Effects of early-life malnutrition on neurodevelopment and neuropsychiatric disorders and the potential mechanisms

Accepted Manuscript Effects of early-life malnutrition on neurodevelopment and neuropsychiatric disorders and the potential mechanisms

Xintian Yan, Xinzhi Zhao, Juxue Li, Lin He, Mingqing Xu PII: DOI: Reference:

S0278-5846(17)30726-1 doi:10.1016/j.pnpbp.2017.12.016 PNP 9310

To appear in:

Progress in Neuropsychopharmacology & Biological Psychiatry

Received date: Revised date: Accepted date:

27 August 2017 21 December 2017 24 December 2017

Please cite this article as: Xintian Yan, Xinzhi Zhao, Juxue Li, Lin He, Mingqing Xu , Effects of early-life malnutrition on neurodevelopment and neuropsychiatric disorders and the potential mechanisms. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Pnp(2017), doi:10.1016/ j.pnpbp.2017.12.016

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ACCEPTED MANUSCRIPT Effects of early-life malnutrition on neurodevelopment and neuropsychiatric disorders and the potential mechanisms

XintianYana,b , Xinzhi Zhaoc,d , Juxue Lie, Lin Hea,b,c, MingqingXua,b,* a

Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric

Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, and Shanghai

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Jiao Tong University School of Medicine, Shanghai, China.

Collaborative Innovation Center for Genetics and Development, Institutes of Biomedical

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Sciences, Fudan University, Shanghai, China;

Children Hospital of Fudan University, Shanghai, China; Shanghai Key Laboratory of

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Prevention and Intervention of Birth Defects, Shanghai, China;

Department of Biochemistry and Molecular Biology, Key Laboratory of Human Functional

Correspondence should be addressed to Prof. Mingqing Xu, Bio-X Institutes, Key Laboratory for

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Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China;

the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai

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Jiao Tong University, Shanghai, China. E-mail address: [email protected];or [email protected]

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Number of Tables: 6

Number of Figures: 7

Number of references:187

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Abstract Lines of evidence have demonstrated that early-life malnutrition is highly correlated with neurodevelopment and adulthood neuropsychiatric disorders, while some findings are conflicting with each other. In addition, the biological mechanisms are less investigated. We systematically reviewed the evidence linking early-life nutrition status with neurodevelopment and clinical observations in human and animal models. We summarized the effects of special nutritious on neuropsychiatric disorders and explored the underlying potential mechanisms. The further understanding of the biological regulation of early-life nutritional status on neurodevelopment might shed light on precision nutrition at an integrative systems biology framework. Keywords: Early life, Malnutrition, Neurodevelopment, Neuropsychiatric disorders, Genetic mutation, Epigenetics, Precision nutrition

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1. Introduction

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During the early stage of human development, fetus obtains various nutrients from the mother through the placental and the umbilical cord. As a consequence, the growth and development of the fetus depend on its mother’s nutritional status, which undoubtedly plays a crucial role in the development of offspring. As a regulatory factor, nutrition affects gene expression with various mechanisms at different levels, such as epigenetic modification, small RNA regulation, and chromatin remodeling. A large number of studies have shown that maternal dietary nutrients, including protein, fat, vitamins, metal elements, can regulate the expression of many genes which impact neuro-development, and then contribute to the susceptibilities of neuropsychiatric disorders [1]. In this review, we firstly focused on human population-based epidemiological findings, and then evaluated early-life animal model studies to disclose the possible effects of early-life malnutrition on the brain development and its related neuropsychiatric disorders, followed with exploring the potential biological mechanisms behind the effects. Finally, we discussed the possible approaches to disclosing the potential mechanisms to point out our future efforts.

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2. Epidemiological findings

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Malnutrition may arise from internal causes, such as eating disorders, or external causes, such as famine. The increased eating disorders are mainly reported from some developed countries due to cultural pressure on the drive for slim [2], and longstanding food deprivation usually happens in some developing countries [3], both of which are becoming a public health problem. Eating disorders (ED) include anorexia nervosa(AN) and bulimia nervosa (BN). A longitudinal cohort study reported that mothers with a history of AN or BN would give birth to infants with reduced head circumference and delayed neurocognitive development, particularly expressive language skills at the age of five [4,5]. However, the underlying mechanisms might not only due to undernutrition but also the maternal stress during pregnancy [6]. The first series of studies regarding the effects of famine exposure on health outcomes were reported based on the Dutch Hunger Winter of 1944–1945 cohorts. These epidemiological findings are in general strongest for mental disorders, especially for neural tube defects (NTDs) [7] and schizophrenia [8-10]. But the effects of toxic food, such as tulip bulbs, and the physiological stress under the exceptionally cold winter on the brain development haven’t been confirmed [11,12]. Later on, the second series of studies were launched recently by us based on the 1959-1961 Chinese famine cohorts, which were consistent with the Dutch famine research[13,14] and successfully addressed several competing explanations for the Dutch findings [15]. There are also many other reports suggesting plausible links between prenatal undernutrition and neurodevelopmental outcomes. including those about poorer cognitive function [16], language delay [17], psychiatric

ACCEPTED MANUSCRIPT diseases in offspring [18]. These studies strengthened the opinion that early-life malnutrition had negative effects on the neural development and neuropsychiatric disorders.

