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

Yukimatsu, Nao; Gi, Min; Okuno, Tatsusada; Fujioka, Masaki; Suzuki, Shugo; Kakehashi, Anna; Yanagiba, Yukie; Suda, Megumi; Koda, Shigeki; Nakatani, Tatsuya; Wanibuchi, Hideki

doi:10.1007/s00204-019-02605-4

Cited by 5 publications

(6 citation statements)

References 48 publications

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“…Thus, OTD was considered as the causative agent of occupational bladder cancer in this plant. In our previous study, we reported that AAOT, produced using OTD as a raw material, can promote urinary bladder carcinogenesis in rats [5]. In another study, we demonstrated high concentrations of OTD in the urine of AAOT-treated rats.…”

Section: Introductionmentioning

confidence: 71%

“…Therefore, AAOT is speculated as a causative agent of urinary bladder cancer, both as a promoter and initiator. We have previously reported high concentrations of OTD in the urine of AAOT-treated rats [5]; hence, we hypothesized that the carcinogenic mechanism of AAOT is the OTD metabolically produced from AAOT. The extent of hyperplasia and the number of Ki67-and γ-H2AX-positive cells in urinary bladders induced by AAOT seemed slightly weaker than those seen in bladders treated by OTD (Figure 1; Table 2).…”

Section: Discussionmentioning

confidence: 95%

“…Thus, it is likely that oxidative stress contributed to the development of urinary bladder cancer after exposure to OTD. Previously, we demonstrated the positive effect of AAOT on BBN-induced urinary bladder carcinogenesis in rats due to the overexpression of JUN, a transcription factor in the activator protein-1 (AP-1) complex, and its downstream target genes [5]. In addition Previously, we demonstrated the positive effect of on BBN-induced urinary bladder carcinogenesis in rats due to the overexpression of JUN, a transcription factor in the activator protein-1 (AP-1) complex, and its downstream target genes [5].…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we demonstrated the positive effect of AAOT on BBN-induced urinary bladder carcinogenesis in rats due to the overexpression of JUN, a transcription factor in the activator protein-1 (AP-1) complex, and its downstream target genes [5]. In addition Previously, we demonstrated the positive effect of on BBN-induced urinary bladder carcinogenesis in rats due to the overexpression of JUN, a transcription factor in the activator protein-1 (AP-1) complex, and its downstream target genes [5]. In addition to the promotion effects, AAOT induced the development of pre-cancerous lesions, such as hyperplasia and γ-H2AX positivity in the urinary bladder epithelium.…”

Section: Discussionmentioning

confidence: 99%

“…The animals in Experiment 1 were fed diets supplemented with 0.6% ANL, 0.6% PT, 1.5% AAOT, or 0.6% OTD for 4 weeks. The dose of AAOT (1.5%) is the same as that used in the previous study [5], and the dose of OTD (0.6%) is the same as that used in other carcinogenicity studies [23]. The doses of ANL and PT were adjusted to be the same as that of OTD.…”

Section: Experimental Designmentioning

confidence: 99%

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Evaluation of the Mechanisms Involved in the Development of Bladder Toxicity following Exposure to Occupational Bladder Cancer Causative Chemicals Using DNA Adductome Analysis

Suzuki,

Gi,

Komiya

et al. 2023

Biomolecules

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Occupational exposure to aromatic amines (AAs) is an important risk factor for urinary bladder cancer. This study aimed to evaluate the toxicity of AAs and analyze the carcinogenic mechanisms in rat bladder by comprehensive analysis of DNA adducts (DNA adductome). DNA was extracted from the bladder epithelia of rats treated with AAs, including acetoacet-o-toluidine (AAOT) and o-toluidine (OTD), and adductome analysis was performed. Principal component analysis–discriminant analysis revealed that OTD and AAOT observed in urinary bladder hyperplasia could be clearly separated from the controls and other AAs. After confirming the intensity of each adduct, four adducts were screened as having characteristics of the OTD/AAOT treatment. Comparing with the in-house DNA adduct database, three of four candidates were identified as oxidative DNA adducts, including 8-OH-dG, based on mass fragmentation together with high-resolution accurate mass (HRAM) spectrometry data. Therefore, findings suggested that oxidative stress may be involved in the toxicity of rat bladder epithelium exposed to AAs. Consequently, the administration of apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase, in six-week-old rats fed with 0.6% OTD in their diet resulted in simple hyperplastic lesions in the bladder that were suppressed by apocynin. The labeling indices of Ki67, γ-H2AX, and 8-OHdG were significantly decreased in an apocynin concentration-dependent manner. These findings indicate that oxidative stress may have contributed to the development of urinary cancer induced by OTD.

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Section: Introductionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 95%