Neurodevelopmental and Behavioral Effects of Variations in Omega-3 Polyunsaturated Fatty Acids Levels in Vulnerable Populations

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19 Neurodevelopmental and Behavioral Effects of Variations in Omega-3 Polyunsaturated Fatty Acids Levels in Vulnerable Populations Danitsa Marcos Rodrigues*,†, Gisele Gus Manfro*,†, Patrícia Pelufo Silveira*,‡,§,¶ ⁎

Postgraduate Program in Neuroscience, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil †Anxiety Disorders Program for Child and Adolescent Psychiatry (PROTAIA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil ‡ Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canada § Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada ¶Sackler Program for Epigenetics & Psychobiology at McGill University, Montreal, QC, Canada

ABBREVIATIONS ADHD ALA ARA BBB DHA EFA EPA FA FADS IUGR LA LC-PUFA PUFA RCTs

attention-deficit hyperactivity disorder α-linolenic acid arachidonic acid blood-brain barrier docosahexaenoic acid essential fatty acids eicosapentaenoic acid fatty acids fatty acid desaturase gene intrauterine growth restriction linoleic acid long chain PUFA polyunsaturated fatty acid randomized controled trials

Omega Fatty Acids in Brain and Neurological Health https://doi.org/10.1016/B978-0-12-815238-6.00019-5

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INTRODUCTION Lipids are a varied group of compounds which have many important biological functions such as working as structural components, energy storage, and participating in signaling pathways.1 Lipids can be classified into five major subcategories including: fatty acids (FAs), triglycerides, phospholipids, sterol lipids, and sphingolipids. Five per cent of all human genes are devoted to lipid synthesis2 and the brain makes use of all five classes of lipids, containing the second highest concentration of lipids in the human body.3 Lipids are indispensable elements in the diet, both for the provision of energy (beta-oxidation of FAs), and for the supply of essential FAs. The brain is highly enriched in lipids and particularly long chain (>20 carbons) polyunsaturated fatty acids (LC-PUFAs), and this lipid composition substantially influences subjective perceptions, mood and emotional behavior, depending on a constant FAs supply. The long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) play an important role in the brain development and functioning,4–6 being essential in the modulation of neurochemical aspects and behavioral disorders related to stress response, mood regulation,5,7 and aggressive and impulsive behaviors. It also modulates neurotransmission,8 such as in the dopaminergic mesocorticolimbic pathway.9,10 The PUFAs influence the metabolic status, ­decreasing cardiovascular risk and other chronic diseases.5 The most abundant PUFA in the Western diet is the linoleic acid (LA), the omega-6 precursor that in addition to its action in mammalian reproduction, is vital for brain function.11 The LA is primarily sourced from practically every commercially manufactured food, mostly sourced from soybean oil, corn oil, and sunflower oil.12 Although LA is a metabolic precursor of arachidonic acid (ARA), the main dietary sources of ARA are red meat and dairy products including eggs.13 The α-linolenic acid (ALA), available in vegetable sources, is metabolized into eicosapentaeoic acid (EPA) and docosahexaenoic acid (DHA), which are considered the two major n-3 FAs. The EPA and DHA are associated with many important functions ­related to neural activity, such as cell membrane fluidity, neurotransmission, ion channels, enzyme regulation, gene expression, and myelination14 and their richest sources are marine fish and seafood.15 The omega-3 FAs mediate a variety of key neurotransmitter functions, including serotonergic responsivity, signal transduction, and phospholipid turnover.16,17 DHA alone is essential for optimal neural function18 composing approximately 30% of the phosphoglycerides19 and preferentially accumulating in growth cones, astrocytes, synaptosomes, ­myelin, and microsomal and mitochondrial membranes of neural tissue.20,21 It is known that adequate dietary intake of LC-PUFA is important for proper neural development during prenatal and postnatal periods up to 2 years of age22–24 Recent research ­suggests that dietary FAs, potentially influenced by genetic variations in enzymes involved in the FA metabolism, contribute to the central nervous system functioning in children with long-­ lasting outcomes. Children exposed to intrauterine growth restriction (IUGR) are at increased risk for chronic adult diseases demonstrating major effects on the incidence of chronic noncommunicable disease.25–27 In addition, research has shown that exposure to an adverse event in the fetal period is associated with childhood impulsivity and altered food preferences, with an increased consumption of palatable choices,28–31 which in the long term seems to contribute for obesity and metabolic risks in adulthood.32 An experimental study demonstrated that early stress associated with deficiency of n-3 PUFAs led, in adulthood, to obesity, insulin and

