Hostname: page-component-74656f9884-2dmjx Total loading time: 0 Render date: 2026-11-08T08:37:43.169Z Has data issue: false hasContentIssue false
  • English
  • Français

Understanding the epigenetics of neurodevelopmental disorders and DOHaD

Part of: Epigenetics as the Mediator of the Gene/Environment Interactions in DOHAD

Published online by Cambridge University Press:  24 February 2015

T. Kubota ,
K. Miyake ,
N. Hariya  and
K. Mochizuki
T. Kubota*
Affiliation:
Department of Epigenetic Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
K. Miyake
Affiliation:
Department of Epigenetic Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
N. Hariya
Affiliation:
Department of Epigenetic Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
K. Mochizuki
Affiliation:
Department of Local Produce and Food Sciences, Faculty of Life and Environmental Sciences, Faculty of Medicine, University of Yamanashi, Kofu, Japan
*
*Address for correspondence: T. Kubota, Department of Epigenetic Medicine, Fuculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. (Email: takeot@yamanashi.ac.jp)
Rights & Permissions [Opens in a new window]

Abstract

The Developmental Origins of Health and Disease (DOHaD) hypothesis refers to the concept that ‘malnutrition during the fetal period induces a nature of thrift in fetuses, such that they have a higher change of developing non-communicable diseases, such as obesity and diabetes, if they grow up in the current well-fed society.’ Epigenetics is a chemical change in DNA and histones that affects how genes are expressed without alterations of DNA sequences. Several lines of evidence suggest that malnutrition during the fetal period alters the epigenetic expression status of metabolic genes in the fetus and that this altered expression can persist, and possibly lead to metabolic disorders. Similarly, mental stress during the neonatal period can alter the epigenetic expression status of neuronal genes in neonates. Moreover, such environmental, stress-induced, epigenetic changes are transmitted to the next generation via an acquired epigenetic status in sperm. The advantage of epigenetic modifications over changes in genetic sequences is their potential reversibility; thus, epigenetic alterations are potentially reversed with gene expression. Therefore, we potentially establish ‘preemptive medicine,’ that, in combination with early detection of abnormal epigenetic status and early administration of epigenetic-restoring drugs may prevent the development of disorders associated with the DOHaD.

Keywords

epigeneticshumanmolecular/cellularnewborn/childrenpregnancy

Information

Type
Review
Information
Journal of Developmental Origins of Health and Disease , Volume 6 , Issue 2 , April 2015 , pp. 96 - 104
Check for updates
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2015 

Introduction

The brain is the organ that is sensitive to abnormal expression of neurological genes. Either underexpression or overexpression of the same genes encoding proteins related to brain function results in a range of neurological disorders. For example, Pelizaeus–Merzbacher disease, a severe congenital disease is caused by either a deletion, mutation or duplication of the proteolipid protein 1 gene (PLP1);Reference Inoue, Kanai and Tanabe 1 lissencephaly, a rare brain formation disorder, is caused by either deletion or duplication of the platelet-activating factor acetylhydrolase 1B subunit alpha gene (PAFAH1B1) that encodes a neuronal migration factor;Reference Reiner, Carrozzo and Shen 2 , Reference Bi, Sapir and Shchelochkov 3 Charcot–Marie–Tooth disease, an adult-onset neuromuscular disease is caused by a mutation or duplication of the peripheral myelin protein 22 gene (PMP22); 4 and Parkinson’s disease is caused by a mutation or multiplication of the α-synuclein gene (snca).Reference Obi, Nishioka and Ross 5 Because these are all neurological disorders and such examples have not been observed in other clinical fields, the brain is thought to be extremely sensitive to perturbations in gene regulation. In other words, the brain is an organ that requires a proper control system for gene expression. Epigenetic mechanisms are one of the ways by which gene expression is controlled in higher vertebrates.

