Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
Arsenic is classified as a human carcinogen (Group 1) by the International Agency for Research on Cancer (IARC), and chronic exposure to inorganic arsenic via drinking water is associated with increased incidences of human bladder, liver, and lung cancers. Toxicities, especially increased risk of cancers due to chronic exposure to arsenic is a worldwide health problem. The Japanese are exposed to low levels of inorganic arsenic mainly through the Hijiki seaweed and rice consumption, therefore carcinogenic risk assessment of inorganic arsenic is extremely important. As it was impossible to assess the carcinogenic risk of arsenic by epidemiological studies alone, there was an urgent need to evaluate the carcinogenic risk using appropriate animal models. However, there was not sufficient evidence for arsenic carcinogenicity in experimental animals, and animal models for risk assessment of arsenic had not been established.
We demonstrated, for the first time, that dimethylarsinic acid (DMA), a major organic urinary metabolite of inorganic arsenic, is a complete urinary bladder carcinogen and promotes carcinogenesis in various organs via induction of oxidative DNA damage and aberrant expression of cell cycle-regulated gene cell using animal models. Moreover, we found that its upstream metabolite (monomethylarsonic acid) and downstream metabolite (trimethylarsenoxide) also exert promoting effects on hepatocarcinogenesis in rats. Based on these findings, IARC concluded that there was sufficient evidence for carcinogenicity of DMA in experimental animals in 2004. Furthermore, we identified the dimethylmonothioarsinic acid, a novel urinary metabolite of DMA, and illustrated that it may play a key role in DMA-induce bladder carcinogenesis and might be a useful biomarker for risk assessment of bladder carcinogenicity.
Recently, epidemiological studies have shown that prenatal arsenic exposure increases the risk of cancer in adulthood. We found that prenatal exposure to DMA increased lung and liver tumors, and prenatal exposure of organic arsenical diphenylarsinic acid increased liver tumors in male offspring of mice. Furthermore, we revealed that epigenetic abnormalities such as DNA methylation and histone modifications are involved in the carcinogenic mechanism of these organic arsenicals during fetal life, suggesting that carcinogenic mechanisms may differ between fetal and adult stages of life.
In summary, we have successfully demonstrated the carcinogenicity of various organic arsenic metabolites of arsenic and clarified experimentally the carcinogenicity and the underlying mechanisms of arsenic. Our findings not only facilitate our understanding of the carcinogenic mechanisms of arsenic, but also contribute to risk assessment arsenic.