3. Animal model-based research

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4.Specific nutrients in early life

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Animal-based experiments have the potential to reveal the relationships among early-life malnutrition, alterations in brain structures, and the possible behavioral and cognitive problems [3, 19]. Due to the extremely high similarity to human beings in the general brain development , rodents have been used to understand the process of brain development in early life [11, 20]. Many animal studies exhibit that malnutrition in early life may affect the morphology [24, 25], neurochemistry [26], and neurophysiology [27] of the hippocampal formation, the main brain region associated with spatial learning and memory [21-23]. Some studies also demonstrate that prenatal or neonatal nutritional deficiency may epigenetically reprogram some gene expression patterns related to adult behavior, learning and memory [3]. Table 1 summarizes the effects of early-life nutritional restriction on the changes of the brain structure and behavior.

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We have summarized the importance of global nutrients on the neurodevelopment, however some specific nutrients seem to be more important than others during the late fetal and neonatal periods. These specific nutrients include four types: 1) energy-yielding nutrients: including protein and long-chain polyunsaturated fatty acids (LC-PUFAs); 2) micronutrients: including zinc, iodine, and iron; 3) vitamins: including folate, vitamin D, and vitamin A; and 4) vitamin-like nutrients: mainly including choline [3,35].

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4.1 Energy-yielding nutrients

The effects of maternal dietary deficiencies of protein and fatty acids, during pregnancy, on the fetus neuronal development have been well investigated. 1) Protein: The migration of neurons is mainly driven by immunoglobulin and chemokines. Lack of these chemicals may affect the migration of neurons, resulting in smaller brain volumes, poor axonal growth, and mental retardation. In contrast, the extreme excess immunoglobulin is associated with schizophrenia. Maternal protein supplements may affect the fetus’ nerve cells volume and number, especially in the limbic system [11]. The amino acid concentration in the neonatal brain is much higher than that in the adult brain, which may ensure the rapid protein synthesis in the neonatal brain. Meanwhile, the effect of protein deficiency on neuron growth is permanent. Neuroanatomical observation showed that protein deficiency could change the brain organization, such as decreasing the thickness of visual cortex [36], parietal neocortex [37], dentate gyrus [37] and cerebellum [37,38], enlarging the size of ventromedial hypothalamic nucleus [32], reducing the size of paraventricular

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hypothalamic nucleus [39], and decreasing the numbers of neurons [40], dendritic arborization [371] and synapses [37]. The main brain and behavior changes under early life protein malnutrition exposure are present in Table 2. 2) Fatty acid: Fatty acid is an important nutritional component for the development of the fetal nervous system. Female during pregnancy need to store 2-4 kg fat every day. Long-chain polyunsaturated fatty acids (LC-PUFAs) are constituted of docosahexaenoic acid (DHA) and Arachidonic acid (AA) in brain tissues, and they are important structural components of the central nervous system [54]. DHA and AA in low concentration may cause the abnormal developments of retina and brain in fetus and infant [55]. DHA deficiency can lead to cognitive impairment [56]and various neurological disorders [57]. Essential fatty acids (EFA) and their derivatives are important for cell membrane function, synapse function, and myelination [58]. In addition, the balance of EFA/LCP, DHA/AA [59] and LCPω-3/LCPω-6 [60] ratios is important for the brain development. But the effects of EFA and the balance of various fatty acids on early-life brain development are not clear. Additionally, well-designed studies should pay more attention to those individuals from low-income families [61].

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4.2 Micronutrients

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Adequate intake of micronutrients is essential for supporting the individual’s development in early life, as well as maintaining overall health across the life-span [62]. Most of the trace elements, especially trace metals, in biological fluids and organs are binding with various proteins, forming “metalloproteins” or “metalloenzymes” that are essential in regulating biological reactions and physiological functions in cells and organs [63]. 1) Zinc: Zinc deficiency can result in the reduction of microtubule polymerization, which may further cause impairment of brain development and function [64]. An experimental study has revealed that zinc deficiency during pregnancy may inhibit the expression of microtubule-associated protein 2 (MAP-2) in the brain while zinc supplement exerts much improvement. The lower level of MAP2 expression is one of the important mechanisms underlying impairments of microtubule polymerization, as a result of zinc deficiency [64]. Maternal severe zinc deficiency, during pregnancy, may lead to synthetic reduction of DNA, RNA, and protein, brain volume reduction, brain ultrastructural changes, and abnormalities of Purkinje cells in the fetal brain. 2) Iodine: Iodine nutritional status plays a very important role in fetal growth and development, and both insufficient and excessive intakes of iodine have negative impacts on the brain development of fetal and newborns. In some developing countries, iodine deficiency is the most widely spread cause of maternal hypothyroxinemia. When the maternal thyroxine (T4) concentration is low in pregnancy, it will potentially damage the neurodevelopment of the fetus. It is medically advised to take additional iodine supplements during pregnancy for women in order to prevent offspring’s learning disability [65,66]. Animal experiments showed that serum free thyroxine (FT4) level was decreased by about 30% of the iodine deficiency rats, and that the brain-derived neurotrophic factor (BDNF) and early growth response factor 1 (EGR1) in hippocampus decreased significantly than those in normal control groups. Meanwhile, low iodine intake may cause cretinism [67,68]. 3) Iron: Iron is an essential structural component of the hemoglobin molecule, which