The term ‘epigenetics’ was originally used to describe ‘the causal interactions between genes and their products, which bring the phenotype into being.’Reference Waddington 6 This definition initially referred to the role of epigenetics in embryonic development, in which cells develop distinct identities despite having the same genetic information. However, the concept of epigenetics has changed to refer to ‘the heritable changes in gene expression that occur independent of changes in the primary DNA sequence during DNA replication at the step of cell division,’Reference Sharma, Kelly and Jones 7 and is known to be associated with a wide variety of biological processes, such as genomic imprinting,Reference Kubota, Das and Christian 8 – 13 inactivation of the X chromosome,Reference Kubota, Wakui and Nakamura 14 , Reference Kubota, Nonoyama and Tonoki 15 embryogenesisReference Sasaki and Matsui 16 and tissue differentiation.Reference Sakashita, Koike and Kinoshita 17 It is known that abnormalities in these biological processes cause a subset of congenital neurodevelopmental disorders; therefore, understanding epigenetic mechanisms, based on DNA methylation and histone modifications, is important for elucidating the pathogenic pathways involved in congenital neurodevelopmental disorders.Reference Kubota, Das and Christian 8 – Reference Kubota, Wakui and Nakamura 14

It is thought that epigenetic modifications are more susceptible to environmental stresses, such as malnutrition and mental stress,Reference Lillycrop, Phillips, Jackson, Hanson and Burdge 18 – Reference Weaver, Cervoni and Champagne 20 than are nucleotide sequences, and that epigenetics is one of the underlying mechanisms proposed by the Developmental Origins of Health and Disease (DOHaD) hypothesis,Reference Lillycrop, Phillips, Jackson, Hanson and Burdge 18 , Reference Lillycrop, Phillips and Torrens 19 in which epigenetic changes induced by various environmental factors during fetal and neonatal periods can cause alterations of epigenetic patterns.

Based on these findings, we introduce possible epigenetic mechanisms associated with congenital neurodevelopmental disorders, acquired neurodevelopmental disorders induced by environmental factors, epigenetic treatments that take advantage of their reversibility and the significance of transgenerational epigenetic inheritance.

Epigenetic mechanisms associated with congenital neurodevelopmental disorders

Genomic imprinting is an epigenetic phenomenon initially discovered in mammals that results in monoallelic gene expression. The inherited maternal and paternal imprints are erased in the germ line and a new imprinting pattern is established in a parent-of origin-specific manner according to the sex of the individual (Fig. 1). This phenomenon underlies a subset of neurodevelopmental disorders, such as Prader–Willi syndrome (PWS), Angelman syndrome (AS) and Beckwith–Wiedemann syndromes (BWS).Reference Kubota, Das and Christian 8 – 13 PWS, characterized by hypotonia in infancy, hyperphagia, obesity and mental retardation, is caused by either paternal chromosome 15q11-q13 deletion or uniparental maternal disomy (Fig. 2a). All these genetic abnormalities lead to loss of function of multiple paternally expressed imprinted genes within the 15q11-q13 region.Reference Kubota, Das and Christian 8 – Reference Nicholls, Saitoh and Horsthemke 9 Conversely, AS, characterized by intractable epilepsy, severe mental retardation and an inappropriate happy demeanor such as frequent laughing, is caused by either maternal 15q11-q13 deletion, uniparental paternal disomy or UBE3A mutation. All these genetic abnormalities lead to loss of function of the maternally expressed imprinted UBE3A within the 15q11-q13 region.Reference Nicholls, Saitoh and Horsthemke 9 A recent study has demonstrated that PWS is caused by defect in the SNORD116 cluster of small nucleolar RNA genes within the paternal 15q11-q13 region, indicating that the cluster region is the smallest critical region for PWS.Reference Duker, Ballif and Bawle 10 Another recent study has shown that AS is associated with unbalanced expression between the maternally expressed UBE3A transcript and the paternally expressed SNURF-SNRPN transcript (antisense transcript of UBE3A), which is a new pathogenic mechanism based on antisense RNA for AS.Reference Runte, Kroisel and Gillessen-Kaesbach 11 BWS, characterized by macroglossia, omphalocele and embryonal tumors, is caused by either paternal uniparental disomy for chromosome 11p15, gain of methylation at imprinting center 1 within the maternal 11p15 region or loss of methylation at imprinting center 2 within the maternal 11p15 region. All these genetic abnormalities perturb expression of imprinted genes within the 11p15 region.Reference Kubota, Saitoh and Matsumoto 12 , 13

Fig. 1

Erasure and establishment of genomic imprinting. Inherited maternal and paternal imprints are erased and new imprinting is established according to the individual’s sex during the processes of spermatogenesis and oogenesis.

Fig. 2

Neurodevelopmental disorders caused by epigenetic abnormalities. (a) Abnormal suppression of the active allele of imprinted genes causes genomic imprinting disorders. (b) Abnormal activation of the inactive X chromosome in females causes X-chromosome inactivation disorders. (c) Mutations in genes encoding a DNA methyltransferase produces a deficiency resulting in insufficient DNA methylation, which in turn leads to aberrant expression of the target genes. (d) Mutations in genes encoding methyl-CpG binding proteins causes abnormal regulation of the target genes.

