Characterization of alterations to hematopoietic stem cells by 2,3,7,8 tetrachlorodibenzo-p-dioxin

Mechanisms by which the potent immunosuppressant, tetrachlorodibenzo- p-dioxin (TCDD) alters lymphocyte developmental processes remain to be clarified. While bone marrow, from which immature thymic progenitors emigrate, has been identified as a target in the course of TCDD-induced thymic atrophy, the exact hematopoietic cellular targets remain obscure. The purpose of these studies was to further elucidate marrow cellular targets and mechanisms of TCDD toxicity by conducting hematopoietic cell phenotypic evaluations following both in vivo and in vitro conditions of TCDD exposure.; Experiments performed in young adult C57BL/6J mice determined effects of varied time-course and dose parameters in the context of single dose TCDD exposure. Besides thymic atrophy induction, the marrow compartment revealed numerically enhanced lineage-negative (lin−) Sca-1 + c-Kit+ hematopoietic stem cells (HSC) relative to control over 24 hours through 31 days post treatment, as well as dose-dependent increases in this population when examined at 2 days. In contrast, these alterations were absent in transgenic knockout mice bearing no functional allele for the aromatic hydrocarbon receptor (AhR). Experiments performed in chimeric mice with TCDD-responsive (AhR+/+) stromal cells and TCDD-unresponsive (AhR−/−) hematopoietic cells, and the reverse, suggested that cellular targets for TCDD reside within the hematopoietic compartment vs. the stromal cell compartment.; Given that estrogen treatment produced molecular and cellular immunosuppressive effects similar to those induced by TCDD upon both marrow and intrathymic lymphocyte development, radiation chimera studies were performed utilizing estrogen receptor alpha (ERα) chimeric mice administered a pharmacological dose of estrogen. Estrogen treatments produced pronounced hematopoietic HSC reductions issuing from an ERα presence within hematopoietic cells, yet additionally dependent upon an ERα constitution within stromal cells. Elevated BrdU incorporation in short-term reconstituting hematopoietic cells was demonstrated over a time course of TCDD administration. Cultures of AhR +/+ and AhR−/− hematopoietic cells differed with respect to their in vitro hematopoietic compartment cell phenotypes and growth characteristics.