ACCEPTED MANUSCRIPT transports oxygen to all the organs of the body, including the brain [58]. Rodent models showed that neurometabolism, neurotransmitters, myelination, and gene expression profiles were altered when iron deficiency exists during gestation [69]. The late sequelae of maternal lack of iron in pregnancy include impaired motor, cognitive and social-emotional development in the offspring [70]. 4.3 Vitamins

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1) Folic acid: Folic acid is a universal methyl donor for methylation reactions, including histone and DNA methylation [71]. Folic acid can not only offer methyl for the synthesis of adenosine methionine, but also promote purine and pyrimidine synthesis in the form of co-enzyme [72]. Numerous studies have revealed that folic acid may affect the growth and development of the nervous system through the epigenetic mechanism. After feeding the male rats diets without folic acid, it was found that the degree of DNA methylation in the brain was affected compared to those with normal diets [73]. People found that the methylation level of the abnormalities neural tube was lower than that in the normal control group, and there was a positive correlative between the maternal folic acid level and the methylation level of the embryo [74]. Two animal model-based studies have also disclosed that the prenatal folic acid deficiency could affect the expression of the progeny of insulin-like growth factor -2(IGF-2) [75,76]. 2) Vitamin D: Vitamin D has an important role in calcium signaling, neurotrophic and neuroprotective actions, as well as in neuronal differentiation, maturation and growth, therefore the optimal concentration of vitamin D is required for the brain to maintain functions [77]. There is a growing body of evidence linking gestational vitamin D deficiency with neurodevelopmental disorders, such as schizophrenia and autism [67-70, 72-85]. A range of persistent gene expression, neurochemical and behavioral changes of interest to neuropsychiatry have been observed in rodent models with transient prenatal exposure to vitamin D deficiency [86]. But the biological mechanisms linking vitamin D deficiency with fetal brain development are still unknown. More animal studies should be focused on using good endo-phenotypes, for example, structural and functional magnetic resonance imaging [87, 88], to better understand the pathways that are involved in the neurodevelopmental disorders induced by vitamin D deficiency in pregnancy. 4.4 Choline

Choline is a vitamin-like nutrient, which is essential for cell membrane formation, DNA methylation, and acetylcholine biosynthesis [89,90]. Brain cholinergic activity plays a role in learning and memory, which was first recognized over 30 years ago. The damage or abnormalities of forebrain cholinergic projections can affect memory structures, such as cortex and hippocampus, and lead to the level of cognitive decline [91,92]. Accumulative evidence suggests that choline deficiency during fetal development reduces proliferation and migration of neuronal precursor cells and the angiogenesis in the developing fetal hippocampus [93,94]. Choline deficiency-induced changes in DNA methylation may mediate the expression of a cell cycle regulator and thereby alter brain development [93]. Choline is

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an important methyl-donor, and dietary insufficient of choline during pregnancy may cause decreased DNA methylation in fetal brain within the promoter of the two genes Vegfc and Angpt2, which are important regulators of angiogenesis [94,95]. One study revealed that the genome methylation level in the hippocampus of the offspring was decreased when maternal feeding with choline deficiency diet during pregnancy, and observed low methylation status of the Cdkn3 gene, a gene that inhibits the cell cycle, which causatively led to an increase in downstream protein expression [96]. All these aforementioned findings suggest that maternal choline deficiency during pregnancy may alter the level of DNA methylation of the correlating genes which are important for cell cycle regulation, thereby affecting progeny brain development.

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5. Potential biological mechanisms

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There is a growing interest in clarifying the biological mechanisms underlying the early-life nutritional stress in brain development. The potential mechanisms mainly include the following six aspects.

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5.1 Genetic selection

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Prenatal malnutrition might influence the genetic selection at different stages. Firstly, if the parents are under conditions of starvation before the fertilization, the de novo genetic mutations might be obtained in the germ cells and then be transmitted to their offspring[13]. Secondly, when starvation happens to a pregnant mother, perhaps the alleles of neuropsychiatric disorders might be preferred to transmit to the offspring [13]. Thirdly, the molecular regulatory mechanisms may be altered under the nutritional stress and the previously accumulated but unexpressed genetic variations released, which is known as the Waddington effect [97,98]. Therefore, the threshold for phenotypic expressivity of a trait, such as schizophrenia, is shifted under the prenatal nutritional stress [11] (see Figure 1). Now, the reasons of genetic selection may attribute to the “thrifty phenotype hypothesis” , in which the fetal may select “thrifty genes” when there is a detrimental factor deficient and then it can survive under the adverse environmental condition [99].

5.2 Epigenetic modification It is increasingly accepted that prenatal malnutrition can produce changes in the genome activities without altering the DNA sequence [100], which can produce stable transgenerational alterations in the phenotype. Although the causative relationship has not been confirmed, recent advances in epigenetics provide insights into the mechanisms of early life predisposition to adult disease risk [100]. It has reported that alterations in DNA methylation and histone modification eventually contribute to many human diseases, such as metabolic disorder, cardiovascular disease, asthma, Alzheimer’s disease, and cancer [101-103].

