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

Mar 25, 2006Molecular pharmacology

A chemical that activates the aryl hydrocarbon receptor changes daily rhythms, rest periods, and clock gene activity in mouse blood stem cells

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Abstract

A single oral dose of 10 µg/kg TCDD disrupts circadian rhythms in murine hematopoietic precursors.

TCDD alters the number of Lin(-) Sca-1(+) cKit(+) bone marrow cells, which are important for blood cell formation.
Treatment with TCDD leads to disrupted rhythms in the populations of myeloid and erythroid precursors.
There is an abnormal rhythm observed in the percentage of LSK cells in the resting phase of the cell cycle.
TCDD exposure results in modest fluctuations in the daily expression of key clock genes, mPer1 and mPer2.
Increased levels of AhR repressor mRNA suggest that TCDD may directly affect the molecular mechanisms regulating circadian rhythms.

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AhR) agonist, has been identified as a potent immunohematopoietic 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 10 mug/kg TCDD. Five days later, bone marrow was harvested every 4 h for 24 h and stained for specific hematopoietic populations using fluorescently labeled antibodies. In addition, cells were placed into semisolid 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 percentage of total number of LSK cells in G(0) phase of the cell cycle, suggesting disruption of stem cell quiescence. Finally, quantitative reverse transcription-polymerase chain reaction revealed that expression of AhR and Arnt mRNA within enriched hematopoietic precursors oscillates with a circadian period. Modest changes in the 24-h expression of mPer1 and mPer2 mRNA and increased AhR repressor mRNA after 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.

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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

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