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

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. Stem Cells 2016;34:470-482 Omega-6 and omega-3 polyunsaturated fatty acids are essential nutrients. Although several studies have suggested that a balanced dietary omega-6:omega-3 ratio is essential for normal brain development, the underlying cellular and molecular mechanism is poorly understood. Here we shows that maternal consumption of an omega-6 rich/omega-3 poor diet impairs offspring's neocortical neuronal layer formation, and reveals its cellular and molecular mechanism; epoxy metabolites of omega-6 and omega-3 regulate the fate of neural stem cells (NSCs). We also show that these offspring demonstrate increased anxiety-related behavior. Our results raise important concerns regarding the increased consumption of such a modern diet, particularly during pregnancy.