A study team at MedUni Vienna’s Center for Brain Research has found that high-fat maternal diets can cause life-long changes in the brain of the unborn offspring.
When a pregnant woman consumes a diet high in polyunsaturated omega-6 fatty acids, her body produces an excess of endogenous cannabinoids (endocannabinoids), which overload the fetal organism and impair the development of healthy brain networks.
Such a mechanism seems relevant to pathologies such as ADHD, schizophrenia and anxiety disorders.
It is unlikely that such damage can simply be reversed by a subsequent change of diet.
The study, which has been published in the journal ‘Molecular Psychiatry’, examined in cell- and mouse models, how intake of high-fat diets throughout pregnancy (rich in polyunsaturated omega-6 fatty acids) impacts fetal brain development.
When the mother consumes a high-fat diet during pregnancy, both mother and child produce an excess of endocannabinoids, which can even be transferred from the mother to the fetus.
As a result, nerve cells will no longer be able to correctly integrate into the brain to fulfil their prospective functions.
The study also shows that these impairments persist throughout life of the affected offspring and can serve as critical triggers to developing psychiatric disorders later in life.
Endocannabinoids are substances produced by the body itself.
They are part of the endocannabinoid system, which serves as a fundamental communication system in the brain as well as other organs.
In the adult brain, endocannabinoids limit communication (‘chemical neurotransmission’) between neurons by binding to cannabinoid receptors. In the developing brain, endocannabinoids determine when and where neurons are positioned and if they form connections with each other.
This means that any substance that influences either endocannabinoid levels or directly affects cannabinoid receptor function will inevitably impinge upon brain development.
“By acting like a ‘stop signal’, a prolonged overload of endocannabinoids impairs the developmental program of many neurons in the fetal brain,” explains principal investigator Tibor Harkany, Head of the Department of Molecular Neurobiology at MedUni Vienna’s Center for Brain Research. “Persistently muting cannabinoid receptors, we believe, alters the epigenetic programs of affected nerve cells.
Epigenetic mechanisms determine the pattern of gene expression in any cell. If damaged, the cells are no longer able to carry out their functions adequately.
This will limit their ability to adapt their proper shape or select communication partners because of a shortage of proteins required as cellular building blocks or signalling molecules.”
On a large scale, an inhibition to the creation of connections between brain cells will impair the formation of important neuronal networks, the functional building blocks of the brain.
This can result in psychiatric disorders such as ADHD, schizophrenia and anxiety disorders.
The study also shows that these impairments persist throughout life of the affected offspring and can serve as critical triggers to developing psychiatric disorders later in life. The image is in the public domain.
Damage is likely irreversible
“As far as we can tell, the pathological changes of nerve cells we have found are irreversible,” explains Harkany. “It is of limited use to changing to a healthy, low-fat diet after birth when the damage has already been done.”
Although the study is based on animal models, Harkany stresses that other studies already indicate harmful effects in humans, while this report identifies the very molecular mechanisms that can also apply to humans.
Is treatment still possible?
“In order to find effective treatments, we will need active agents that directly intervene in the epigenetic regulation of gene expression,” explains lead author Valentina Cinquina.
“We have not yet trialed any such drugs but it is an exciting prospect to work on such interventions, which can perhaps be used safely and effectively in the future.” For example, so-called histone deacytylase Inhibitors (HDACs) are extensively tested for their treatment potential in Alzheimer’s disease and various cancers.
Maternal mental health problems are increasingly recognized as major public health concerns, due to high prevalence rates worldwide and poor outcomes affecting not only mothers but also new-borns and other family members .
Postpartum depression (PPD) is the most common complication related to childbearing; approximatively 10 to 20% of mothers experience a depressive episode following delivery in developed countries [2,3].
Beyond maternal suffering [4,5], PPD affects the mother-baby interaction in a negative way [6,7]. This situation is likely to have short and long-term adverse consequences on several aspects of the child development, including emotional, cognitive and behavioural skills [8,9].
Management for mood disorders is challenging due to its multifactorial aetiology, ranging from biological pathways to psychosocial adjustment.
The evidence base is still inadequate to fully support clinical decision-making about pharmacotherapy.
The effectiveness of antidepressants has been questioned for a few years, and data concerning the prevention of postpartum depression remains very limited [10,11,12]. Furthermore, the benefit-risk ratio associated with depression treatment remains to be further evaluated in pregnant and lactating women .
Such a situation has drawn attention to lifestyle factors for the prevention and treatment of mental illnesses. The new field of nutritional psychiatry provides compelling support for nutrition as a modifiable risk factor .
Omega-3 polyunsaturated fatty acids (n-3 PUFA) are thought to be particularly relevant to mental health as they are critical for brain development and function throughout all stages of life .
