Defense Seminar: Natasha Kovalova, Phamarcology and Toxicology, MSU

DATE:             Tuesday, July 12, 2016         
TIME:               1:30pm – 2:30pm
LOCATION:     B448 Life Science
Mentor:           Dr. Norb Kaminski


Multiple studies have demonstrated that most of the intraspecies variation in sensitivity to the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including suppression of antibody responses, in murine models is due to single nucleotide polymorphisms (SNPs) within the aryl hydrocarbon receptor (AhR) gene.  The underlying reason for the variation in sensitivity to TCDD-induced suppression of IgM responses among humans is not well understood but is thought, in part, to be a result of different polymorphic forms of the AhR expressed by different individuals.  In this dissertation work, the functional properties of six (P517S, R554K, V570I, V570I+P517S, R554K+V570I and P517S+R554K+V570I) human AhR variants were examined in the human B cell line, SKW 6.4.  This dissertation work is the first to demonstrate that the R554K human AhR SNP alone altered the sensitivity of human B cells to TCDD-mediated induction of CYP1B1 and CYP1A2.  By contrast, attenuation of TCDD-induced IgM suppression required a combination of all three SNPs P517S, R554K, and V570I.  These studies are the first to comprehensively evaluate the correlation between B cell sensitivity to TCDD-mediated suppression of the IgM response and previously identified SNPs within the human AhR.