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LC-PUFAs Structure and Synthesis

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leptin resistance, being preceded by hyperphagia in adolescence.33 A recent research has shown that poor inhibitory control predicts childhood fussiness-type food intake and also suggests a protective effect of dietary n-3 PUFAs in vulnerable children.34 Therefore, it may be assumed that neurocognitive functions could be nutritionally programed early in life, resulting in increased risk for maladaptive behaviors. Understanding the importance of dietary FAs to human neurodevelopment is challenging because of the complexity of FAs metabolism, incomplete knowledge of the pathways of transfer and FA uptake in the brain, and the functional roles of DHA. Although lipids have multiple functions in the brain, including energy substrate and bioactive molecules, the most essential role for lipids in the brain is as components of cellular structural machinery. The lipid composition of the brain can be altered through long-term changes in the diet, which seems to produce consequences on cognitive and emotional behavior.35–38 These results suggest that increased availability of FAs in the brain can have a beneficial effect on neurodevelopment reflected in mental health and behavioral outcomes. In this review, we discuss the LC-PUFAs structure, synthesis, and accumulation focusing on the DHA importance in the context of neurodevelopment and brain functions.

LC-PUFAS STRUCTURE AND SYNTHESIS The FAs can be classified based on the number of double bonds present in side chains: saturated (SFAs, no double bonds), monounsaturated (MUFAs, a single double bond), and polyunsaturated (PUFAs, ≥2 double bonds); FAs can also be classified by their carbon chain length and the position of the first double bond on methyl terminal (omega; ω; or n − FAs).39 The PUFAs are subdivided into the omega- 3 (n-3) series (the first double bond is 3 carbons from the end carbon atom of the molecule) that are synthetically derived from LA, and the omega-6 (n-6) series that are derived from ALA, both 18‑carbon atom-containing FAs. These two essential fatty acids,40 LA and ALA, cannot be synthesized in the body and must be obtained from diet and act as precursors of other FAs.41 In the liver, the LA and ALA fatty acids may be desaturated and elongated to become other LC-PUFAs. LA can be converted sequentially via a biosynthetic pathway into other omega-6 fatty acids, the gamma linolenic acid (GLA), and the ARA and dihomogammalinolenic acids (DGLA). Similarly, ALA is converted into LC n-3 PUFAs such as EPA and DHA. The n-3 and n-6 PUFAs share the same enzymes and compete for their desaturation and elongation on the endoplasmic reticulum.42 Synthesized fatty acids can be transported into the blood as lipoproteins. These two classes of essential fatty acids (EFA) are not interconvertible, are metabolically and functionally distinct, and often have important opposing physiological functions. The balance of EFA is important for good health and normal development: recent studies indicate that human beings evolved on a diet with equal amounts of n-6 and n-3 PUFAs43,44; a high ratio of around ~16: 1 is found in today’s typical Western diets.45 A high dietary intake of n-6 fatty acids as occurs today promotes many inflammatory and autoimmune diseases,46 whereas increased levels of n-3 PUFAs (lower n-6/n-3 ratio) exert suppressive effects.47,48 This balanced ratio of n-6 to n-3 is critical to human development during pregnancy and lactation in the prevention of chronic diseases and in their management.49,50 Considering the proportion and the opposing effects of n − 3 C.  DIET AND BRAIN DISEASE TREATMENT AND PREVENTION