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In animals, it has widely reported that nutritional exposure during pregnancy can affect the DNA methylation patterns of offspring [104-108]. The classic cited example is the laboratory Agouti mouse model [104, 107, 109]. In this model, when feeding nutritional supplements comprising methyl donors to the pregnant mouse, the DNA methylation level of the Avy allele in embryos increased and then the offspring’s hair color shifted from the yellow phenotype towards brown or “pseudoagouti” phenotype [104, 105]. Moreover, most of the offspring had obesity, diabetes and increased susceptibility to tumors [100]. DNA methylation events in animal brain tissues induced by the different early-life unbalanced nutrients are summarized in Table 3. In our pilot epigenetic study with prenatal malnutrition rat model(RLP50), through DNA methylome profiling of the rat hippocampus, we found 87% gene were hypermethylated compared with normal nourished rats [118]. In human epigenetic epidemiology research, the first reported evidence on the relationship among prenatal malnutrition and schizophrenia is the alterations of DNA methylation in the regulatory regions of several genes potential related to schizophrenia [110-113], which were identified with the Dutch Hunger famine cohorts. The offspring prenatally encountered with the Dutch Hunger famine exhibited less methylation of the IGF2 locus in whole-blood samples when they were approximately 60 years old, and higher methylation levels in some specific genes, including IL10, LEP, ABCA1, GNASAS and MEG3, but no discernible difference in global DNA methylation patterns [114-117]. Based on blood samples drawn through the 1959-1961 Chinese famine cohort, our recent study on epigenome-wide association test of schizophrenia with prenatal famine exposure identified that the methylation levels in promoter regions of 73 genes showed average difference above 20% in 40 discordant sib-pairs. Among these, 67 promoter regions showed lower methylation rate in schizophrenic cases. Top 8 differentially methylated genes were independently verified by using an additional cohort with 20 discordant sib-pairs. These genes include DHX40P1,TUBA3E,SYTL4,DNASE1L1,GRIA3,FAM48B1,ZMYM3,and SLC35A2. A list of differentially methylated genes responded to the early life nutritional aberration in human population-based epigenetic epidemiology studies is provided in Table X. These established studies shown that there may have at least two possible biological pathways that prenatal malnutrition affects the global genomic DNA methylation patterns. First, some nutritional factors, especially methyl donors, are essential for epigenetic regulation. There are two important studies which emphasized the critical role of folate and vitamin B12 on brain global DNA methylation patterns in rat offspring. Maternal micronutrient imbalance resulted in brain DNA hypomethylation in the offspring [122,123]. Second, the pathway for metabolic cycling of methionine is probably involved in prenatal nutrition-induced DNA methylation aberration [124]. Vitamins B is the one-carbon units carrying cofactors, it can provide the enzymatic for the dietary folate to feed into the one-carbon metabolism cycle to replenish cellular S-adenosyl-methionine (SAM)[125] (see Figure 2). Prenatal environment-induced epigenetic modification and transgenerational inheritance are either through maternal or paternal line in mammalian [126]. However, the evidence on the transgenerational inheritance is insufficient, and not all the environmental exposures can lead to epigenetically modified transgenerational inheritance. The potential epigenetic mechanisms in mammals are probably as follows: First, some toxicants can lead to the change of DNA methylation in the male germline which can escape from post-fertilization DNA

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methylation erasure, and then induce the alteration of transcriptomic patterns in some specific somatic cells which resulting in adult-onset diseases [127,128]. Second, some genetic mutations may induce epigenetic instability and be transmitted to the later generations through germ cells [129]. Third, RNAs may mediate paramutation-like effect and this may be transmitted to the later generations [130]. To further understand the prenatal malnutrition-induced epigenetic mechanism of transgenerational inheritance, we need to investigate the interactions between the nutritional factors, genomic variants, and methylation patterns through transcriptomic and proteomic changes at different stages of the brain development [130]. To date, DNA methylation, which is mediated by a lot of dedicated enzymes, has the most widely investigated epigenetic modification. However, the study on DNA hydroxymethylation is much limited. Hydroxymethylation in intragenic regions is associated with higher gene expression compared with methylation of CpG islands [131]. Accumulating evidence supports the role of hydroxymethylcytosine in mental disorders because it is enriched in the brain, especially in synapse-related genes, and it exhibits dynamic regulation during the brain development [131]. To date, the biological role of DNA hydroxymethylation in the process of early-life malnutrition-induced abnormal neurodevelopment has not been disclosed.

