title: Aryl hydrocarbon receptor SNP -130 C/T associates with dioxins susceptibility through regulating its receptor activity and downstream effectors including interleukin 24.
abstract: Dioxins are persistent environmental pollutants that cause multiple adverse health effects in humans, mainly through binding to the ligand-activated transcription factor, aryl hydrocarbon receptor (AhR). Genetic variation in AhR may modulate the susceptibility to dioxins. In this study, we aimed to evaluate the effects of the single nucleotide polymorphism (SNP) -130 C/T in the AhR promoter on dioxin-inducible gene transcription, and to investigate interleukin-24 (IL-24) and interleukin-1β (IL-1β) as proxies for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Using primary human chorionic stromal cells, we found that cells with the TT genotype showed higher AhR mRNA and protein levels than did those of the CC genotype. Microarray was carried out to analyze the gene expression profiles of cells (CC and TT genotype) after exposing the cells to TCDD. Several genes associated with human disorders were more highly up-regulated in cells of the TT genotype. Higher up-regulation of IL-24 and IL-1β mRNA in cells with the TT genotype was observed. Furthermore, blood samples from 64 Yusho patients who were accidentally exposed to high concentrations of dioxins were analyzed for the genotype, dioxins concentrations and serum levels of IL-24 and IL-1β. We observed higher serum IL-24 levels and lower serum IL-1β levels in Yusho patients with the TT genotype than in those with the CC genotype. AhR SNP -130 C/T affects serum IL-24 and IL-1β levels, independently of serum dioxins concentrations in Yusho patients. Our observations demonstrate that SNP -130 C/T modulates AhR expression and expression levels of IL-24 and IL-1β, and suggest an association of AhR SNP -130 C/T with the susceptibility to dioxins.
authors.affiliation: Department of Genomic Epidemiology, Research Center for Environment and Developmental Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ge
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Asanoma
authors.affiliation: Department of Genomic Epidemiology, Research Center for Environment and Developmental Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Takao
authors.affiliation: Department of Obstetrics, Fukuoka Children's Hospital, Fukuoka, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Tsukimori
authors.affiliation: Research and Clinical Center for Yusho and Dioxins, Kyushu University Hospital, Fukuoka, Japan; Department of Dermatology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchi
authors.affiliation: Research and Clinical Center for Yusho and Dioxins, Kyushu University Hospital, Fukuoka, Japan; Department of Dermatology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Genomic Epidemiology, Research Center for Environment and Developmental Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: wake@med.kyushu-u.ac.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Wake
mesh_terms: D000328:Adult; D044466:Asian People; D002824:Chorionic Villi / Q000187:drug effects / Q000378:metabolism; D004147:Dioxins / Q000506:poisoning / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D007378:Interleukins / Q000378:metabolism*; D007564:Japan; D046228:Microarray Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011164:Porphyrias / Q000235:genetics* / Q000378:metabolism*; D011247:Pregnancy; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D017154:Stromal Cells / Q000187:drug effects; D000099180:Interleukin-24
chemical_list: D004147:Dioxins; D004785:Environmental Pollutants; D053583:Interleukin-1beta; D007378:Interleukins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D000099180:Interleukin-24
keywords: Aryl hydrocarbon receptor; Dioxins; Genetic susceptibility; Interleukin 24; Single nucleotide polymorphism; Yusho