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and n − 6 PUFAs, especially dietary LA and ALA play a significant role in regulating body homeostasis,51 or by locally acting bioactive signaling lipids called eicosanoids derived from ARA, EPA, and DHA.52 In animals, primarily in the endoplasmic reticulum of liver cells, biosynthesis of LC-PUFAs starts with desaturation of LA and ALA, thus generating γ-linolenic acid (GLA) and stearidonic acid (SDA). By a specific elongase these desaturated FAs are elongated to yield dihomo-γ-linolenic acid (DGLA) and eicosatetraenoic acid (ETA) respectively. Finally, a desaturase, by adding a carbon double bond and carrying out one more desaturation produces ARA and EPA, respectively. By a desaturase, GLA, DHGLA, and ARA can be converted to SDA, ETA, and EPA, respectively. In mammals EPA undergoes two successive elongation cycles. First, docosapentaenoic acid (DPA, clupanodonic acid) is generated. Then tetracosanolpentaenoic acid is produced which then yields tetracosahexaenoic acid (THA) by desaturation. This PUFA is then subjected to β-oxidation by which its chain is shortened by two carbons to yield very-longchain (VLC, FAs containing 22 or more carbon atom) PUFA DHA, the final product.53 Since members of n-6 and n-3 PUFAs compete for corresponding desaturase and elongase enzymes, bioconversion of LA and ALA to their respective LC and VLC-PUFAs in humans depends on the ratio of ingested n-6 and n-3 FAs, with the highest rate of formation of EPA and DHA occurs when a 1:1 ratio of LA and ALA is present.54 Compared to ALA and EPA, DHA supplementation is the most effective way to improve body DHA levels. It is important to note that genetic variation in genes encoding FAs desaturases also influences essential fatty acid metabolism and may increase requirements in some individuals. Recent studies have demonstrated that the metabolic capacity of the LC-PUFA biosynthetic pathway differs among individuals and populations, suggesting that genetic and epigenetic variations are highly associated with the levels of LC-PUFAs produced in human circulation, cells, and tissues.55,56 Advances in nutrigenomics allowed to identify three factors involved in the regulation of the conversion of ALA and LA to n-3 LC-PUFAs and n-6 LC-PUFAs, such as (i) high heritability of LC-PUFA biosynthetic capacity (i.e., strong genetic regulation), (ii) marked epigenetic regulation (i.e., potential gene environment interplay in regulation), and (iii) differences in dietary PUFA intake (i.e., variability in the environment).57 Understanding the relationship between these factors will enable the prediction of physiological and pathological outcomes of human nutrition and potentially guide nutritional recommendations and interventions to individuals and populations throughout the life span. In a recent study, our group created a multilocus genetic score from the fatty acid desaturase (FADS) gene cluster and investigated if these genes moderated the association between being born small for gestational age and having altered eating behaviors in childhood.58 The fatty acid desaturase (FADS) 1 and 2 genes are important for PUFAs metabolism because they code for fatty acid desaturase enzymes D5D and D6D, which are responsible for the synthesis of highly unsaturated fatty acids such as eicosopentaenoic and docosahexaenoic acids (synthesized from α-linolenic acid), and arachidonic acid (synthesized from LA). Several SNPs in the FADS1–2 gene complex influence PUFAs short, medium, and long-term plasma availability.59–61 We observed interactions between being born small for gestational age and the genetic score on obesogenic eating behaviors, suggesting that genetic markers associated with higher plasma PUFAs levels in childhood in these children relate to a more adaptive eating behavior with no effects on body mass index (BMI).58 The findings of vulnerability and protection factors through eating behavior and PUFAs consumption have potential clinical applications in primary prevention of chronic metabolic diseases in this population.