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5.3 Mediation of brain-immune communications

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Lines of evidence have shown the nutrients may modulate inflammation by regulating immune cell function or differentiation via epigenetic pathways [132]. Maternal or fetal immune dysfunction may impact fetal brain development or neurodevelopmental disorders, but the definitive pathophysiological mechanisms are still poorly understood [133]. Some special nutrient aberration and phytochemical nutrients are relevant to inflammation (see Table 5). The relationship between nutrition and epigenetic modification has been discussed aforementioned. Many epigenetic mechanisms, such as DNA methylation, post-translational histone modifications and microRNAs (miRNAs) have been described in relation to the modification of immune function as they modulate the expression of immune genes [140, 141]. And the immune dysfunction may modulate inflammation which may lead to many neuropathic diseases. On the other hand, the immune system may modulate neurodevelopment directly through communication pathways between the brain and immune system [140]. These pathways include: 1. autonomic nervous system (ANS); 2. the hypothalamic-pituitary-adrenal (HPA) axis; 3. cytokines, chemokines, leukocytes, and immune signal that can travel across the blood-brain barrier (BBB) [140] (see Figure 3). 5.4 Abnormal metabolism pathways A potential reason why prenatal malnutrition exposure is associated with fetal neurodevelopment may be the essential micronutrient deficiency. Folate, essential fatty acids, retinoids, vitamin D, and iron might be candidate micronutrients as potential risk factors for neurological diseases, such as schizophrenia [142]. These micronutrients may affect the

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malnourished pregnant rats and normal rats and found the abnormalities of a number of metabolic pathways in fetal rats including the folate cycle and methionine pathway, the monoamine pathway, and tri-iodothyronine (T3) metabolism pathway [63].

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5.5 Synthetic mediation of hormones and hypothalamic–pituitary–adrenal axis

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A series of studies have raised the “fetal programming” hypothesis, which implies that adverse environmental factors lead to permanent adaptations in fetal homeostatic mechanisms, producing long-term changes in physiology in adults [145]. It has been shown that maternal nutrient restriction can permanently modify the development and function of the hypothalamic–pituitary–adrenal (HPA) axis in offspring [11, 146-149], which has been reported to play important roles in the programming of the later disease risk [148, 150, 151]. The potential mechanism may be that the maternal nutrition changes the hormone release, which reduces the HPA axis responsiveness. Normal pregnancy entails substantial production of hormones in the maternal, placental, and fetal compartments, which can be affected by maternal nutrition and affect fetal development, such as glucocorticoids, insulin-like growth factors and leptin [2]. Between them, glucocorticoids are essential for maturation of fetal tissues [152, 153]. Maternal global nutrient restriction during late gestation induced over exposure to glucocorticoids in the fetus and disturbed the HPA axis in the newborn, which could reduce fetal growth and predispose to anxiety disorders [154]. Moreover, the increase in basal corticosterone levels in the newborn rat could accelerate age-related neural and cognitive deficits, including atrophy of dendritic processes and cell death [153,154]. One study disclosed the roles of Corticotropin-releasing hormone (CRH) and proenkephalin(PENK) in the hypothalamic paraventricular nucleus (PVN) in mediating the reduction of fetal HPA axis responsiveness in moderately nutrient restricted mothers with pregnancy [5] (see Figure 5). 5.6 Mediation of microbiota-gut-brain axis Gut microbiota is a complex ecosystem which is formed mainly by bacteria, viruses, archaea, protozoa and fungi [156]. Diet is the most important factor affecting gut microbiota establishment and composition throughout the life [157]. Maternal nutrition patterns, such as high-fat diet (HFD), may induce a shift in microbial ecology that negatively influences social behaviors of offspring, which is known as the microbiota-gut-brain (MGB) axis [158], defined as a multi-organ bidirectional signaling system between the gut microbiota and the central nervous system (CNS) that plays fundamental roles in host homeostasis, behavior and stress response Maternal obesity induced by high-fat diet has been shown to alter the gut microbiome and metabolism of offspring which can cause a state of dysbiosis [158, 159].

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6. Perspectives

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This alteration in the balance of symbionts/pathobionts can induce some metabolic and inflammatory disorders, visceral pain and some disfunctions of CNS [160, 161]. The potential mechanisms involved in the MGB axis may probably include four aspects. First, diet changes the host gut microbiota that can determine what the host can extract from its diet, such as bioactive signaling molecules, neuro-metabolites, vitamins and short-chain fatty acids (SCFA) [162]. And then the microbiota may modulate neural signal within the enteric nervous system and consequently influence brain function and host behaviors [163]. Second, microbial neurometabolite products, such as serotonin, butyrate and propionate, can modulate brain function [164]. Third, the alteration of gut microbiota may increase intestinal permeability and lipopolysaccharide (LPS) in the bloodstream, and then induces inflammatory. Chronic inflammation has been reported to the associated with a number of neuropsychiatric disorders, including depression and dementia [165]. Fourth, the vagus nerve plays an important role in bidirectional signaling between the gastrointestinal and nervous systems. Bravo et al. found that probiotics could modulate the gut microbiota and induce behavioral and neurochemical changes in mice. However, the probiotics might lose efficacy under the vagotomy [166] (see Figure 6). Many different diet patterns, such as high-fiber diets [167], high-protein diets [168], vegan diets [169, 170], may change the gut microbiota and then alter brain function However, to date, studies about the effects of maternal nutrition patterns on the brain function of offspring through the MGB axis have only limited to high fat diet. Whether other nutrition affects the brain development hasn’t been researched. In summary, the changes under nutrition pressure are multifarious, therefore, these potential physiologic or molecular responses to prenatal nutritional stress are, of course, not mutually exclusive [11]. The relationship between these potential mechanisms is present in Figure 7. These neuropsychiatric disorders appear to result from interactions among genetic background, intrauterine, embryonic, fetal, and prenatal environmental factors, and postnatal life-style [171, 172].

