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.