Notable interest in the role of n-3 PUFA in maternal mental health was triggered by a cross-national ecological study showing an association between both lower seafood consumption and lower docosahexaenoic acid (DHA) content in mothers’ milk and higher rates of postpartum depression .
Some observational studies also reported that low n-3 PUFA intake increased the risk of maternal mood disorders [17,18]. Da Rocha et al. found a 2.5-fold higher prevalence of postpartum depressive episodes in women who had a dietary n-6/n-3 ratio greater than 9 in the first trimester of pregnancy . However, other studies have not been able to detect such a link [20,21].
The current literature suggests that the maternal diet does not satisfy the increased demands for long-chain polyunsaturated fatty acids (LCPUFA) during pregnancy and lactation. Food surveys reported insufficient dietary intakes of n-3 LCPUFA among a large portion of European pregnant women .
Longitudinal studies focusing on fatty acids markers observed a significant decline in maternal DHA status throughout pregnancy with a slow normalization of postpartum levels [23,24]. Maternal DHA status seems to normalize over a period of 6 months to 1 year after delivery.
Subsequent depletion in maternal DHA stores and a lack of recovery postpartum have been associated with an increased risk of postpartum depression [25,26]. Therefore, an omega-3 index (erythrocyte eicosapentaenoic acid (EPA) plus DHA expressed as weight percentage of total fatty acids) lower than 5% in late pregnancy was suggested as a biological risk factor for PPD .
There is considerable biological/mechanistic evidence linking n-3 PUFA to mental health. Omega-3 polyunsaturated fatty acids and their mediators would be able to regulate several biological processes involved in the development of depression, including neurotransmission, neuroinflammation and neuroplasticity . DHA content in brain phospholipids contributes to membrane fluidity, which would affect monoamine neurotransmission as well as membrane-bound proteins and cellular signal transduction. In animal models, chronic n-3 PUFA deficiency altered the storage and release processes of serotonergic and dopaminergic neurotransmitters . The sodium-potassium pump (Na+/K+-ATPase) is an example of a membrane protein whose activity is specifically related to the DHA composition. A disturbance of its activity has been associated with mood disorders [29,30].
Long-chain n-3 PUFA are hypothesized to prevent or decrease neuroinflammatory processes which have been more recently connected with depression [31,32]. Many other possible mechanisms, including modulation of gene transcription via peroxisome proliferator-activated receptors (PPARs) and regulation of the production of neuroprotective factors, would also explain the anti-depressant effects of n-3 PUFA.
While accumulating biological evidence supports the hypothesis that PUFA status plays a role in maternal mental health, results from well-designed observational prospective studies are contradictory and inconsistent [1,33].
Fatty acids have recently been recognised as the nutritional biomarker most frequently related to pre- and postnatal depression, but the number of such studies is still limited . To our knowledge, only five studies [27,35,36,37,38] have assessed maternal erythrocyte fatty acid composition despite it appearing to be the most appropriate measure of long-term incorporation of fatty acids in tissues [39,40].
A particular consideration in designing a cohort study is the timing of exposure measurement. We previously demonstrated that n-3 LCPUFA deficiency could occur as soon as the early stages of pregnancy .
Considering the importance of nutrient status for pregnancy outcomes, we tested the hypothesis that low maternal erythrocyte n-3 PUFA levels at the beginning of pregnancy may be a risk factor for postpartum depression.
In conclusion, these findings supported the hypothesis that low n-3 PUFA status and imbalance between n-6 and n-3 PUFA status in early pregnancy increase the risk of postpartum depression during the year after childbirth. Prevention of maternal depression should be an important public health priority.
Management of maternal n-3 PUFA deficiency can be a simple, safe, and cost-effective strategy at the early stages of pregnancy (and ideally in preconception care). Benefits could be expected not only for the mother, but also the future child, with potential advantages beyond the sphere of maternal mental health alone [68,69].
Faced with a multifactorial disease, n-3 PUFA interventions will probably have to be integrated into a global management, mixing nutritional, psychotherapeutic and/or pharmacological strategies.
Medical University of Vienna
Tibor Harkany – Medical University of Vienna
The image is in the public domain.
Original Research: Closed access
“Life-long epigenetic programming of cortical architecture by maternal ‘Western’ diet during pregnancy”. Valentina Cinquina, Daniela Calvigioni, Matthias Farlik, Florian Halbritter, Victoria Gernedl, Sally L. Shirran, Matthew A. Fuszard, Catherine H. Botting, Patrick Poullet, Fabiana Piscitelli, Zoltán Máté, Gábor Szabó, Yuchio Yanagawa, Siegfried Kasper, Vincenzo Di Marzo, Ken Mackie, Chris J. McBain, Christoph Bock, Erik Keimpema, Tibor Harkany.
Molecular Psychiatry doi:10.1038/s41380-019-0580-4.