title: Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant that activates the aryl hydrocarbon receptor (AhR) resulting in altered gene expression. In vivo, in vitro, and ex vivo studies have demonstrated that B cells are directly impaired by TCDD, and are a sensitive target as evidenced by suppression of antibody responses. The window of sensitivity to TCDD-induced suppression of IgM secretion among mouse, rat and human B cells is similar. Specifically, TCDD must be present within the initial 12h post B cell stimulation, indicating that TCDD disrupts early signaling network(s) necessary for B lymphocyte activation and differentiation. Therefore, we hypothesized that TCDD treatment across three different species (mouse, rat and human) triggers a conserved, B cell-specific mechanism that is involved in TCDD-induced immunosuppression. RNA sequencing (RNA-Seq) was used to identify B cell-specific orthologous genes that are differentially expressed in response to TCDD in primary mouse, rat and human B cells. Time course studies identified TCDD-elicited differential expression of 515 human, 2371 mouse and 712 rat orthologous genes over the 24-h period. 28 orthologs were differentially expressed in response to TCDD in all three species. Overrepresented pathways enriched in all three species included cytokine-cytokine receptor interaction, ECM-receptor interaction, focal adhesion, regulation of actin cytoskeleton and pathways in cancer. Differentially expressed genes functionally associated with cell-cell signaling in humans, immune response in mice, and oxidation reduction in rats. Overall, these results suggest that despite the conservation of the AhR and its signaling mechanism, TCDD elicits species-specific gene expression changes.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI 48824, USA; Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824, USA. Electronic address: kovalova@msu.edu.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kovalova
authors.affiliation: Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824, USA; Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: naultran@msu.edu.
authors.forename: Rance
authors.initials: R
authors.lastname: Nault
authors.affiliation: Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824, USA. Electronic address: crawfo28@msu.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Crawford
authors.affiliation: Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824, USA; Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: tzachare@msu.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Zacharewski
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI 48824, USA; Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824, USA. Electronic address: kamins11@msu.edu.
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics*; D013045:Species Specificity
chemical_list: D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon
keywords: AhR; B cell; IgM; TCDD