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The LC-PUFAs and their metabolites are present in practically all cells and tissues of the body and act as potent signaling molecules that impact a wide range of physiologic and pathophysiologic processes and can also be converted to a diverse family of metabolites including m ­ ultiple forms of prostaglandins, thromboxanes, hydroxyeicosatetraenoic acids, epoxyeicosatrienoic acids, leukotrienes, lipoxins, resolvins, protectins, maresins, and endocannabinoids.62–67 The synthesized and/or dietary-derived FAs are taken up from circulating blood into the brain through the blood-brain barrier (BBB). The transport of fatty acids from blood into the brain is a complex mechanism due to the presence of tight junctions in the BBB and has been the subject of research.68 Once FAs are within the brain, they can be subsequently converted into various metabolites, such as eicosanoids and endocannabinoids. Eicosanoids are hormone-like compounds that function locally and are produced from either ARA or EPA/DHA released from membrane phospholipids. Eicosanoids have important and complex functions in the brain and participate in the control of numerous physiological systems, involved in the regulation or halting of blood flow (prostacyclin and thromboxanes, respectively), in the anti-­ inflammatory processes (prostaglandins), and tissue homeostasis.11,69 Eicosanoids have been involved in long-term potentiation, spatial learning, synapse plasticity, and sleep induction; they also reduce neuroinflammation and have neuroprotective properties.16 The reports suggest that decresead n-3 PUFAs levels during critical stages of neurogenesis may alter parameters of cell signaling, including within neurotransmitter systems, resulting in impairments in behavior, learning, and cognition.70–73 Low intake diets of n-3 PUFAs result in reductions of DHA in the brain with simultaneous increase in the turnover of ARA to eicosanoids,74 which can be reverted by the supplementation of n-3 PUFAs. Endocannabinoids are another important class of PUFAs, which are derived from ARA, acting in the central nervous system to modulate synaptic plasticity, neurotransmitter release, and have protective actions.75 It is well established that higher levels of ARA are associated with increased ­production of endocannabinoids,76 but it remains unclear if the diet fat intake could alter brain endocannabinoid production.

LC-PUFAS BRAIN ACCUMULATION About 50%–60% of the dry weight of an adult brain is comprised of lipid and at least 15%–30% of the lipid content is made up of LC-PUFAs.77 These fatty acids are highly spe­ cialized with particular metabolic functions and unique biophysical properties. The lipid brain components consist mainly of phosphoglycerides and cholesterol rich in ARA and DHA.78 The DHA is the most abundant n-3 fatty acid in the mammalian brain and its level in the brain membrane lipids is altered by the type and amount of fatty acids in the diet and with life stage, increasing with age.79 The DHA accumulation in the brain starts during the brain growth spurt in the intrauterine stage and continues up to 2 years of age, then maintaining high levels throughout the life span.80 The intrauterine LC-PUFAs supply derives mainly from the maternal circulation across the placenta81 and postnatal accumulation on infant tissues is supported by maternal transfer of LC-PUFAs through breast milk.82 The embryo requires approximately 40–60 mg of n-3 LC-PUFAs per kilogram of body weight per day during the third trimester of pregnancy.83 The DHA and ARA, the most abundant LC-PUFAs in the brain and retina play a special and distinct role in neurodevelopment, requiring ­specific

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balance ratios for optimal mental health.84 The last trimester of pregnancy appears to be a critical period of time for DHA and ARA accretion in the fetal brain.85 Importantly, ­experimental ­evidence suggests that DHA and ARA accumulation in the neural tissue is regulated by distinct mechanisms, showing also that DHA levels vary with diet but ARA levels remain relatively constant during early childhood through adolescence.86

LC-PUFAS IN BRAIN DEVELOPMENT AND FUNCTION Maternal diet is a major determinant of offspring health.26,87,88 The dietary-induced modifications appear to directly affect the fetal and childhood neurodevelopment,89,90 and this may have a long-term impact on the onset of neurodegenerative disease later in life.91 Thus, the quantity and quality of the fatty acids ingested can significantly influence a wide range of brain functions, including maintence of axons and dendrites, cell shape, lipid raft formation, G protein-coupled signaling (leading to altered gene expression), polarity, neuronal plasticity, dopamine storage, vesicle formation and transport, glucose uptake, and hypothalamic regulations.92 The PUFAs have several important behavioral and neurochemical roles in the central nervous system, such as: (i) regulation of energy intake and glucose homeostasis, (ii) m ­ odulation of neuroinflammatory mechanisms, and (iii) support and regulation of neurotransmission.41 DHA affects the blood–brain-barrier function, neuronal membrane fluidity, and also regulates neurotransmission systems,93,94 with a significant effect on neuronal membrane dynamics and transporter, receptor, and neurotransmitter functions.77 These mechanisms of action provide support for possible neuroprotective effects of n3-PUFAs on mental health outcomes. Experimental evidence has investigated the nutritional effects of PUFAs, demonstrating that its consumption is associated with neurogenesis and neuroprotection in animals supple­ mmented with DHA.95–97 Other animal studies examined declines in memory functioning related to deficits in n3-PUFA in the diet, which could be fully or partially restored by n3-PUFAs correction.98 Recent work with n3-PUFAs supplementation in nonhuman primates has demonstrated reduction in anxiety levels and an enhanced cognitive performance.99 Prematurely born infants are at particular risk for LC-PUFA deficiency and its supplementation in breast milk and formula has been suggested to improve both cognitive and visual development in these children.100 A recent review showed conflicting results in supplementation of DHA for preterm infants with inconsistent long-term improvements and supporting benefits only at the short-term.101 Moreover, interventions linking early nutrition and cognitive development have shown ambiguous evidence of benefits associated with LC-PUFAs s­ upplementation. A recent meta-analysis does not reveal that LC-PUFA supplementation has a significant impact on the level of intelligence in low birth weight infants.102 Another m ­ eta-analysis concluded that there were no beneficial effects or harms of LC-PUFA ­supplementation on neurodevelopmental outcomes and no consistent benefits on visual acuity on full-term infants.103 Recent reports have demonstrated that n-3 PUFAs exert a protective effect in IUGR children by limiting impulsive eating.34,104 Thus, for the newborn infants, the recommendation that has an unequivocal benefit in relation to the functional effects of LC-PUFA supplementation in childhood is that which improves the rate of development of visual acuity.105

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The brain DHA deposition continues to increase in childhood, and although the accretion rate declines, the incorporation of DHA is still high at least during the preschool years. Once high levels of DHA are achieved in the brain, these are maintained during later life and this presumably also depends on an optimal dietary supply, as dietary intake of DHA from fish in adults has been shown to be the dominant determinant of DHA levels in various lipid pools.24 High-quality evidence demonstrates that increasing children’s dietary intake of the n-3 LC- PUFAs may improve concentration, reduce disruptive behavior, and lead to better reading and spelling, with benefits in cognitive performances in children and adolescents with ADHD.106,107 A randomized controled trial (the DOLAB I study) provided the first good evidence for the benefits of DHA, with significant improvement over placebo on behavior and learning among healthy but under-performing children, aged 7–9 years.108 Surprisingly, the DOLAB II study did not replicate the original findings of significant, positive effects of omega-3 DHA on either learning or behavior.109 A recent methylome-wide study suggests that altered early life methylation in the peroxisomal network, which is essential in DHA formation, could contribute to an impulsive phenotype, including Attention-deficit/hyperactivity disorder (ADHD) in children at age 7.110 Despite all the contradictory results explained in part by the variety of interventions and part by the modulating effects of age and gender, it should be noted that children considered at risk, like IUGR individuals, might benefit the most from supplementation of LC n3-PUFA with regard to neurodevelopmental outcomes (e.g., memory, non-verbal cognitive development, processing speed, visual-perceptive capacity, attention, and executive function) and school achievement (e.g., reading and spelling). We have recently shown that a genetic variant of the PLIN4 gene (rs8887) - associated with enhanced sensitivity to the protective effects of dietary n-3 PUFAs on metabolic outcomes111 – interacts with fetal growth and influences impulsivity in childhood.112 In humans, the perilipin gene (PLIN) has been localized to chromosomal location 15q26,113 a region previously linked to obesity, hypertriglyceridemia, and diabetes.114,115 The PLIN4 protein, previously referred to S3–12, belongs to the PAT family.116 In adulthood, full brain development is already achieved. However, at this stage of life stressful events can alter mood states and cognition, increasing the susceptibility to psychopathologies.117 Clinical trials on supplying n-3 PUFAs among healthy young adults report improved effects on decision-making118 and attentional funtion,93 contrasting to other with no consistent evidence for significant effects on memory and cognitive functioning119 and for negative effect and impulsivity traits.120 The studies in the elderly population have contradicting results: a meta-analysis of fish consumption indicates that n-3 LCPUFAs was associated with protection against neurocognitive deficits121 but other meta-analyses assessments have described no evidence for the efficacy of omega-3 supplements in the treatment of Alzheimer’s disease122 which was corroborated by another randomized study that found no improvement in the global cognitive function in institutionalized elderly people.123 Omega-3 FAs seem to play a role in the regulation of the stress-response, influencing the activity of the hypothalamic–pituitary–adrenal (HPA) axis. It was proposed that glucocorticoid receptor (GR) sensitivity contributes to n-3 PUFAs deficiency-related emotional problems.124 Furthermore, data relates consequences of maternal low PUFA intake and the development of neuropsychiatric disorders. Maternal malnutrition has been linked to the development of different neuropsychiatric disorders in infancy [Autism Spectrum Disorder (ASD)],125

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in childhood [Attention deficit disorder (ADHD)],126 in adolescence [Schizophrenia spectrum disorders (SSD)]127 or in adulthood (depression and anxiety).128 Thus, it is possible to correlate altered stress response following maternal poor intake of n-3 PUFAs129 with many psychiatric diseases, particularly depression130 and psychosis.131 It has been shown in animal and human trials that n-3 PUFAs may improve memory performance. Patients with Major Depression Disorder (MDD) have decreased intake of n-3 PUFAs and limited metabolism when compared to healthy controls.132 Affective disorder and Schizophrenia (SZ) are characterized by emotional and cognitive dysfunction encompassing several domains. Cognitive dysfunction is closely related to several impaired functioning and deteriorating health conditions. Epidemiological studies show that the dietary intake of n-3 PUFAs through fish consumption is inversely correlated with the prevalence of depression, thus suggesting that n-3 PUFAs have a protective effect.133 Individuals with bipolar disorder (BD), MDD, and SZ are thought to have a disturbed lipid metabolism: the levels of DHA, ALA, and EPA in erythrocytes of these patients seem to be lower compared to healthy controls.5 Importantly, there is evidence of a higher prevalence of bipolar spectrum disorders ­associated with lower fish consumption, added to the finding that first-degree relatives of these patients showed a trend toward lower levels of n-3 PUFAs, suggesting a connection between FAs with BD.134 A recent prospective study showed that the n-6/3 PUFA ratio, used as a risk biomarker,135 was associated with an increased ratio of mood disorders in young people exhibiting an high risk phenotype.136 Abnormalities in phospholipid metabolism are suggested to be involved in the pathogenesis of SZ. Accordingly, there have been several investigations of the n3-PUFA content of membrane phospholipids in SZ. The literature shows that n3-FAs provide numerous health benefits and changes in their concentration are connected to a variety of psychiatric symptoms and disorders including stress, anxiety, cognitive impairment, mood disorders, and schizophrenia but results at this moment are non-conclusive.137,138 Further studies are necessary to confirm n-3 FAs’ supplementation as a potential rational treatment in psychiatric disorders.

