Transcriptome analyses demonstrate that Peroxisome Proliferator-Activated Receptor α (PPARα) 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) α in HDBB hepatotoxicity, however, direct evidence that HDBB can activate PPARα 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. PPARα agonist activity of HDBB was elucidated by comparison with gene expression data of typical PPARα agonist, i.e. clofibrate, WY-14643, gemfibrozil, and fenofibrate, from TG GATEs database. Moreover, we analyzed for PPARα mRNA expression in the liver of developing male and female rats. PPARα 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 PPARα signal pathway and the sex-related difference in PPARα expression may contribute to the sex-related difference in susceptibility to hepatotoxicity.
Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences.
Mutsuko
M
Hirata-Koizumi
Ryota
R
Ise
Hirohito
H
Kato
Takashi
T
Matsuyama
Tomoko
T
Nishimaki-Mogami
Mika
M
Takahashi
Atsushi
A
Ono
Makoto
M
Ema
Akihiko
A
Hirose
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013997:Time Factors; D014230:Triazoles / Q000633:toxicity*
D047493:PPAR alpha; D012333:RNA, Messenger; D014230:Triazoles; C525485:2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole