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. STEM CELLS 2016;34:470-482 SIGNIFICANCE STATEMENTBalanced maternal intake of omega-6 and omega-3 polyunsaturated fatty acids is believed to be necessary for normal brain development; however, the precise neurodevelopmental outcome, the underlying mechanism, and neurodevelopmental impact on emotion in adulthood were poorly understood. Here we found that feeding pregnant mice an omega-6 rich/omega-3 poor diet impaired neocortical neurogenesis in the offspring. We also performed the first comprehensive quantification of lipid metabolites in the developing brain, and identified epoxy metabolites as key fate regulators of neural stem cells through neurosphere assays. We also found that these offspring exhibited more anxious behavior. This report underscores the dangers associated with the current dietary situation in many countries.

Maternal Nutritional Imbalance between Linoleic Acid and Alpha-Linolenic Acid Increases Offspring’s Anxious Behavior with a Sex-Dependent Manner in Mice

“…1B). We have also confi rmed that both food intake and body weight of the mother mice were unaff ected by the same diet as shown in our previous study (Sakayori et al 2016). These data indicate that maternal LA:ALA imbalance does not cause notable hypoplasia or obesity in their off spring.…”

“…Fatty acid composition of each diet was shown in Table 1. Regarding intake of oleic acid, which was abundant in the control diet, our previous study has shown that maternal intake of the control diet did not increase the level of oleic acid in the embryonic brain compared to that of the LA ex /ALA def diet (Sakayori et al 2016), suggesting that oleic acid in these diets did not have important roles in brain development. After two weeks, mice were mated, and pregnant mice were maintained on their respective diet through gestation and the first 10 days of lactation.…”

“…Fatty acid analysis was performed according to the method (Sakayori et al 2016). One day after behavioral analyses, the offspring maintained under free-feeding condition were deeply anesthetized.…”

“…Dietary LA and ALA are metabolized and detected as arachidonic acid (ARA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), respectively, in the brain (Sastry 1985). We have previously shown that maternal intake of the LA ex /ALA def diet increased the level of ARA and decreased that of DHA in the embryonic and postnatal offspring's brains (Sakayori et al 2016). Importantly, the ratio of n-6 to n-3 PUFAs in the adult brain shows positive correlation with fear memory (Yamada et al 2014).…”

“…We have recently shown that maternal consumption of a LA ex /ALA def diet caused abnormal brain development and increased anxiety-related behavior in the mouse offspring (Sakayori et al 2016). However, it is still unknown whether such maternal dietary imbalance causes different behavioral consequences between the male and female offspring and whether such offspring also show abnormal depressive behavior.…”