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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. Environ Health Perspect 2016 07;124(7):957-65

Date

10/27/2015

Pubmed ID

26495820

Pubmed Central ID

PMC4937855

DOI

10.1289/ehp.1509820

Scopus ID

2-s2.0-84977111532   10 Citations

Abstract

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 long-term self-renewal of fetal hematopoietic stem cells.

METHODS: Pregnant C57BL/6 or AHR+/- mice were exposed to the AHR agonist, 2,3,7,8-tetra-​chlorodibenzo-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 long-term 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 long-term self-renewal of hematopoietic stem cells.

CITATION: Laiosa MD, Tate ER, Ahrenhoerster LS, Chen Y, Wang D. 2016. 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. Environ Health Perspect 124:957-965; http://dx.doi.org/10.1289/ehp.1509820.

Author List

Laiosa MD, Tate ER, Ahrenhoerster LS, Chen Y, Wang D

Author

Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Basic Helix-Loop-Helix Transcription Factors
Gene Expression Regulation, Developmental
Hazardous Substances
Hematopoietic Stem Cells
Mice
Mice, Inbred C57BL
Polychlorinated Dibenzodioxins
Receptors, Aryl Hydrocarbon
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75