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

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


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.

Keywords: Anxiety; Arachidonic acid; Docosahexaenoic acid; Epoxides; Metabolomics; Neural stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fatty Acids, Omega-3*
  • Fatty Acids, Omega-6 / deficiency*
  • Fatty Acids, Omega-6 / metabolism
  • Female
  • Maternal Exposure / adverse effects*
  • Mice
  • Neocortex / growth & development*
  • Neocortex / pathology
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Neurogenesis*
  • Pregnancy


  • Fatty Acids, Omega-3
  • Fatty Acids, Omega-6