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We have little understanding of the effects of maternal nutritional factors in pregnancy on the neuropsychiatric problems in offspring [173]. Furthermore, we are challenged by the complexity of variety nutrition fetus obtained from maters, and transfer of different nutrients between the maters and fetus. As demanded, this paper provides an in-depth study on the mechanisms of prenatal brain development problems induced by maternal malnutrition. Animal models were used to investigate behavioral and neurobiological mechanisms of the functional deficits observed in lead-exposed humans [76]. By using high-throughput omic data-driven approaches, it is much easy to reveal the mechanisms behand the effects of maternal nutrition on fetal neurodevelopment. Meanwhile, developing new drugs to guide the treatment options for nutrition-related brain diseases.

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6.2 Early-life over-nutrition is worse?

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There are eight major necessary nutrients for children's brain development, namely protein, taurine, fatty acid, iron, zinc, iodine, selenium, B vitamins. However, the relationship among the maternal levels of taurine, selenium, and B vitamins during pregnancy and fetus brain development has not been reported. In addition, studies on methyl group donors, including folic acid, vitamin B12, choline, betaine, and methionine, which directly affect the methylation of DNA, are not available. Even though there are some reports on the associations of folic acid intake, choline level during pregnancy with the fetus brain development, studies on the potential effects of vitamin B12, betaine and methionine on fetus brain development through the change of methylation, are greatly needed to be investigated. The issue of whether the deficiency of a single nutrient or a group of nutrients could impact the neurodevelopment is a matter of broad biological importance [174]. An animal study found that a limitation of the maternal nutrients (vitamin B12, folic acid and methionine) during pregnancy significantly increased the incidence of obesity and insulin resistance [175]. However, there was no research demonstrating the relationship between the interactions of multiple nutrient deficiencies during pregnancy and fetal brain development.

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Due to the continuous improvement of people's living standards, over-nutrition during pregnancy is not a rare phenomenon. So the impact of over-nutrition or the excess of some nutrients during pregnancy on the health of offspring has also become a hot topic for researchers. The additional folic acid supplements during pregnancy may also cause excessive folic acid, resulting in a number of unfavorable factors for offspring health [96]. But the epidemiological findings are still controversial. Shorter et al. recalled the literature in recent years and found that with the growth of folic acid consumption, the risk of autism also relatively increased, ranging from 1/250 in 2000 to 1/68in 2013 [176]. A study showed that excessive folic acid supplementation during pregnancy increased the risk of progenitor autism [177]; but another study found that the plasma folic acid and methionine levels of autistic children’s mothers were lower than the normal group [178]; and the most recent study shows that there is no correlation between folic acid and autism [179]. Although the effect of folic acid supplementation during pregnancy on the autism is not clear, autistic patients may demonstrate multiple methylation status abnormalities compared with normal individuals. Some other nutrition excesses have also been suggested negative effects on the brain development and behavioral development (see Table 6). 6.3 Possible approaches to disclosing biological mechanisms A two-step epigenetic Mendelian randomization approach, as a novel epidemiological methodology, can be employed to establish associations among exposure, DNA methylation and outcome. It can test whether DNA methylation changes following prenatal maternal

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exposure to adverse nutritional environments, which may increase the risk of complex disorders such as schizophrenia in offspring [143]. But it has some limitations, such as large sample sizes and some notable statistical genetic issues [185]. Due to various deficiencies of anthropological experiments, experimental animal studies are getting more and more attention. Currently, the initial step toward characterizing the hypothesized molecular mechanisms of maternal malnutrition exposure-induced various of neuropsychiatric disorders is the latest high-throughput techniques, such as the genome-wide screen of transcriptome and DNA methylome [118], and integration of metallomic and metabonomic profiles to interpret biological pathway changes resulting from malnutrition [63]. In our previous studies, we have established a prenatal malnutrition rat model, named RLP50 [118]. Through metabonomic and metallomic profiling studies, we observed significantly different patterns of metabolites and trace elements in pregnant rats of the RLP50 group [63]. And then, through genome-wide screen of transcriptome in RLP50 group, we found that the offspring of RLP50 exhibit different expression in some gene in the prefrontal cortex and hippocampus [118]. Between these gene, Mecp2 plays a critical role in neurodevelopment, no matter loss function or increased dosage of its human homologue can cause a number of neuropsychiatric disorders [186]. Recently, people reported a novel miRNA-mediated pathway downstream of MeCP2 that influences neurogenesis via interactions with central molecular hubs linked to autism spectrum disorders [187]. In our pilot epigenetic study with RLP50, through DNA methylome profiling of the hippocampus, we found 87% gene were hypermethylated [118]. Based on our generated multi-omic data, our next research would be illuminating the mechanism about the aberrantly epigenetic modifications in the fetus neurodevelopment, which are induced by the maternal low protein exposure, at an integrative systems biology framework. Meanwhile, the change of other epigenetic modification also will be investigated, such as DNA hydroxymethylation, and histone methylation. This investigation would shed light on precision nutrition in the future.

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Author contributions

MX designed and supervised the study and drafted the manuscript, MX and XY executed the study and drafted the manuscript. All authors contributed to editing and revising the manuscript. All authors read and approved the final manuscript.

