title: Maternal dietary imbalance between omega-6 and omega-3 polyunsaturated fatty acids impairs neocortical development via epoxy metabolites.
abstract: 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.
authors.affiliation: 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.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sakayori
authors.affiliation: Department of Developmental Neuroscience, Center for Neuroscience, United Centers for Advanced Research and Translational Medicine, Tohoku University School of Medicine, Miyagi, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Kikkawa
authors.affiliation: Institute for Health Care Science, Suntory Wellness Ltd, Osaka, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Tokuda
authors.affiliation: Department of Developmental Neuroscience, Center for Neuroscience, United Centers for Advanced Research and Translational Medicine, Tohoku University School of Medicine, Miyagi, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Kiryu
authors.affiliation: Department of Developmental Neuroscience, Center for Neuroscience, United Centers for Advanced Research and Translational Medicine, Tohoku University School of Medicine, Miyagi, Japan.
authors.forename: Kaichi
authors.initials: K
authors.lastname: Yoshizaki
authors.affiliation: Institute for Health Care Science, Suntory Wellness Ltd, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawashima
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University School of Medicine, Miyagi, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Massachusetts, USA.
authors.forename: Jing X
authors.initials: JX
authors.lastname: Kang
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University School of Medicine, Miyagi, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.affiliation: Institute for Health Care Science, Suntory Wellness Ltd, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shibata
authors.affiliation: Department of Paediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Innis
authors.affiliation: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.|Laboratory for Metabolomics, Center for Integrative Medical Sciences, RIKEN, Kanagawa, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.affiliation: Department of Developmental Neuroscience, Center for Neuroscience, United Centers for Advanced Research and Translational Medicine, Tohoku University School of Medicine, Miyagi, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Osumi
mesh_terms: D000818:Animals; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6 / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D019579:Neocortex / Q000254:growth & development* / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis; D011247:Pregnancy
chemical_list: D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6
keywords: Anxiety; Arachidonic acid; Docosahexaenoic acid; Epoxides; Metabolomics; Neural stem cells