2,3,7,8-Tetrachlorodibenzo-p-dioxin Does Not Directly Alter the Phenotype of Maturing B Cells in a Murine Coculture System

Wyman, Amber; Lavin, Amy L.; Wilding, Gregory E.; Gasiewicz, Thomas A.

doi:10.1006/taap.2002.9396

Cited by 11 publications

(9 citation statements)

References 39 publications

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“…The present mice showed multiple TCDD-related differences in B cells at 48 weeks-of-age including an increase in the earliest bone marrow B progenitor (B220 lo CD24 - AA4.1 + ) and a decrease in total bone marrow-derived lymphoid cells expressing B220. The increase in the earliest B progenitor cells may agree with an increase in pre-pro-B cells detected in a S17 stromal line exposed to TCDD (Wyman et al 2002). Functional or other changes in bone marrow B-lineage cells that may accompany these alterations in phenotypic distribution have not been studied but may be important.…”

Section: Discussionsupporting

confidence: 76%

A single mid-gestation exposure to TCDD yields a postnatal autoimmune signature, differing by sex, in early geriatric C57BL/6 mice

Mustafa¹,

Holladay²,

Witonsky³

et al. 2011

Toxicology

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We recently observed an autoimmune profile in 24-week-old C57BL/6 mice that received a 2.5 or 5.0 μg/kg mid-gestation dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Mustafa et al., 2008). The clinical signs were consistent with a lupus-like syndrome and included: increased autoantibody levels, renal IgG and C3 immune complex deposition with associated inflammation, and increased peripheral Vβ+ T cells. No studies currently exist following the progression of such disease into middle or advanced ages, when human autoimmune diseases may manifest. Therefore in the present study, littermates of mice from the previous 24 week prenatal TCDD study were allowed to age to 48 weeks, considered early geriatric in mice. Similarities and differences in the disease profile based on age and sex were observed. Peripheral autoreactive Vβ+ T cells were increased in both sexes at 48 weeks, in contrast to males only at 24 weeks. Activated T cells from 48-week-old prenatal TCDD females over-produced the proinflammatory cytokine IFN-γ while males over-produced IL-10, effects again not seen at 24 weeks. Splenic transitional-2 B cells (CD21intCD24hi) were increased in males while transitional-1 B cells (CD23neg CD1neg) were increased in females at 48 weeks. Autoantibodies to cardiolipin and CD138+ spleen plasma cells were significantly increased in the aged males but not females. Anti-IgG and anti-C3 immune complex renal deposition were also significantly increased in the prenatal TCDD males but not females. These selective changes in the aged male mice may be noteworthy, in that the prevalence of SLE in humans shifts dramatically toward males with aging. The collective findings in aged mice suggest that prenatal TCDD permanently biases the postnatal immune response in C57BL/6 mice toward autoimmunity, and support a significant B cell component to the induced renal autoimmune disease.

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Section: Discussionsupporting

confidence: 76%

A single mid-gestation exposure to TCDD yields a postnatal autoimmune signature, differing by sex, in early geriatric C57BL/6 mice

Mustafa¹,

Holladay²,

Witonsky³

et al. 2011

Toxicology

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“…Bone marrow cells were flushed from both femurs and tibiae with PBS ϩ 2% FBS ϩ 1% penicillin/ streptomycin as described previously (Wyman et al, 2002;Laiosa et al, 2003). The bone marrow cells were placed in to a single-cell suspension before passing through an 80-m nylon mesh (TETKO Inc., Briarcliff Manor, NY).…”

Section: Methodsmentioning

confidence: 99%

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

Garrett

Gasiewicz

2006

Mol Pharmacol

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2,3,7,, an aryl hydrocarbon receptor (AhR) agonist, has been identified as a potent immunohematopoietic toxicant with the ability to alter the number of Lin Ϫ Sca-1 ϩ cKit ϩ (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 g/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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“…That the effect was not specific for just the T-lymphoid precursor population was suggested by studies showing that numbers of cells in the immature B cell compartment also decreased following TCDD exposure [20]. However, the further differentiation of committed, but immature, B cells to more mature cells was not affected by the direct exposure of these cells to TCDD under culture conditions [21]. These studies suggested that either more immature progenitors or stem cells were directly affected by TCDD or that TCDD was targeting cell populations in the microenvironment in vivo that are, in part, responsible for directing B cell differentiation and which may not be active or present under culture conditions.…”

Section: Evidence That the Ahr Has A Role In Hsc Regulationmentioning

confidence: 99%

The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations

Singh

Casado

Opanashuk

et al. 2009

Biochemical Pharmacology

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The aryl hydrocarbon receptor (AhR) is known mainly as the mediator for the toxicity of certain xenobiotics. However, there is also much information to indicate that this transcription factor has important biological functions. Here we review the evidence that the AhR has a significant role in the regulation of hematopoietic stem cells (HSCs). Data to support this comes from studies with xenobiotic AhR ligands, phenotypic analyses of mice lacking AhR, examining the presence and regulation of the AhR within HSCs, knowledge of genes and signaling pathways regulated by the AhR, and investigations of hematopoietic disorders. Based on this information, we hypothesize that AhR expression is necessary for the proper maintenance of quiescence in HSCs, and that AhR downregulation is essential for "escape" from quiescence and subsequent proliferation of these cells. This implicates the AhR as a negative regulator of hematopoiesis with a function of curbing excessive or unnecessary proliferation. This provides an important advantage by preventing the premature exhaustion of HSCs and sensitivity to genetic alterations, thus preserving HSC function and longterm multi-lineage generation over the lifespan of the organism. This also implicates a role of the AhR in aging processes. AhR dysregulation may result in the altered ability of HSCs to sense appropriate signals in the bone marrow microenvironment leading to hematopoietic disease. It is also reasonable to hypothesize that this protein has an important function in the regulation of other tissue stem cell populations. Suggestive evidence is consistent with a role in skin and neural stem cells.

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2,3,7,8-Tetrachlorodibenzo-p-dioxin Does Not Directly Alter the Phenotype of Maturing B Cells in a Murine Coculture System

Cited by 11 publications

References 39 publications

A single mid-gestation exposure to TCDD yields a postnatal autoimmune signature, differing by sex, in early geriatric C57BL/6 mice

A single mid-gestation exposure to TCDD yields a postnatal autoimmune signature, differing by sex, in early geriatric C57BL/6 mice

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

The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations

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