In mammals, the X chromosome is much larger than the Y chromosome and carries substantially more active genes. Consequently, females ought to have greater gene expression from their two X chromosomes than males do from their single X. However, this potential imbalance between females and males is prevented by the epigenetic inactivation of one of the two X chromosomes in females. If X-chromosome inactivation (XCI) does not occur properly, it can be lethal for in the affected female embryo; this effect is evident in mouse embryonic clones produced by somatic nuclear transfer in which a majority of clones abort due to failure of XCIReference Nolen, Gao and Han 21 (Fig. 2b). If one of the two X chromosomes is very tiny due to a chromosome rearrangement (e.g. a small ring-shape X chromosome with a centromere), then this tiny X chromosome may escape XCI. In this case, the female has a normal X chromosome and a small ring X chromosome that are both active. Such genotypes do not always cause embryonic lethality, but they are associated with extremely severe neurodevelopmental delay,Reference Kubota, Wakui and Nakamura 14 , Reference Kubota, Nonoyama and Tonoki 15 indicating that proper epigenetic chromosome inactivation is essential for normal development.

Mutations in the genes that encode proteins associated with the epigenetic gene control machinery can also cause congenital neurodevelopmental disorders. For example, DNA methyltransferases (DNMTs) mediate addition of a methyl group (CH3) to CpG dinucleotides. Mutations in DNMT3B, a DNMT gene, cause ICF syndrome, characterized by immunodeficiency, centromere instability, facial anomalies, and mild mental retardation.Reference Okano, Bell and Haber 22 – Reference Kubota, Furuumi and Kamoda 24 Thus, dysregulation of gene expression as a result of a DNMT mutation may cause the features of this syndrome (Fig. 2c). A recent report indicates that mutation in another DNMT gene, DNMT3A, also causes an overgrowth syndrome with intellectual disability.Reference Tatton-Brown, Seal and Ruark 25

Methyl-CpG-binding domain proteins (MBDs) also play an important role in epigenetic gene regulation. Mutation of MECP2, an MBD gene, causes Rett syndrome, characterized by seizures, ataxic gait, language dysfunction and autistic behavior.Reference Amir, Van den Veyver and Wan 26 , Reference Chunshu, Endoh and Soutome 27 A recent study showed that MeCP2 controls expression of neuronal genes,Reference Miyake, Hirasawa and Soutome 28 suggesting that dysregulation of multiple neuronal genes may cause the neurological features of this syndrome (Fig. 2d).

Epigenetic mechanisms of acquired neurodevelopmental disorders

Epigenetic controls of gene expression are generally very stable; thus, DNA and histone modification patterns within the genome are faithfully reconstructed after DNA replication (i.e. cell division). The only exception to this expected stability are the changes associated with carcinogenesis, in which defects in the epigenetic mechanisms are thought to be induced by lifelong environmental stimuli.Reference Sharma, Kelly and Jones 7 Although epigenetic mechanisms are generally stable, they can also be altered by certain conditions of short-term stress. Epidemiological studies of populations affected by famines in the Netherlands and China demonstrated that the offspring born to the mothers exposed to famine during their first and second trimester had lower birthweights than offspring born to the mothers not exposed to famine,Reference Lumey 29 and the offspring had increased risks of metabolic disorders (e.g. obesity, diabetes mellitus) and mental disorders.Reference Painter, de Rooij and Bossuyt 30 , Reference St Clair, Xu and Wang 31 A similar phenomenon appears to be occurring in Japan where birth weights have decreased over the last 30 years due to intentional dieting in young Japanese women, which has resulted in fetal malnutrition.Reference Gluckman, Seng, Fukuoka, Beedle and Hanson 32

