Adverse effects of gestational ω-3 and ω-6 polyunsaturated fatty acid imbalance on the programming of fetal brain development

Abstract

Obesity is a key medical challenge of our time. The increasing number of children born to overweight or obese women is alarming. During pregnancy, the circulation of the mother and her fetus interact to maintain the uninterrupted availability of essential nutrients for fetal organ development. In doing so, the mother's dietary preference determines the amount and composition of nutrients reaching the fetus. In particular, the availability of polyunsaturated fatty acids (PUFAs), chiefly their ω-3 and ω-6 subclasses, can change when pregnant women choose a specific diet. Here, we provide a succinct overview of PUFA biochemistry, including exchange routes between ω-3 and ω-6 PUFAs, the phenotypes, and probable neurodevelopmental disease associations of offspring born to mothers consuming specific PUFAs, and their mechanistic study in experimental models to typify signaling pathways, transcriptional, and epigenetic mechanisms by which PUFAs can imprint long-lasting modifications to brain structure and function. We emphasize that the ratio, rather than the amount of individual ω-3 or ω-6 PUFAs, might underpin physiologically correct cellular differentiation programs, be these for neurons or glia, during pregnancy. Thereupon, the PUFA-driven programming of the brain is contextualized for childhood obesity, metabolic, and endocrine illnesses.

Keywords: arachidonic acid; dietary requirement; neurodevelopmental disorder; neuronal wiring; nutrient conversion.

FIGURE 1

A summary of synthesis and metabolic pathways for both ω‐3 and ω‐6 PUFAs. Intermediates for both ω‐3 and ω‐6 PUFAs are produced through elongation and desaturation steps of their respective essential precursors, α‐linolenic acid (α‐LA) and linoleic acid (LA), respectively. Rate‐limiting enzymes were color‐coded in light blue.

FIGURE 2

Neural progenitor subtypes and neurogenic stages during development of the cerebral cortex in mice. Cortical neurogenesis commences with the intense proliferation of progenitor cells in the ventricular zone (VZ) by embryonic day 10.5. During an initial phase, stem cells expand symmetrically, thus allowing the clonal expansion of radial glia. These progenitors then divide asymmetrically to generate neurons and glia, either directly or indirectly through intermediate progenitor cells or basal radial glia (alike tanycytes in the hypothalamus). Post‐mitotic neurons then migrate towards the pial surface and complete their differentiation in the cortical plate (CP). Neurogenesis is followed by a gliogenic phase with the generation of, for example, astrocytes. Arrows indicate lineage relationships as demonstrated by time‐lapse imaging and/or retroviral lineage tracing. CP, cortical plate; IZ, intermediate zone; MZ, marginal zone; SP, subplate; SVZ, subventricular zone; VZ, ventricular zone.

FIGURE 3

Metabolic pathways converting PUFAs into pro‐, as well as anti‐inflammatory mediators. Cyclooxygenase (COX) and lipoxygenase (LOX)‐dependent enzymatic processes are in grey.