Acknowledgments

This project was supported by the National Key Basic Research Program of China (2013CB530700), Shanghai Municipal Commission of Science and Technology Program

ACCEPTED MANUSCRIPT (13JC1403700), “Eastern Scholar” project supported by Shanghai Municipal Education

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Commission, and Shanghai Key Laboratory of Psychotic Disorders (13dz2260500,14-K06).

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ACCEPTED MANUSCRIPT Table 1. Brain and behavior changes under nutrient restriction exposure

Model

Dispose

Outcomes

Reference No.

rats

daily food intake reduced by 50%

number of hippocampal neurons decreased

[28]

1.glucocorticoid

minera

locorticoid

receptor expressions in the hippocampus 50% food restriction decreased during the last week of 2.corticoliberin expression in the gestation hypothalamic paraventricular nucleus

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rats

and

decreased 1.female displayed more hyperactivity

50% nutrient restriction

rats

0% protein diet

neuropeptide Y (NPY) distribution delay

rats

semi-starvation

1.brain 5-HT system dysfunction 2.anxiety disorders increased

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rats

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2.both female and male exhibited anxiety

[29]

[30] [31] [32]

mice

nutrient

restriction between birth and weaning

increased

2.orexigenic agouti-related peptide (AgRP) in the paraventricular nucleus of the hypothalamus (PVH) increased 3.anorexigenic proopiomelanocortin

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transient

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1.permanent modulation of the arcuate nucleus of the hypothalamus (ARH)

[33]

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70% food restriction

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baboons

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(POMC) projections to PVH 1.aggressive behavior in males more than in females increased 2.playing behavior in males decreased 3. anxiety levels in males possibly increased

[34]

ACCEPTED MANUSCRIPT Table 2. Brain and behavior changes under early life protein malnutrition exposure

Model

Period of LP diet

Mice

Before

from

mating

before mating to end of lactation from 6 weeks

2.working memory errors increased 3.reference memory errors increased

before mating to end of

increased

Mice

interneurons

1.physical growth delayed

mating

lactation

2.neurological reflexes increased 3.neuromuscular strength increased

from mating to end of lactation from mating to

1.hippocampal progenitors decreased 2.deficits in object recognition during adult life 3.depressive behavior increased 1.the index of lipid peroxidation in the

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After

mating to birth from mating to

[43]

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[44]

2.total antioxidant reactivity levels decreased 1.brain cortical thickness decreased

pregnancy

pregnancy

2.astrocytogenesis delayed 3.neuronal differentiation abnormal

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During

experiment first 2 weeks of

during gestation during gestation

[45]

[46]

[47]

4.synaptogenesis abnormal 5.programmed cell death decreased neuron numbers in the CA1 decreased 1.alpha1 and beta2 decreased 2.alpha3

from conception

After birth

[42]

cerebellum and cerebral cortex increased

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Rats

glutamic acid decarboxylase

cells at P7 decreased and P30 increased

end of

Rats

[41]

before

Rats

Rat Rats

1.Hippocampal volume decreased

Bromodeoxyuridine (BrDU) immunolabeled

Rats

Rats

Ref.

experiment from 5 weeks

Rats

Mice

6 weeks

Outcomes

increased

in

the

[48] [49]

hippocampal

formation 1.lipid oxidation levels increased

[50]

to end of experiment

2.Protein oxidative damage increased

from P0 to P30

the number and span of dendritic basilar processes decreased

[51]

1.playful social behavior decreased 2.nonsocial behavior decreased

[52]

Rats

from birth lactation

to

Rats

from birth lactation

to

3.nonplayful social behaviors decreased

(PM) or till adulthood (M)

1.dominance behavior decreased in M 2.non-socialbehavior increased in M and PM

[53]

ACCEPTED MANUSCRIPT DNA methylation events in animal brain tissues induced by the different early-life unbalanced nutrients Table 3.

Nutrients

epigenetic modification

Model &

Ref.

Target Undernutrition

1. 87% gene were hypermethylation 2. methylation of Slc2a1 decreased

Overfeeding

Sp1-related

High fat

binding

Rat& hippocampus

sequences Rat&

methylation increased

hypothalamic

1.global methylation decreased

mouse&

[118] [119] [120]

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2.methylation of DAT, MOR and PENK brain gene decreased 1.global methylation increased

Rat&

[121]

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Cholinedeficiency

Choline supplementation

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2.methylation of G9a and Suv39h1 brain decreased

1.H3K4me2 decreased Rat& 2.methylation of G9a and Suv39h1 brain

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increased

[121]

ACCEPTED MANUSCRIPT Table 4. Differentially methylated genes responding to the early life nutritional aberration in human populations exposed to famine

Gene symbol

1944-45 Dutch

IGF2

Average Difference Compared to Normal Nourished Individuals -41%, hypomethylated

Description insulin like growth factor 2 INS-IGF2 readthrough, two alternatively

Famine INSIGF

-84.8%, hypomethylated

spliced read-through transcript variants which align to the INS gene in the 5'

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Cohort

region and to the IGF2 gene in the 3' region. 20.8%,hypermethylated

28.6%,hypermethylated

Leptin, secreted by white adipocytes into the circulation and plays a major role in the regulation of energy

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LEP

primarily by monocytes and to a lesser extent by lymphocytes

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IL10

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interleukin 10, a cytokine produced

ABCA1

48.8%,hypermethylated 54.0%,hypermethylated

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MEG3

ATP

binding

cassette

subfamily

A

member 1 GNAS antisense RNA 1 maternally expressed 3 (non-protein coding), a maternally expressed imprinted gene

DHX40P1

-41%, hypomethylated

DEAH (Asp-Glu-Ala-His) box polypeptide 40 pseudogene 1 (DHX40P1), non-coding RNA.

