Received for publication November 21, 2005.
Revised March 3, 2006.
Accepted for publication March 23, 2006.

The Aryl Hydrocarbon Receptor Agonist 2,3,7,8- Tetrachlorodibenzo-p-dioxin Alters the Circadian Rhythms, Quiescence, and Expression of Clock Genes in Murine Hematopoietic Stem and Progenitor Cells

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AhR) agonist, has been identified as a potent immuno-hematopoietic toxicant with the ability to alter the number of Lin^- Sca-1⁺ cKit⁺ (LSK) bone marrow cells, a population enriched for murine hematopoietic stem cells. The biology of these cells is governed by circadian rhythms and TCDD has been shown to disrupt circadian rhythms of other biological endpoints. We investigated the effect of TCDD on the circadian rhythms of hematopoietic precursors. Female C57Bl/6 mice were treated with a single oral dose of 10µg/kg TCDD. Five days later, bone marrow was harvested every four hours for twenty-four hours and stained for specific hematopoietic populations using fluorescently-labeled antibodies. In addition, cells were placed into semi-solid culture to measure different functionally-defined populations. Activation of the AhR by TCDD elicited disruptions in the rhythms of LSK cell numbers and phenotypically-defined myeloid and erythroid precursors. Simultaneous DNA and RNA staining revealed an abnormal in vivo rhythm of %G0 LSK cells, suggesting disruption of stem cell quiescence. Finally, quantitative RT-PCR revealed that expression of AhR and Arnt mRNA within enriched hematopoietic precursors oscillates with a circadian period. Modest changes in the twenty-four hour expression of mPer1 and mPer2 mRNA and increased AhR repressor mRNA following TCDD exposure suggest a direct effect on the molecular machinery responsible for these rhythms. Together, these data demonstrate that activation of the AhR by TCDD disrupts the circadian rhythms associated with murine hematopoietic precursors.

Key words: Regulation - physiological, Ah receptor, Toxicant-induced gene express, Stem cells

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