Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
We are constantly exposed to chemicals in the environment and food that may be toxic our body, and it is difficult to avoid them completely. In particular, neurotoxic substances are involved in brain diseases and abnormal brain development of pups, and hence it is important to search for substances that can protect neuronal cells and to elucidate their mechanisms of action. Intake of polyunsaturated fatty acids such as docosahexaenoic acid (DHA) has been shown to be important for brain development and maintenance of normal brain function and to have neuroprotective effect, but their mechanisms of these actions have not been clarified. I found that DHA intake in adult mice and rats did not change the amount of DHA in the brain but increased the amount of DHA diols (DHDPs) produced from DHA by cytochrome P450 (P450) and soluble epoxide hydrolase (sEH). Therefore, I focused on DHA metabolites to elucidate the mechanism underlying the beneficial effects of DHA intake.
Rotenone, a pesticide, is known to cause Parkinson's disease-like symptoms. Administration of rotenone to rats resulted in decreased motor function, decreased tyrosine hydroxylase and increased oxidative stress in the striatum. On the other hand, these symptoms induced by rotenone were suppressed by supplementation with DHA. However, these effects of DHA intake were inhibited by cosupplementation with an inhibitor of sEH TPPU. In addition, DHA intake increased expression of antioxidant genes such as SOD1 and catalase in the striatum, but these effects were also inhibited by the sEH inhibitor. These results indicate that the actions of DHDPs, DHA metabolites produced by P450 and sEH, may be important in the effects of DHA intake. Indeed, in primary neurons, addition of 19,20-DHDP increased the expression of antioxidant genes, indicating the importance of DHA metabolites in the beneficial effect of DHA intake.
Although DHA is abundant in fish, seafood also contains neurotoxic substances such as methylmercury that adversely affect brain development. High consumption of seafood by pregnant women may lead to methylmercury-induced neurotoxicity in their pups. I have shown that the neurotoxicity of methylmercury was also reduced by DHA intake, and that DHDP can reduce it more effectively than DHA. In fact, DHA intake in mother significantly increased 19,20-DHDP in the brains of the pups and significantly reduced methylmercury-induced motor and memory deficits in the pups. These results revealed a new physiological actions of DHA metabolites in reducing neurotoxicity, and it is expected that direct addition of DHA metabolites to infant formula will provide more efficient neuroprotection against toxic substances. In the future, we would like to further elucidate the mechanism underlying the action of DHA metabolites in more detail, including the search for direct targets of DHA metabolites.
