Molecular Mechanisms of Toxic Expression Induced by Endocrine Disruptors via AHR

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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.