Short-term stress-related epigenetic changes due to malnutrition during the fetal period underlie the DOHaD. Recent studies in rats demonstrated that malnutrition during the fetal period decreases DNA methylation and increases expression of the peroxisome proliferator-activated receptor alpha gene (PPARa) in the liver, which may increase risks of metabolic disorders (Fig. 3).Reference Lillycrop, Phillips, Jackson, Hanson and Burdge 18 , Reference Lillycrop, Phillips and Torrens 19 Indeed, altered DNA methylation status was identified in the whole blood of individuals who suffered malnutrition during a period of famine in the Netherlands, in which the methylation of INSIGF was lower among individuals who were periconceptionally exposed to the famine compared with their unexposed same-sex siblings, whereas methylation of IL10, LEP, ABCA1, GNASAS and MEG3 was higher.Reference Tobi, Lumey and Talens 33 It was also reported that assisted reproductive technologies (e.g. in vitro fertilization and intracytoplasmic sperm injection), which are now widely used due to increases in maternal and paternal ages, lead to a decrease in the DNA methylation status at multiple maternally methylated imprinted loci.Reference Lim, Bowdin and Tee 34 , Reference Tee, Lim and Dias 35 Another example in which short-term stress induces epigenetic changes is that mental stress within the 1st week of life in neonatal rats alters the pattern of DNA methylation in the promoter region of the glucocorticoid receptor gene (Gr; also known as NR3C1) in the brain, resulting in long-term abnormal behavior. The level of Gr methylation normally decreases in the brains of offspring given high maternal care in the 1st week after parturitionReference Weaver, Cervoni and Champagne 20 (Fig. 4 left). By contrast, rat pups separated from their mothers during this period show aberrant hypermethylation of the Gr promoter and repression of Gr expression in the hippocampusReference Weaver, Cervoni and Champagne 20 (Fig. 4 right). This observation may hint at a possible mechanism for the etiology of neurodevelopmental abnormalities associated with neonatal and childhood neglect and maltreatment in humans. The ability of stress to induce long-term changes was supported by postmortem brain analyses of suicide victims with a history of childhood abuse; in these individuals, hypermethylation of the neuron-specific promoter of NR3C1 as well as reduced expression were observed in the hippocampus.Reference McGowan, Sasaki and D’Alessio 36 Overall, there is growing evidence that mental stress in early life can induce long-lasting epigenetic changes that have a lifelong effect on personality.Reference Murgatroyd, Patchev and Wu 37 Taken together, these human and animal findings suggest that the DNA methylation changes due to assisted reproductive technologies, fetal malnutrition and neonatal stress possibly contribute to recent rapid increase of children with mild neurodevelopmental disorders, which is reported in many countries, including Korea.Reference Kim, Leventhal and Koh 38

Fig. 3

Epigenetic basis of the linkage between maternal nutrition and predicting future neurodevelopmental outcomes in the offspring. Maternal malnutrition (especially folic acid deficiency, a methylation residue) induces a low DNA methylation status of metabolic genes in the liver of the fetus, which causes overexpression of the target genes and development of an origin of obese in the fetus. This status is good for survival of the fetus in the malnutritional environment, but if it then nurtured in a well-fed society after birth, it will develop obesity and diabetes mellitus during its adult period. A recent report demonstrated that the in utero malnutrition-programmed liver lipid metabolism can be inherited by the second generation, suggesting that the nutritional environment-induced ‘DOHaD nature’ can be transmitted to the descendants.

Fig. 4

Epigenetic mechanism that bridges mental stress and neuronal gene function. Environmental factors (e.g. maternal separation-stress during the 1st week of life) can alter the epigenetic status (e.g. DNA methylation) in a neuronal gene (e.g. the glucocorticoid receptor gene promoter) in the rat brain, which leads to persistent gene expression changes, that result in abnormal behavior throughout the lifespan of the individual.

In addition to malnutrition during the fetal period and mental stress during the neonatal period, several lines of evidence suggest that extrinsic (environmental) factors, such as drugs,Reference Tsankova, Berton and Renthal 39 – Reference Wang, Xu and Li 43 mental, neuronal stimulationReference Ma, Jang and Guo 44 and environmental chemicals, such as via smoking,Reference Breitling, Yang, Korn, Burwinkel and Brenner 45 , Reference Shenker, Polidoro and van Veldhoven 46 alter the epigenetic status and thereby affect brain function. Therefore, it is intriguing to speculate that acquired neurodevelopmental disorders, including autistic disorders, may be the result of epigenetic dysregulation caused by environmental factors (Fig. 5).

Fig. 5

Current understanding of extrinsic mechanisms of acquired neurodevelopmental disorders. Acquired neurodevelopmental disorders may be caused by dysregulations of epigenetic mechanisms due to harmful environmental factors; these failures might be reversed by favorable factors that restore the normal epigenetic mechanism.

