Life-long epigenetic programming of cortical architecture by maternal 'Western' diet during pregnancy
Cinquina V, Calvigioni D, Farlik M, Halbritter F, Fife-Gernedl V, Shirran SL, Fuszard MA, Botting CH, Poullet P, Piscitelli F, Máté Z, Szabó G, Yanagawa Y, Kasper S, Di Marzo V, Mackie K, McBain CJ, Bock C, Keimpema E, Harkany T (2019) Mol Psychiatry. 2019 Nov. doi: 10.1038/s41380-019-0580-4. [Epub ahead of print]
Abstract:
The evolution of human diets led to preferences toward polyunsaturated fatty acid (PUFA) content with 'Western' diets enriched in ω-6 PUFAs. Mounting evidence points to ω-6 PUFA excess limiting metabolic and cognitive processes that define longevity in humans. When chosen during pregnancy, ω-6 PUFA-enriched 'Western' diets can reprogram maternal bodily metabolism with maternal nutrient supply precipitating the body-wide imprinting of molecular and cellular adaptations at the level of long-range intercellular signaling networks in the unborn fetus. Even though unfavorable neurological outcomes are amongst the most common complications of intrauterine ω-6 PUFA excess, cellular underpinnings of life-long modifications to brain architecture remain unknown.Here, we show that nutritional ω-6 PUFA-derived endocannabinoids desensitize CB1 cannabinoid receptors, thus inducing epigenetic repression of transcriptional regulatory networks controlling neuronal differentiation. We found that cortical neurons lose their positional identity and axonal selectivity when mouse fetuses are exposed to excess ω-6 PUFAs in utero. Conversion of ω-6 PUFAs into endocannabinoids disrupted the temporal precision of signaling at neuronal CB1 cannabinoid receptors, chiefly deregulating Stat3-dependent transcriptional cascades otherwise required to execute neuronal differentiation programs. Global proteomics identified the immunoglobulin family of cell adhesion molecules (IgCAMs) as direct substrates, with DNA methylation and chromatin accessibility profiling uncovering epigenetic reprogramming at >1400 sites in neurons after prolonged cannabinoid exposure.
We found anxiety and depression-like behavioral traits to manifest in adult offspring, which is consistent with genetic models of reduced IgCAM expression, to suggest causality for cortical wiring defects. Overall, our data uncover a regulatory mechanism whose disruption by maternal food choices could limit an offspring's brain function for life.
FAB RESEARCH COMMENT:
Previous research in both animals and humans already indicates that the diets of mothers during pregnancy can affect the health of their offspring not just in infancy and childhood, but throughout life - and that these 'nutritional programming' effects apply to brain as well as body health.Higher rates of anxiety and depression are reliably found in the children of mothers who consume modern, western-type diets, rich in ultra-processed foods.
The aim of this study was to investigate some of the mechanisms behind these effects of early diet on mental health and wellbeing - and particularly the effects of a modern, western-type diet rich in omega-6 fats (found in vegetable oils), and relatively lacking in omega-3.
Results showed that when mothers eat omega-6-rich diets in pregnancy, this permanently changes brain's structure and connectivity in the children, who then go on to show more anxious and depressive traits even as adults.
These effects were traced to the de-sensitisation of certain brain cells and signalling systems to substances known as endocannabinoids. These are natural versions of cannabinoids (the active substances found in marijuana) that are made within the body from both omega-3 and omega-6 fatty acids.
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