TUBA3E

-38%, hypomethylated

tubulin, alpha 3e (TUBA3E), mRNA.

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1959-61 Chinese Famine

19.9%,hypermethylated

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GNASAS

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homeostasis

SYTL4

-31%, hypomethylated

DNASE1L1

-31%, hypomethylated

GRIA3

-30%, hypomethylated

FAM48B1

-30%, hypomethylated

ZMYM3

-29%, hypomethylated

SLC35A2

-28%, hypomethylated

synaptotagmin-like 4 (SYTL4), transcript variant 3, mRNA. deoxyribonuclease I-like 1 (DNASE1L1), transcript variant 4, mRNA. glutamate receptor, ionotrophic, AMPA 3 (GRIA3), transcript variant 2, mRNA. family with sequence similarity 48, member B1 (FAM48B1), mRNA. zinc finger, MYM-type 3 (ZMYM3), transcript variant 3, mRNA. solute carrier family 35 (UDP-galactose transporter), member A2 (SLC35A2), transcript variant 3, mRNA.

ACCEPTED MANUSCRIPT Table 5. Association between nutrition and inflammation

Nutrition(or dispose) folic aciddeficient

The change of inflammatoryresponses Ref. 1.the expression of inflammatory mediators：Il-b, Il-6, Tnf-a [134] increased 2. the expression of monocyte chemoattractant protein-1 (Mcp-1) increased

vitamin D

1. suppress inflammatory responses in adult humans with

[135]

multiple sclerosis 2.the expression IL-17gene decreased

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3.block activating T cells (NFAT) transcription factors curcumin and

[136,137]

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4.recruitmenthistone deacetylase (HDAC) control inflammation responsesby altering DNA methylation andvia micro-RNA

epigallocatechin gallate

inflammationvia modulation of histone acetyltransferase activity decreased

[138]

garlic allylsulfur compounds

Inflammation decreased

[139]

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curcumin-derived synthetic analogs

ACCEPTED MANUSCRIPT Table 6. Brain and behavior changes under early-life over-nutrition exposure

Model

dispose

Outcoms

Ref.

Rats

overnutrition

hippocampus

Mice

high-fat

influenced neuronal survival,

spatial

memory

learning,

and

formation

[180]

memory

[181]

decreased high

SFA

(lard-based

tasks performed decreased

diet, 40% calories

(includeolton’s

from fat

interval

radial armmaze,

delayed

alternation

Hebb-Williams maze series) Rats

high-protein

variable

task,and

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hippocampus-dependent memory impairment

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high zine dose

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a

the

nucleus tractussolitarius and in the arcuate nucleusactivation increased

Mice

[182]

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Rats

[183] [184]

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ACCEPTED MANUSCRIPT

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Figure 1. The potential mediating mechanisms with genetic selection.

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Figure 2 The three potential mediating mechanisms with epigenetic modification.

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DNMT: DNA methyltransferase; Met: Methionine; SAM:S -Adenosyl methionine; Hcy: Homocysteine

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Figure 3. The potential mediating mechanisms with brain-immune communications. ANS : autonomic nervous system; HPA axis: hypothalamic-pituitary-adrenal axis; BBB: blood-brain

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barrier; A: cytokines; B: chemokines; C: leukocytes; D: immune signal

ACCEPTED MANUSCRIPT

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Figure 4 The potential mediating mechanisms with abnormal metabolism pathways.

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（dashed lines represent the mechanism between them is still unknown）

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ACCEPTED MANUSCRIPT

Figure 5 The potential mediating mechanisms with HAP axis.

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CRH: Corticotropin-Releasing Hormone; ACTH: adrenocorticotropic hormone; GCS ：glucocorticoid

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(dashed lines represent negative feedback)

ACCEPTED MANUSCRIPT

Figure 6 The potential mediating mechanisms with MGB axis.

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(This figure is originally quoted from reference 156, with further modifications)

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ACCEPTED MANUSCRIPT

Figure7. The potential mechanisms which linking early life nutrition to later Neurodevelopmental disorders.

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(This figure is originally quoted from reference 75, with further modifications,

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Dashed lines represent that the mechanism between them have not been investigated clearly)

ACCEPTED MANUSCRIPT Highlights

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 

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

A large number of studies have shown that maternal dietary nutrients can regulate the expression of many genes which impact neuro-development. We firstly reviewed human population-based epidemiological findings, and then evaluated early-life animal model studies to disclose the possible effects of early-life malnutrition on the brain development and its related neuropsychiatric disorders. The potential biological mechanisms behind the effects were explored. We discussed the possible approaches to disclosing the potential mechanisms to point out our future efforts.

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