Aryl hydrocarbon receptor activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs human B lymphopoiesis

Li, Jinpeng; Phadnis-Moghe, Ashwini S.; Crawford, R. J.; Kaminski, Norbert E.

doi:10.1016/j.tox.2016.12.010

Cited by 25 publications

(20 citation statements)

References 47 publications

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“…In a prior study (34), we also observed decreased B lymphopoiesis with TCDD treatment using culture systems containing various stromal cell components; however, the magnitude of suppression was not as profound as in the current study. Differences in sensitivity to TCDD using the different culture systems are not surprising and can likely be attributed to several factors.…”

Section: Discussioncontrasting

confidence: 67%

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Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis

Bhattacharya

Zhou

et al. 2017

The Journal of Immunology

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Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates biological responses to endogenous and environmental chemical cues. Increasing evidence shows that the AHR plays physiological roles in regulating development, homeostasis and function of a variety of cell lineages in the immune system. However, the role of AHR in human B cell development has not been investigated. Toward this end, an in vitro feeder-free human B cell developmental model system was employed using human cord blood CD34+ hematopoietic stem/progenitor cells (HSPC). Using this model, we found that AHR activation by the high affinity ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), significantly suppressed the generation of early-B cells and pro-B cells from HSPCs, indicating the impairment of B cell lineage specification and commitment. Addition of an AHR antagonist reversed TCDD-elicited suppression of early-B and pro-B cells, suggesting a role of AHR in regulating B lymphopoiesis. Gene expression analysis revealed a significant decrease in the mRNA level of EBF1 and PAX5, two critical transcription factors directing B cell lineage specification and commitment. In addition, binding of the ligand-activated AHR to the putative dioxin response elements in the EBF1 promoter was demonstrated by electrophoretic mobility shift assays and chromatin immunoprecipitation analysis, suggesting transcriptional regulation of EBF1 by AHR. Taken together, this study demonstrates a role for the AHR in regulating human B cell development, and suggests that transcriptional alterations of EBF1 by the AHR are involved in the underlying mechanism.

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Section: Discussioncontrasting

confidence: 67%

“…Likewise, our prior studies using human CD34 + hematopoietic stem/progenitor cells (HSPC) have demonstrated an impairment of B lymphopoiesis by AHR activation (34). The underlying mechanism by which AHR regulates B lymphopoiesis remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis

Bhattacharya

Zhou

et al. 2017

The Journal of Immunology

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“…The ability of PrimeFlow™ to measure gene specific mRNA on a per cell basis enables quantification of cell stage specific gene expression in transitional cell populations during hematopoiesis. For instance, we have reported that 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) treatment impairs the development of human hematopoietic stem/progenitor cells (HSPC) to lineage committed B cells(Li et al , 2017). To study the molecular mechanisms underlying the impaired B cell development, PrimeFlow™ was used to measure the changes in mRNA expression of lineage specific genes in the HSPC-derived heterogeneous cell population.…”

Section: Measuring Changes In Gene Specific Mrna Levels In Transitionmentioning

confidence: 99%

“…The regulation of gene expression is involved in almost every aspect of immune responses, including : 1) cytokine production and cell surface receptors expression after activation (Chen et al , 2012; Phadnis-Moghe et al , 2015; Henriquez et al , 2017; Li et al , 2017); 2) clonal expansion (Sablitzky et al , 1985; van Stipdonk et al , 2001); and 3) terminal differentiation into mature effector and memory cell types (Rissoan et al , 1999). The most ubiquitous and reliable method of gene transcriptional analysis is Real-Time Quantitative PCR (RT-qPCR).…”

Section: Introductionmentioning

confidence: 99%

Application of gene specific mRNA level determinations in individual cells using flow cytometry-based PrimeFlow™ in immunotoxicology

Henriquez

Zhou

et al. 2017

Toxicology and Applied Pharmacology

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Determining changes in gene expression by measuring mRNA levels is an important capability in biological research. Real-Time Quantitative PCR (RT-qPCR) is the most ubiquitous technique for measuring changes in mRNA transcript levels, but heterogeneity of cell populations and low cell number are serious technical limitations. Recent advances in flow cytometric analytical techniques have enabled the quantification of mRNA levels in individual cells. Here, we present examples demonstrating the strength and challenges of concurrently measuring mRNA using PrimeFlow™ with other endpoints in immunotoxicological studies. Specifically, we demonstrate how measuring gene specific mRNA levels on a per cell basis was used to study:1) markers of activation and differentiation; 2) cell signaling by measuring intracellular proteins in mature and developing cell types; and 3) a cell type that constitutes a minor population in peripheral blood. We also discuss cell type-specific modifications to the parent technique, which facilitated optimal performance in these cells. While the examples provided are focused on immunotoxicological questions and endpoints, this new strategy can be applied to a wide variety of toxicological research problems.

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“…Developmental immunotoxicity can be evaluated using in vitro models capitalizing on the availability of human cord blood-derived hematopoietic stem cells. For example, in studying human B cell development, Li and coworkers [15] have used a combination of flow cytometry-based and cell culture-based approaches to show that the environmental contaminant TCDD decreased the total number of hematopoietic stem cells and lineage committed CD19 + B cells, suggesting the impairment of human B lymphopoiesis. This study illustrates another novel approach utilizing human primary cells as an adjunct to more traditional rodent based strategies.…”

Section: Current Approaches To Immunotoxicity Testing Using Primarmentioning

confidence: 99%

Immunotoxicity testing using human primary leukocytes: An adjunct approach for the evaluation of human risk

Phadnis-Moghe

Kaminski

2017

Current Opinion in Toxicology

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Historically, immunotoxicity testing for chemicals, pesticides and pharmaceuticals has relied heavily on animal models to identify effects on the immune system followed by extrapolation to humans. Substantial progress has been made in the past decade on understanding human immune cell regulation, adaptive and innate immune responses and its modulation. The human immune system is complex and there exists diversity within composition, localization, and activation of different immune cell types between individuals. The inherent variation in human populations owing to genetics and environment can have a significant influence on the response of the immune system to infectious agents, drugs, chemicals and other environmental factors. Several recent reports have highlighted that mouse models of sepsis and inflammation are poorly predictive of human disease physiology and pathology. Rodent and human immune cells differ in the expression of cell surface proteins and phenotypes expressed in disease models, which may significantly influence the mechanism of action of xenobiotics and susceptibility yielding a different profile of activity across animal species. In the light of these differences and recent trends toward precision medicine, personalized therapies and the 3Rs (reduce, replace and refine animal use) approaches, the importance of using ‘all human’ model systems cannot be overstated. Hence, this opinion piece aims to discuss new models used to assess the effects of environmental contaminants and immune modulators on the immune response in human cells, the advantages and challenges of using human primary cells in immunotoxicology research and the implication for the future of immunotoxicity testing.

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Aryl hydrocarbon receptor activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs human B lymphopoiesis

Cited by 25 publications

References 47 publications

Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis

Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis

Application of gene specific mRNA level determinations in individual cells using flow cytometry-based PrimeFlow™ in immunotoxicology

Immunotoxicity testing using human primary leukocytes: An adjunct approach for the evaluation of human risk

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