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Environmental Biology Laboratory Faculty of Medicine University of Tsukuba
環境生物学研究室

The 23rd Symposium of the  Japanese Arsenic Society

Environmental Biology Laboratory 
Faculty of Medicine University of Tsukuba
1-1-1 Tennodai, Tsukuba Ibaraki,
305-8575, Japan

Japanese

Research Motives

Understanding the biological response and
adaptive system to electrophilic stress

 Welcome to the environmental biology laboratory, led by me, Yoshito Kumagai, a member of the Faculty of Medicine at the University of Tsukuba.
 In order to lead richer lives, we all seek jobs and places to live, as well as eat meals, as we strive to maintain our health and well-being. Food preferences vary from individual to individual, with some people eating mainly meat, while others are vegetarians. In addition, some people smoke and eat between meals to avoid stress, even though they believe that it is not so good for their health. Chronically maintaining such complex environmental factors is known to cause a presymptomatic health status (a condition in which diseases are not diagnosed, but which cannot be regarded as healthy), eventually resulting in the development of diseases. Our laboratory focuses on environmental electrophiles as reactive chemical substances that enter the body through people’s diets, living environments and lifestyles. For example, 1,2- and 1,4-naphthoquinone are produced by the burning of gasoline, and are both contained in PM2.5 particles and volatile fractions in the air, which are air pollutants. Additionally, 1,4-benzoquinone and crotonaldehyde are constituents of tobacco smoke, while (E)-2-alkenals are found in vegetables and herbs such as coriander. Acrylamide is found in certain heat-processed foods such as potato chips. Methylmercury, which is the causative agent of Minamata disease—considered one of Japan's four major pollution-caused diseases—accumulates in large edible fish, such as tuna, through the food chain and bioaccumulation. Cadmium, meanwhile, which is famous as the causative agent of the so-called Itai-Itai disease—another of the four major pollution-caused diseases—is contained in rice. In other words, we are routinely exposed to electrophilic stress (Fig. 1).
 Electrophiles have low electron-density sites that form adducts by covalently binding to nucleophilic substituents such as high electron-density DNA guanine residue or protein cysteine residue. There is much research demonstrating that the adduct formation of such macromolecules causes cancer and tissue injury, which shows that electrophiles have long been perceived as bad for us. However, it is also known that there are low-molecular-weight nucleophiles in the body, such as glutathione (GSH), and that adduct formation with GSH is responsible for the detoxification and elimination of electrophilic substances. Therefore, it can be said that electrophilic stress becomes dominant when environmental electrophile exposure exceeds the quantity of low-molecular-weight nucleophiles present in the body, resulting in harmful effects that lead to people’s health being compromised (Fig. 1).
 Given that it was the Japanese people who suffered from pollution-related illnesses such as the Minamata and Itai-Itai diseases, caused by excessive exposure to methylmercury and cadmium, conventional toxicology research in this country has focused its attention on evaluating toxicity and elucidating the mechanisms of the occurrence of toxicity in terms of compounds. While it is safe to say that the concentration of methylmercury and cadmium contained in fish and rice is low from the environmental point of view, most Japanese still consume fish and rice as their staple diet on a daily, long-term basis, so anxieties remain about the health effects of that practice. What needs to be considered is the fact that our dietary habits, living environment and lifestyles routinely give us a combined exposure to different doses of multiple environmental electrophiles. One can expect that although the various environmental electrophiles, as described above, have different structures, their chemical properties are all electrophilic, suggesting that the separate effects observed in individual exposures affect each other additively and synergistically during combined exposure. In order to elucidate that issue, our laboratory is conducting research on the role of both intracellular redox signaling and reactive sulfur species (RSS) as key factors for sensing and regulation in reducing the risks of environmental electrophiles. Please refer to the Research Focus below for details.