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Stem Cells. 2016 Feb;34(2):470-82. doi: 10.1002/stem.2246. Epub 2015 Nov 27.

Maternal dietary imbalance between omega-6 and omega-3 polyunsaturated fatty acids impairs neocortical development via epoxy metabolites.

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Department of Developmental Neuroscience, Center for Neuroscience, United Centers for Advanced Research and Translational Medicine, Tohoku University School of Medicine, Miyagi, Japan.
Research Fellow of the Japan Society for the Promotion of Science, Tokyo, Japan.
Institute for Health Care Science, Suntory Wellness Ltd, Osaka, Japan.
Department of Metabolism and Diabetes, Tohoku University School of Medicine, Miyagi, Japan.
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Massachusetts, USA.
Department of Paediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
Laboratory for Metabolomics, Center for Integrative Medical Sciences, RIKEN, Kanagawa, Japan.


Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are essential nutrients. Although several studies have suggested that a balanced dietary n-6:n-3 ratio is essential for brain development, the underlying cellular and molecular mechanism is poorly understood. Here, we found that feeding pregnant mice an n-6 excess/n-3 deficient diet, which reflects modern human diets, impairsed neocortical neurogenesis in the offspring. This impaired neurodevelopment occurs through a precocious fate transition of neural stem cells from the neurogenic to gliogenic lineage. A comprehensive mediator lipidomics screen revealed key mediators, epoxy metabolites, which were confirmed functionally using a neurosphere assay. Importantly, although the offspring were raised on a well-balanced n-6:n-3 diet, they exhibited increased anxiety-related behavior in adulthood. These findings provide compelling evidence that excess maternal consumption of n-6 PUFAs combined with insufficient intake of n-3 PUFAs causes abnormal brain development that can have long-lasting effects on the offspring's mental state.


Anxiety; Arachidonic acid; Docosahexaenoic acid; Epoxides; Metabolomics; Neural stem cells

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