Transcriptome analyses demonstrate that Peroxisome Proliferator-Activated Receptor a (PPARa) activity of an ultraviolet absorber, 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl) benzotriazole, as possible mechanism of their toxicity and the gender differences

2-(2'-Hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), the Benzotriazole UV-stabilizer (BUVSs) known as UV-320, is widely used in plastic materials for protection against UV-irradiation. Previously, we reported that oral ingestion of HDBB induce hepatotoxicity including hepatocyte hypertrophy and necrosis in rats and, males was more susceptible compared with females in young rats while no sex-related difference was observed in preweaning rats. Phenotypes observed in our previous study imply involvement of peroxisome proliferator-activated receptor (PPAR) alpha in HDBB hepatotoxicity, however, direct evidence that HDBB can activate PPAR alpha has not been provided and the mechanism which underlying the gender difference of HDBB hepatotoxicity was not clearly elucidated. Here, we conduct transcriptome analysis using microarray expression profiles in the livers of rats administered HDBB. PPAR alpha agonist activity of HDBB was elucidated by comparison with gene expression data of typical PPAR alpha agonist, i.e. clofibrate, WY-14643, gemfibrozil, and fenofibrate, from TG GATEs database. Moreover, we analyzed for PPAR alpha mRNA expression in the liver of developing male and female rats. PPAR alpha mRNA expression level was higher in males than in females on postnatal days (PNDs) 28 and 35, whereas no sex-related difference was found on PNDs 7 and 22. These results suggest that HDBB exerts its hepatotoxicity through the PPAR alpha signal pathway and the sex-related difference in PPAR alpha expression may contribute to the sex-related difference in susceptibility to hepatotoxicity.