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 12 h 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.

Modulatory Influence of Segmented Filamentous Bacteria on Transcriptomic Response of Gnotobiotic Mice Exposed to TCDD

“…Before inferring if TCDD and presence/absence of SFB would have a similar influence on humans compared to the murine model, both the host and microbial phenotype must be considered. Differences in host phenotype have been described previously ( Kreisman and Cobb, 2011 ), with varied gene expression in response to TCDD depending on the measured tissue and host species ( Kovalova et al, 2017 ). In regards to microbiota, recent meta-analysis has shown that 90 and 89% of bacterial phyla and genera, respectively, are shared between mice and the human gut microbiota ( Krych et al, 2013 ), with the most abundant bacterial species being common in both.…”

Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma

“…Analysis of TCGA/SKCM data was performed using OncoLnc portal [ http://www.oncolnc.org ] 62 . The raw data count matrix composed of 479 samples; from SKCM melanoma cohort was downloaded from the OncoLnc for the pigmentation genes ( n = 14) 12 , the AhR target genes ( n = 19) 63 , or the BRAFi resistant genes ( n = 19) 17 . Expression heatmap of differentially expressed genes between samples was obtained on log2 fold change using heatmap3 package in R/Bioconductor.…”

Developments in toxicogenomics: understanding and predicting compound-induced toxicity from gene expression data

“…The cytochrome P450 isoenzyme CYP1A1 had concordant increased expression regardless of the species and tissue. 86 …”