thymus; bone marrow; lymphocyte development; bHLH-PAS; AHR.
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