Nancy Bigley (Committee Member), David Cool (Committee Member), Mauricio Di Fulvio (Committee Member), Courtney Sulentic (Advisor)
Master of Science (MS)
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent and persistent environmental toxin known to inhibit immunoglobulin (Ig) gene expression in various animal models. TCDD is thought to modulate gene expression through the aryl hydrocarbon receptor (AhR) and thereby a subsequent alteration in gene expression. The AhR is a ligand-activated transcription factor that regulates xenobiotic-metabolizing enzymes. The mouse 3'Ig heavy chain regulatory region (3'IghRR) is a sensitive transcriptional target of TCDD that may mediate, in an AhR-dependent manner, the inhibitory effect of TCDD on Ig expression. Human B cells could also be a sensitive target of TCDD. The current study focuses on determining the effects of TCDD and the AhR on human Ig expression utilizing a human Burkitt lymphoma cell line (CL-01) model that can be activated to secrete Ig and undergo class switch recombination (CSR) from IgM to IgA, IgG or IgE antibody isotypes. Our results suggest that TCDD has variable effects on IgM secretion, but significantly inhibits IgG secretion, an effect reversed by addition of the AhR antagonist. Surprisingly, the AhR antagonist alone markedly increased IgG secretion above stimulation. At transcript level, TCDD has variable effects on µ IGH functional transcripts, inhibits γ1-4 germline/functional transcripts and Cε germline transcripts. Additionally, CD40L and IL-4 stimulation induced de novo synthesis of Cε germline transcripts, a precursor to CSR. However, α1-2 germline/functional transcripts increased in response to TCDD. Notably, TCDD and stimulation had no effect on CYP1A1 transcript expression. Additionally, in CL-01 cells, we recently discovered SNPs in the Exon-10 of the AhR, the transactivation domain of the AhR that regulates expression of other genes but does not affect ligand binding and the AhR is heterozygous with one non-functional transactivation domain. Results also indicate that a small proportion of the cells have undergone spontaneous class switch to all of the γ and α isotypes rather than being induced to CSR.
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
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