Epigenetic treatment based on epigenetics’ reversibility

We are hopeful that the environmentally induced adverse epigenetic changes can be reversed by appropriate drugs. In fact, some of the drugs used for mental disorders have been found to restore the normal epigenetic status of neuronal genesReference Tsankova, Berton and Renthal 39 – Reference Wang, Xu and Li 43 (Fig. 5). Folic acid, for example, is a nutritional component that supplies methyl residues to DNA, RNA and proteins, and its administration to pregnant rats resulted in altered DNA methylation in the offspring.Reference Waterland and Jirtle 47 Furthermore, the offspring of rats given folic acid supplementation during pregnancy under malnutrition conditions exhibited higher levels of methylation of a hepatic gene than did offspring of malnourished mothers not given the supplement.Reference Lillycrop, Phillips, Jackson, Hanson and Burdge 18 Administration of folic acid is known to be beneficial for the treatment of neurodevelopmental disorders (e.g. autistic spectrum disorder) in children, an effect that may be mediated via restoration of the normal DNA methylation status in disease-related gene regions.Reference Rimland 48 , Reference Moretti, Sahoo and Hyland 50 In addition to folic acid, other environmental factors have also been reported to alter DNA methylation and histone modification status in the brain and other organs of mice and other species: royal jelly,Reference Kucharski, Maleszka, Foret and Maleszka 51 drugs for mental disorders,Reference Tsankova, Berton and Renthal 39 – Reference Wang, Xu and Li 43 environmental chemicals,Reference Yaoi, Itoh and Nakamura 52 , Reference Gore, Walker, Zama, Armenti and Uzumcu 53 external stimuli (electro-convulsive treatment for psychiatric diseases)Reference Ma, Jang and Guo 54 and regular exercise.Reference Ling and Rönn 55

As described above, mental stress in the 1st week of life can cause epigenetic abnormalities in the brains of mice. Conversely, several mouse studies demonstrated that environmentally stimulating conditions can ameliorate behavior abnormalities. Mice that live in an enriched environment, consisting of larger-sized home cages with a variety of objects including running wheels, show improved motor coordination and decreased anxiety-related behavior in heterozygous Mecp2 +/− female mice, a model of Rett syndrome.Reference Kondo, Gray and Pelka 56 , Reference Lonetti, Angelucci and Morando 57 Enriched environments also improved locomotor activity, reduced ventricular volume and restored the expression of synaptic markers, including synaptophysin and PSD95 in the hypothalamus and syntaxin 1a and synaptotagmin in the cortex of hemizygous Mecp2 −/Y male mice.Reference Nag, Moriuchi and Peitzman 58 , Reference Kerr, Silva, Walz and Young 59

It is widely accepted that curing patients with congenital neurodevelopmental disorders is very difficult. However, it was recently demonstrated that the epigenetic disorder Rett syndrome might be an exception to this expectation, partly because MECP2 does not encode a product required for brain structure, but rather encodes a ‘lubricant’ that works at a relatively late period of brain development. As a consequence, reintroduction of MECP2 into Mecp2-null mice either beforeReference Luikenhuis, Giacometti, Beard and Jaenisch 60 or even after birth was sufficient to rescue Rett-like neurological symptoms.Reference Guy, Gan, Selfridge, Cobb and Bird 61 Furthermore, restoration of MeCP2 function in astrocytes restored dendritic morphology and substantially improved locomotion, anxiety levels and respiratory abnormalities in hemizygous Mecp2 −/Y male mice.Reference Lioy, Garg and Monaghan 62 These results suggest that upregulation of MECP2 might help to improve brain function in Rett syndrome patients. Valproic acid, one of the most popular drugs against epileptic seizures and a known HDAC inhibitor, also restore MeCP2 expression;Reference Vecsler, Simon, Amariglio, Rechavi and Gak 63 , Reference Abel and Zukin 64 similar effects were seen with fluoxetine, a drug for mental disorders, and cocaine.Reference Cassel, Carouge and Gensburger 65 Taken together, these results indicate that neurodevelopmental disorders caused by epigenetic abnormalities are potentially treatable.

Transgenerational epigenetic inheritance

According to current understanding in the field of biology, one’s acquired character is not inherited by the next generation of offspring. Based on this notion of Darwinian inheritance, acquired changes induced by harmful habits (e.g. smoking) during one’s lifetime should not be transmitted to one’s children. However, recent advances in epigenetics have revealed that such undesirable acquired traits (e.g. smoking-induced DNA methylation changesReference Breitling, Yang, Korn, Burwinkel and Brenner 45 , Reference Shenker, Polidoro and van Veldhoven 46 ) might be transmitted to the next generation.

