Promotion effects of acetoaceto-o-toluidide on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder carcinogenesis in rats

被引:6
|
作者
Yukimatsu, Nao [1 ,3 ]
Gi, Min [1 ,2 ]
Okuno, Takahiro [1 ]
Fujioka, Masaki [1 ]
Suzuki, Shugo [1 ]
Kakehashi, Anna [1 ]
Yanagiba, Yukie [4 ]
Suda, Megumi [4 ]
Koda, Shigeki [4 ]
Nakatani, Tatsuya [3 ]
Wanibuchi, Hideki [1 ]
机构
[1] Osaka City Univ, Grad Sch Med, Dept Mol Pathol, Abeno Ku, 1-4-3 Asahi Machi, Osaka, Japan
[2] Osaka City Univ, Grad Sch Med, Dept Environm Risk Assessment, Osaka, Japan
[3] Osaka City Univ, Grad Sch Med, Dept Urol, Osaka, Japan
[4] Japan JNIOSH, Natl Inst Occupat Safety & Hlth, Ind Toxicol & Hlth Effects Res Grp, Kawasaki, Kanagawa, Japan
基金
日本学术振兴会;
关键词
AAOT; OTD; Bladder carcinogenicity; Rat; Occupational urinary bladder cancer; GENE-EXPRESSION; C-JUN; CYCLOOXYGENASE-2; EXPRESSION; UROTHELIAL CELLS; UP-REGULATION; CANCER; URINE; AP-1; NORMALIZATION; TRANSCRIPTION;
D O I
10.1007/s00204-019-02605-4
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Recent epidemiological studies have indicated that occupational exposure to the aromatic amine acetoaceto-o-toluidide (AAOT) was associated with a marked increase in urinary bladder cancers in Japan. However, little is known about the carcinogenicity of AAOT. To evaluate the urinary bladder carcinogenicity of AAOT, male and female F344 rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks followed by dietary administration of 0, 0.167, 0.5, or 1.5% AAOT for 31 weeks. The incidences and multiplicities of bladder tumors were significantly increased in the 0.5 and 1.5% groups of male and female rats in a dose-response manner. AAOT and seven downstream metabolites were detected in the urine of the male and female rats administered AAOT with levels increasing in a dose-dependent manner. The most abundant urinary metabolite of AAOT was the human bladder carcinogen o-toluidine (OTD), which was at least one order of magnitude higher than AAOT and the other AAOT metabolites. In a second experiment, male F344 rats were administered 0, 0.167, or 1.5% AAOT for 4 weeks. Gene expression analyses revealed that the expression of JUN and its downstream target genes was increased in the urothelium of male rats treated with 1.5% AAOT. These results demonstrate that AAOT promotes BBN-induced urinary bladder carcinogenesis in rats and suggest that overexpressed of JUN and its downstream target genes may be involved the bladder carcinogenicity of AAOT. In conclusion, AAOT, like other carcinogenic aromatic amines, is likely to be a carcinogen to the urinary bladder, and OTD metabolized from AAOT is the ultimate carcinogen.
引用
收藏
页码:3617 / 3631
页数:15
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