||Environmental Biology Laboratory
Faculty of Medicine University of Tsukuba
1-1-1 Tennodai, Tsukuba Ibaraki,
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
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.