Aryl hydrocarbon receptor SNP-130 C/T associates with dioxins susceptibility through regulating its receptor activity and downstream effectors including interleukin 24

作者：Liu Ge; Asanoma Kazuo; Takao Tomoka; Tsukimori Kiyomi; Uchi Hiroshi; Furue Masutaka; Kato Kiyoko; Wake Norio^*

来源：Toxicology Letters, 2015, 232(2): 384-392.

DOI：10.1016/j.toxlet.2014.11.025

• Aryl hydrocarbon receptor
• Single nucleotide polymorphism
• Genetic susceptibility
• Dioxins
• Interleukin 24
• Yusho

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 dioxininducible gene transcription, and to investigate interleukin-24 (IL-24) and interleukin-1 beta (IL-1 beta) 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-1 beta 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-1 beta. We observed higher serum IL-24 levels and lower serum IL-1 beta 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-1 beta 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-1 beta, and suggest an association of AhR SNP -130 C/T with the susceptibility to dioxins.

• 出版日期2015-1-22