Effects of Developmental Activation of the Aryl Hydrocarbon Receptor by 2,3,7,8-Tetrachlorodibenzo-p-dioxin on Long-term Self-renewal of Murine Hematopoietic Stem Cells.
| Autor: | Laiosa, Michael D.1 laiosa@uwm.edu, Tate, Everett R.1, Ahrenhoerster, Lori S.1, Yuhong Chen2, Wang, Demin2 |
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| Předmět: |
*Animal experimentation
*Dioxins *Hydrocarbons *Environmental exposure RNA analysis Reactive oxygen species Analysis of variance Cell culture Cell differentiation Cell physiology Cell receptors Chi-squared test Confidence intervals Gene expression Hematopoiesis Hematopoietic stem cells Immune system Immunoglobulins Mice Polymerase chain reaction Probability theory Research funding Stains & staining (Microscopy) Statistics T cells T-test (Statistics) Data analysis Reverse transcriptase polymerase chain reaction Data analysis software Descriptive statistics In vitro studies |
| Zdroj: | Environmental Health Perspectives. Jul2016, Vol. 124 Issue 7, p957-965. 9p. 2 Charts, 3 Graphs. |
| Abstrakt: | BACKGROUND: Human epidemiological and animal studies suggest that developmental exposure to contaminants that activate the aryl hydrocarbon receptor (AHR) lead to suppression of immune system function throughout life. The persistence of immune deficiency throughout life suggests that the cellular target of AHR activation is a fetal hematopoietic progenitor or stem cell. OBJECTIVES: The aim of this study was to identify the effects of transplacental exposure to an AHR agonist on longterm self-renewal of fetal hematopoietic stem cells. METHODS: Pregnant C57BL/6 or AHR[sup +/-] mice were exposed to the AHR agonist, 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD). On day 14 of gestation, hematopoietic progenitors from wild-type or AHR- deficient fetuses were placed into in vitro T-lymphocyte differentiation cultures to identify the effects of transplacental TCDD on AHR activation in the fetus. We next analyzed the fetal hematopoietic progenitor cells for changes in reactive oxygen species (ROS). Finally, hematopoietic progenitors from fetuses exposed transplacentally to TCDD were mixed 1:1 with cells from congenic controls and used to reconstitute lethally irradiated recipients for analysis of longterm self-renewal potential. RESULTS: Our findings suggested that the effects of TCDD on the developing hematopoietic system were mediated by direct AHR activation in the fetus. Furthermore, developmental AHR activation by TCDD increased ROS in the fetal hematopoietic stem cells, and the elevated ROS was associated with a reduced capacity of the TCDD-exposed fetal cells to compete with control cells in a mixed competitive irradiation/reconstitution assay. CONCLUSIONS: Our findings indicate that AHR activation by TCDD in the fetus during pregnancy leads to impairment of longterm self-renewal of hematopoietic stem cells. [ABSTRACT FROM AUTHOR] |
| Databáze: | GreenFILE |
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