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Ortho (o)‐toluidine is a widely known carcinogenic substance associated with cancers of the human bladder. A study on British chemical factory workers exposed to 2‐mercaptobenzothiazole, phenyl‐β‐naphthylamine, aniline, and o‐toluidine demonstrated the crucial roles of o‐toluidine, 2‐mercaptobenzothiazole, and phenyl‐β‐naphthylamine in the development of bladder cancer. As genotoxic events are crucial steps in the initiation of cancer, in the present study, we aimed to examine the genotoxic potential of the four chemicals using phosphorylated histone H2AX (γ‐H2AX), which is a sensitive and reliable marker of DNA damage, in cultured human urothelial cells. Of the four chemicals, 2‐mercaptobenzothiazole was a particularly potent DNA‐damaging agent. Moreover, mechanistic studies revealed that γ‐H2AX generation by 2‐mercaptobenzothiazole was mainly associated with the generation of reactive oxygen species via cytochrome P450 2E1‐mediated metabolism. The findings of this study may provide information that is important for the assessment of risks associated with chemicals as well as the interpretation of epidemiological studies investigating occupational bladder cancer. [ABSTRACT FROM AUTHOR]

Abstract: Trichloroethylene (TCE), a chlorinated hydrocarbon, was recently reclassified as a human carcinogen by the International Agency for Research on Cancer. Genotoxic events are known to be crucial steps in the initiation of cancer. The genotoxic properties of TCE have been examined in many studies using a standard battery of genotoxicity tests both in vitro and in vivo. However, consistent results have not been obtained, and studies investigating the mechanism behind the genotoxicity of this compound are lacking. In the present study, we examined the genotoxicity of TCE by assessing phosphorylated histone H2AX (γ‐H2AX), a new sensitive and reliable marker of DNA damage, in WRL‐68 cells, cultured human hepatocytes and mouse livers. Our results showed that TCE exposure results in the generation of γ‐H2AX, both in vitro and in vivo. By investigating the in vitro mechanism, we found that TCE increases the levels of intracellular reactive oxygen species (ROS) and that this increase in ROS levels is attenuated in the presence of disulfiram, a specific cytochrome P450 2E1 (CYP2E1) inhibitor. Furthermore, γ‐H2AX induced by TCE was also attenuated by CYP2E1 inhibitors and the antioxidant N‐acetylcysteine. These results suggested that ROS, produced via cytochrome P450 2E1‐mediated metabolic processing, is a major causal factor for γ‐H2AX generation upon exposure to TCE. [ABSTRACT FROM AUTHOR]

The article discusses an experiment based on the leukocytes DNA damage of knockout mice when exposed in ethyl tertiary butyl ether (ETBE). It is mentioned that the experiment was performed on male and female mice with different genotypes. The article shows that damage DNA measured by the alkaline comet assay and expressed as Tail intensity (TI). The article also discusses the result of the experiment which explains male mice are more susceptible than females.

1,2-Dichloropropane (1,2-DCP), a synthetic chlorinated solvent, was recently classified as carcinogenic. Genotoxic events are known as a crucial step in the initiation of cancer. However, studies on the genotoxicity of 1,2-DCP are very limited, particularly studies investigating the mechanism behind DNA damage by 1,2-DCP. In this study, we examined the genotoxicity of 1,2-DCP using phosphorylated histone H2AX (γ-H2AX), a sensitive DNA damage marker. 1,2-DCP showed dose- (1–10 mM: 4 h) and time-dependent (1–24 h: 5 mM) γ-H2AX generation in cultured human hepatocytes (WRL-68) and cholangiocytes (MMNK-1). Additionally, γ-H2AX generation was observed in the livers of mice inhalationally exposed to 1,2-DCP at concentrations of 100, 200, and 400 ppm. During an in vitro mechanistic investigation, we found that γ-H2AX generation by 1,2-DCP was clearly attenuated in the presence of disulfiram and 4-methylpyrazole, a specific cytochrome P450 2E1 (CYP2E1) inhibitor. Furthermore, we showed that 1,2-DCP increased the levels of intracellular reactive oxygen species (ROS), with the increase significantly inhibited by CYP2E1 inhibitors. These results suggested that ROS produced via the cytochrome P450 2E1 metabolic process of 1,2-DCP was a major causal factor for γ-H2AX generation by treatment with 1,2-DCP. [ABSTRACT FROM AUTHOR]

Recently, it was reported that ten cases of bladder cancer occurred among employees, who handled several kinds of aromatic amines, at a Japanese chemical plant. The common aromatic amines were identified as ortho -toluidine, para -toluidine, aniline, ortho -chloroaniline, ortho -anisidine, and 2,4-dimethylaniline. All of these aromatic amines, except ortho -chloroaniline, have been found to be carcinogenic in animals and/or humans. Genotoxic events are known to be crucial steps in the initiation of cancer; information on the genotoxicity of these aromatic amines is insufficient and consistent results have not been obtained. In this study, we examined the genotoxicity of the six different aromatic amines associated with bladder cancer by assessing phosphorylated histone H2AX (γ-H2AX) in a cultured human urothelial cell line, 1T1. We showed that all six aromatic amines generated γ-H2AX. In addition, the γ-H2AX-inducing potential of these six aromatic amines was distinctly different; ortho -chloroaniline and 2,4-dimethylaniline showed particularly high potential, followed by ortho -toluidine, ortho -anisidine, para -toluidine ≒ aniline. The findings of this study may provide important information for the risk assessment of chemicals and for interpreting epidemiological studies on occupational bladder cancer. • The genotoxicity of six aromatic amines used in chemical plants was assessed. • DNA damage was examined by phosphorylated histone H2AX (γ-H2AX) analysis. • All six aromatic amines possessed γ-H2AX-inducing potential. • The γ-H2AX-inducing potentials were found to be amine-specific. • o -Chloroaniline and 2,4-dimethylaniline had high γ-H2AX-inducing potentials. [ABSTRACT FROM AUTHOR]