Epigenetic marks, either DNA methylation or histone modifications, allow the mitotic transmission of gene activity states from one cell to its daughter cells. A fundamental question in epigenetics is whether these marks can also be transmitted meiotically through the germline. In mammals, epigenetic marks should be cleared by demethylating factors such as the cytidine deaminases and re-established in each generation, but this clearing is incomplete at some loci in the genome of several model organisms possibly due to deficient demethylating factors.Reference Popp, Dean and Feng 66 Therefore, ‘transgenerational epigenetic inheritance,’ which refers to the germline transmission of an environment-induced epigenetic mark,Reference Daxinger and Whitelaw 67 , Reference Horsthemke 68 may provide a direct biological proof for Lamarckism, the hypothesis that an organism can pass on to its offspring characteristics that it acquired during its lifetime; that is, an hypothesis of the heritability of acquired characteristics.

Transgenerational inheritance of epigenetic marks was first demonstrated in a specific mouse strain. The methylation status at the Axin (Fu) locus in mature sperm reflects the methylation state of the allele in the somatic tissue of the animal, is linked to the shape of the animal’s tail, and does not undergo epigenetic reprogramming during gametogenesis.Reference Rakyan, Chong and Champ 69

Environmental factors, notably the fungicide vinclozilin, stress responses and nutritional challenges, have been associated with transgenerational epigenetic inheritance in animal models. However, it is often difficult to dissect evidence of transmission of epigenetic marks per se from transmission of the exposure itself.Reference Relton and Davey Smith 70 , Reference Kappeler and Meaney 71 Therefore, transgenerational effects should be distinguished from parental and grandparental effects. In addition to contributing to their DNA, parents can influence their offspring in many other ways: for example, by contributing bioactive molecules in the egg and sperm cytoplasm, and by providing nutrients and hormonal information during embryogenesis. Malnutrition during pregnancy affects not only the pregnant mother and fetus but also the fetus’s primordial germ cells, which can lead to phenotypic changes in the grandchildren (second generation). Actually, the specific diet- (supplementation of folic acid) induced methylation status at the Axin (Fu) locus linked to hair color of the animal’s skin was inherited over two generations, but this status was lost by the third generation.Reference Waterland, Travisano and Tahiliani 72 These reports indicated that, while the specific diet leads to parental and grandparental effects, the acquired epigenetic information was not simply inherited transgenerationally, and further suggested that the Axin (Fu) locus was resistant to environmentally induced acquisition of new germ-line epigenetic information.Reference Waterland, Travisano and Tahiliani 72

Transgenerational effects of environmental toxins (e.g. the endocrine disruptors vinclozolin, an anti-androgenic compound), and methyoxychlor, an estrogenic compound), were demonstrated in the fourth generation (F4) in rats with decreased spermatogenic capacity and increased male infertility. Moreover, the effects on reproduction correlated with altered DNA methylation patterns in the germ line.Reference Anway, Cupp, Uzumcu and Skinner 73 It was also demonstrated that plastic-derived endocrine disrupters, including bisphenol-A, increased the risk of pubertal abnormalities, diseases of the testes and ovaries, in the F3 generation in rats, and that differential DNA methylated patterns were identified for the plastic- and control-lineage F3 generation sperm,Reference Manikkam, Tracey, Guerrero-Bosagna and Skinner 74 suggesting the existence of ‘true’ transgenerational epigenetic inheritance up to the third generation in experimental animals. This observation has also been confirmed in Drosophila, in which an aberrant epigenetic mark (defective chromatin state) induced by environmental stress (e.g. heat shock) was inherited by the next generation.Reference Seong, Li, Shimizu, Nakamura and Ishii 75