CONCLUSIONS The role of n-3 PUFAs in healthy brain development has been explored through intense scientific research and because of its importance for public health. Regarding the supplementation of n-3 PUFAs, there are some promises and nonconclusive evidence for clinical protective benefits for affective, cognitive disorders and for neural health, particularly in vulnerable individuals. Given the crucial role of DHA in neuropsychiatric diseases involved in altered prefrontal cortex (PFC) and subcortical circuitries, special attention should be paid to define the best dietary options. Investigations on mental health and disease highlighted the importance of lipidomics for the identification of risk biomarkers in subjects with high-risk phenotypes, revealing associations between membrane PUFA levels and mood disorders. As shown, the available evidence is not always consistent, probably for the heterogeneity of the methods and samples in the original studies, which often had small and not homogeneous sample sizes, different selection criteria, diverse subtypes and dosage of LC-PUFAs as well as duration of supplementation. Another limiting methodological factor is the variable nature of the neuropsychological outcomes. It is noteworthy that the evidence is

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still emerging but that randomized controlled trials (RCTs) have been inconsistent with many design limitations. A major challenge is to conduct rigorous RCTs to provide the evidence for dietary recommendations for DHA. Despite these limitations, results seem to highlight the beneficial role of n-3 PUFAs under certain conditions. Based on epidemiological evidence, the nutritional recommendations by health agencies are to reduce excessive intake of omega-6 PUFAs, and avoid the high omega-6/ omega-3 ratio of the current western diets. Furthermore, intake of large amounts of fish combined to natural antioxidants is strongly recommended. This guideline can be translated into a weekly ingestion of 2–3 portions of oily fish or a daily 450–500 mg of EPA + DHA for general health improvements in the adult population.139 The Food and Agriculture Organization (FAO) of the United Nations jointly with the World Health Organization (WHO) and the European Food Safety Authority (EFSA) recommend a daily EPA + DHA intake of at least 250 mg; increased amounts of up to 1 to 3–4 g/day of omega-3 LC-PUFAs should be ingested during pregnancy and lactation or to prevent most cardiovascular, neurodegenerative, and pro-inflammatory disorders140. Because of its differentiated characteristics of low conversion rates and participation in numerous neural processes (neurotransmission, neurogenesis, and protection against oxidative stress), DHA is one of the main nutrients capable of acting in neural programming, maximizing neurodevelopment, and minimizing neurodegeneration. Continued research into the need for adequate n-3 FAs for optimal brain development and function may better elucidate dietary conditions and diet-gene or diet-disease interactions that present a risk for brain damage.

CONFLICT OF INTEREST The authors declare no conflict of interest.

FUNDING Researchers were funded by Brazilian National Council for Technological and Scientific Development (CNPq), Coordination for the Improvement of Higher Education Personnel (CAPES), Ludmer Centre for Neuroinformatics and Mental Health, JPB Network on Toxic Stress.

References 1. Calder  PC. Functional roles of fatty acids and their effects on human health. JPEN Journal of Parenteral and Enteral Nutrition. 2015;39(1 Suppl):18S–32S. 2. van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008;9(2):112–124. 3. Hamilton JA, Hillard CJ, Spector AA, Watkins PA. Brain uptake and utilization of fatty acids, lipids and lipoproteins: application to neurological disorders. J Mol Neurosci. 2007;33(1):2–11. 4. Schuchardt  JP, Huss  M, Stauss-Grabo  M, Hahn  A. Significance of long-chain polyunsaturated fatty acids (PUFAs) for the development and behaviour of children. Eur J Pediatr. 2010;169(2):149–164. 5. Balanza-Martinez  V, Fries  GR, Colpo  GD, et  al. Therapeutic use of omega-3 fatty acids in bipolar disorder. Expert Rev Neurother. 2011;11(7):1029–1047.

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Further Reading 141. Moreira DKT, Ract JNR, Ribeiro APB, Macedo GA. Production and characterization of structured lipids with antiobesity potential and as a source of essential fatty acids. Food Res Int. 2017;99(Pt 1):713–719.

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