Journal
ARCHIVES OF TOXICOLOGY
Volume 93, Issue 3, Pages 753-762Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-019-02396-8
Keywords
Aromatic amine; gamma-H2AX; o-Anisidine; o-Toluidine; Rat; Urinary bladder
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Funding
- Health and Labour Sciences Research Grant for the Research on Risk of Chemical Substances from the Ministry of Health, Labour and Welfare, Japan
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Although aromatic amines are widely used as raw materials for dyes, some of them have been concerned about carcinogenicity in the urinary bladder. We examined early changes in histopathology and the formation of gamma-H2AX, a biomarker of DNA damage, in the urinary bladder of rats to investigate the mechanisms of mucosal damage induced by monocyclic aromatic amines. 6-week-old male F344 rats were administered 0.4% or 0.8% o-toluidine, 0.3% or 1.0% o-anisidine, 0.4% 2,4-xylidine, 0.2% p-toluidine, or 0.6% aniline in the diet for 4 weeks. Animals were sequentially killed from day 2 to after 2 weeks of recovery, and histopathological and immunohistochemical analyses were performed. In the 0.8% o-toluidine group, there was sequential progression of bladder lesions, characterized by edematous changes and intramucosal hemorrhage at day 2 and formation of granulation tissue with mononuclear cell infiltration at week 1, followed by diffuse hyperplasia at weeks 2 and 4. In the 1.0% o-anisidine group, simple hyperplasia only with slight inflammation was detected from week 1. Whereas gamma-H2AX-positive bladder epithelial cells in the 1.0% o-anisidine group were significantly increased in a time-dependent manner, transient increases in gamma-H2AX-positive cells were detected at day 2 and week 1 in the 0.8% o-toluidine group. No apparent bladder lesions or increases in gamma-H2AX formation were observed in any other groups. These results revealed different mechanisms of bladder mucosal damage associated with o-toluidine and o-anisidine. Moreover, immunohistochemical analysis for gamma-H2AX suggested that both compounds may induce DNA damage in epithelial cells, mainly basal cells, of the bladder mucosa.
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