As described above, short-term mental stress due to maternal-neonate separation immediately after birth alters the epigenetic status in the brain of the neonate and results in persistent abnormal behaviorReference Sasaki and Matsui 16 (Fig. 4). It has further been demonstrated that such environmentally induced epigenetic changes occur not only in the brain but also in the sperm and, thus, aberrant environmentally induced epigenetic marks acquired in one generation can be inherited by the next generation.Reference Franklin, Russig and Weiss 76 In other words, chronic maternal separation altered behaviors and DNA methylation of the promoter of several genes in the germline of maternally separated mice; the altered epigenetic changes were then observed in the brains of the offspring along with altered gene expression, including decreases in the expression of the corticotropin releasing factor receptor 2 gene (Crfr2) in the amygdala and hypothalamus.Reference Franklin, Russig and Weiss 76 In this study, abnormal behavior was observed even in the third generation and altered DNA methylation in the CpG islands of Mecp2, the cannabinoid receptor-1 gene (Cb1), and Crfr2 were observed in F1 sperm and F2 brain.Reference Franklin, Russig and Weiss 76 In a separate study, chronic maternal separation increased cytosine methylation of the estrogen receptor-alpha1b gene promoter, indicating that individual differences in maternal behavior are epigenetically transmitted from the mother to her female offspring.Reference Champagne, Weaver and Diorio 77 A recent study also suggested that abnormal liver lipid metabolism programmed by in utero undernutrition was transmitted to the next generation with hypomethylation of the liver X receptor alpha gene (Lxra) in sperm from F1 to F2 in mice.Reference Martínez, Pentinat and Ribó 78 , Reference Jones 79 These findings provide biological evidence suggesting that environmental factors, including undernutrition during the fetal period and traumatic experiences in early life, are risk factors for the development of behavioral and emotional disorders not only in one generation but also in the successive generations.

Future perspectives

It was believed that environmentally induced epigenetic alterations were thoroughly erased during the two large waves of resetting of epigenetic marks at gametogenesis, which establishes a new imprinting pattern, and after fertilization, which establishes tissue-specific epigenomic patterns as described above (Fig. 1). However, as discussed, several lines of evidence suggest that environmentally induced epigenetic alterations are not completely erased but are at least partially maintained at gametogenesis, and thus such information (epigenomic signature) is transmitted to the next generation. It is therefore important to detect epigenomic signatures (epigenetic alterations induced by environmental factors) during early postnatal life to allow preemptive treatments, including early intervention by supplying appropriate nurturing, nutrition and drugs (e.g. HDAC inhibitorReference Tsankova, Berton and Renthal 39 , Reference Jessberger, Nakashima and Clemenson 40 , Reference Xu, Spragni, Jacques, Rsche and Gottesfeld 80 , Reference leiman, Berlin and Basso 81 ) to restore the normal epigenetic patterns (Fig. 6). To identify epigenomic signatures (e.g. changes in DNA methylation), methylation arrays or next-generation sequence-based techniques are powerful and useful. Once several genomic regions that are useful for assessing health or diagnosing diseases are identified, simple and cost-effective detection methods, such as pyrosequencing/mass spectrometry-based methods and HPLC columns for detection of DNA methylation alteration (Miyake, Kubota et al. manuscript in preparation) will be useful. Also, the integration of neuroimaging methods with ‘epigenomic signature’ analyses to detect epigenetic abnormalities in the brain in ‘real-time’ will be essential.Reference Wiers 82 – Reference Wang, Schroeder and Hooker 85

Fig. 6

Epigenetic-based preemptive treatment of neurodevelopmental disorders. Early detection, via blood analyses or neuroimaging, of epigenomic signatures induced by environmental stresses during fetal and infant periods opens a path for early intervention in neurodevelopmental disorders by offering an appropriate environment, nutrition or drugs to restore normal epigenetic patterns.

In conclusion, epigenetic modifications can be altered by various environmental factors, such as nutrition, mental stress and environmental chemicals. Therefore, targets for the screening of epigenomic signatures will be individuals who previously suffered from these environmental factors as well as their descendants. Furthermore, because altered epigenetic modifications are reversible, epigenomic signatures are potentially useful not only as disease-diagnostic markers but also as therapeutic markers. To date, objective markers are not available for neurodevelopmental disorders; thus, the establishment of epigenomic signature for these disorders holds the promise of preemptive treatment for the patients. Moreover, healthcare based on epigenomic signatures will be important because it not only treats the patient, but can also has an impact on potential future generations.

Financial Support

The research described in this review was partially supported by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Grants-in-Aid (KAKENHI) for Scientific Research (B) (#26293245 to T.K.), for Exploratory Research (#25670473 to T.K.), and by the Ministry of Economy, Trade and Industry (METI) for ‘Development of core technologies for innovative drug development based upon IT’ in the Project focused on developing key technology of discovering and manufacturing drug for next-generation treatment and diagnosis (the Biological verifying studies to T.K.).

Conflicts of Interest

None.

