title: Role of aryl hydrocarbon receptor polymorphisms on TCDD-mediated CYP1B1 induction and IgM suppression by human B cells.
abstract: Previous 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 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 study, 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. TCDD-induced Cyp1B1 and Cyp1A2 mRNA expression levels and Cyp1B1-regulated reporter gene activity, used for comparative purposes, were markedly lower in SKW cells containing the R554K SNP than in SKW-AHR(+) (control AhR) cells. Furthermore, all AhR variants were able to mediate TCDD-induced suppression of the IgM response; however, a combined P517S+R554K+V570I variant partially reduced sensitivity to TCDD-mediated suppression of IgM secretion. Collectively, our findings show that the R554K human AhR SNP alone altered 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.
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. Electronic address: ale.manzan@gmail.com.
authors.forename: Maria
authors.initials: M
authors.lastname: Manzan
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: 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
authors.initials: N
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D065633:Cytochrome P-450 CYP1B1 / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*
chemical_list: D007075:Immunoglobulin M; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C504573:CYP1A2 protein, human; C585496:CYP1B1 protein, human; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1
keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin; B cells; Single nucleotide polymorphisms