Molecular Mechanisms of Toxic Expression Induced by Endocrine Disruptors via AHR

多环芳烃（PAHs）是环境内分泌干扰物，通过芳烃受体（AHR）发挥多种毒理学效应。然而，多环芳烃诱导的毒性表达机制尚未阐明。因此，本研究的目的是通过差异显示技术和基因芯片技术来阐明多环芳烃诱导的毒性表达机制。首先，从处理的野生型小鼠和AHR敲除小鼠肝脏制备总RNA。与3-甲基胆蒽（MC）反应。我们利用差异显示技术和基因芯片技术发现了新的AHR靶基因。有趣的是，PAH处理通过AHR抑制了过氧化物酶体增殖物激活受体（PPAR）α靶基因的mRNA表达。我们还证明AHR通过抑制其异源二聚体伴侣维甲酸X受体（RXR）α来抑制PPARα信号。脂肪酸代谢相关基因受PPARα调控。提示抑制PPARα信号在脂肪肝的发生中起重要作用。

Polycychc aromatic hydrocarbons (PAHs) which are known as the Environmental Endocrine Disruptors exert the various toxicological effects via aryl hydrocarbon receptor (AHR). However the mechanisms of toxic expression induced by PAHs have not been clarified yet. Therefore, the purpose of this study was to clarify the mechanisms of toxic expression induced by PAHs using differential display method and DNA microarray method. First, total RNA were prepared from the wild type mouse and AHR knock out mouse livers treated. with 3-methylcholanthrene (MC). We found the novel AHR target genes using differential display method and DNA microarray method. Interestingly, the mRNA expressions of the peroxisome prolifilator-activated receptor (PPAR) α target genes were suppressed by PAH treatment through AHR. We also demonstrated that AHR inhibited PPARα signals through the suppression of its heterodimeric partner, retinoid X receptor (RXR)α. The genes responsible for the fatty acid metabolism were regulated by PPARα. Therefore, it was suggested that the suppression of the PPARα signal was important for the occurrence of fatty liver.