Ethical Standards

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guides on the care and use of laboratory animals (University of Yamanashi) and has been approved by the institutional committee (University of Yamanashi).

References

1. Inoue, K, Kanai, M, Tanabe, Y, et al. Prenatal interphase FISH diagnosis of PLP1 duplication associated with Pelizaeus–Merzbacher disease. Prenat Diagn. 2001; 21, 1133–1136.Google Scholar
2. Reiner, O, Carrozzo, R, Shen, Y, et al. Isolation of a Miller-Dieker lissencephaly gene containing g protein beta-subunit-like repeats. Nature. 1993; 364, 717–721.Google Scholar
3. Bi, W, Sapir, T, Shchelochkov, OA, et al. Increased LIS1 expression affects human and mouse brain development. Nat Genet. 2009; 41, 168–177.CrossRefGoogle ScholarPubMed
4. Online Mendelian Inheritance in Man (OMIM): #118220. Retrieved 31 January 2015 from http://www ncbi nlm nih gov/entrez/ Google Scholar
5. Obi, T, Nishioka, K, Ross, OA, et al. Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology. 2008; 70, 238–241.Google Scholar
6. Waddington, CH. Epigenotype. Endeavour. 1942; 1, 18–20.Google Scholar
7. Sharma, S, Kelly, TK, Jones, PA. Epigenetics in cancer. Carcinogenesis. 2010; 31, 27–36.Google Scholar
8. Kubota, T, Das, S, Christian, SL, et al. Methylation-specific PCR simplifies imprinting analysis. Nat Genet. 1997; 16, 16–17.CrossRefGoogle ScholarPubMed
9. Nicholls, RD, Saitoh, S, Horsthemke, B. Imprinting in Prader-Willi and Angelman syndromes. Trends Genet. 1998; 14, 194–200.Google Scholar
10. Duker, AL, Ballif, BC, Bawle, EV, et al. Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader-Willi syndrome. Eur J Hum Genet. 2010; 18, 1196–1201.Google Scholar
11. Runte, M, Kroisel, PM, Gillessen-Kaesbach, G, et al. SNURF-SNRPN and UBE3A transcript levels in patients with Angelman syndrome. Hum Genet. 2004; 114, 553–561.Google Scholar
12. Kubota, T, Saitoh, S, Matsumoto, T, et al. Excess functional copy of allele at chromosomal region 11p15 may cause Wiedemann-Beckwith (EMG) syndrome. Am J Med Genet. 1994; 49, 378–383.CrossRefGoogle ScholarPubMed
13. Gene Reviews (internet): Beckwith-Wiedemann syndrome. Retrieved 31 January 2015 from http://www.ncbi.nlm.nih.gov/books/NBK1394/ Google Scholar
14. Kubota, T, Wakui, K, Nakamura, T, et al. Proportion of the cells with functional X disomy is associated with the severity of mental retardation in mosaic ring X Turner syndrome females. Cytogenet Genome Res. 2002; 99, 276–284.CrossRefGoogle ScholarPubMed
15. Kubota, T, Nonoyama, S, Tonoki, H, et al. A new assay for the analysis of X-chromosome inactivation based on methylation-specific PCR. Hum Genet. 1999; 104, 49–55.Google Scholar
16. Sasaki, H, Matsui, Y. Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet. 2008; 9, 129–140.CrossRefGoogle ScholarPubMed
17. Sakashita, K, Koike, K, Kinoshita, T, et al. Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development. J Clin Invest. 2001; 108, 1195–1204.CrossRefGoogle ScholarPubMed
18. Lillycrop, KA, Phillips, ES, Jackson, AA, Hanson, MA, Burdge, GC. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr. 2005; 135, 1382–1386.Google Scholar
19. Lillycrop, KA, Phillips, ES, Torrens, C, et al. Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br J Nutr. 2008; 100, 278–282.CrossRefGoogle ScholarPubMed
20. Weaver, IC, Cervoni, N, Champagne, FA, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004; 7, 847–854.Google Scholar
21. Nolen, LD, Gao, S, Han, Z, et al. X chromosome reactivation and regulation in cloned embryos. Dev Biol. 2005; 279, 525–540.Google Scholar
22. Okano, M, Bell, DW, Haber, DA, et al. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999; 99, 247–257.Google Scholar
23. Shirohzu, H, Kubota, T, Kumazawa, A, et al. Three novel DNMT3B mutations in Japanese patients with ICF syndrome. Am J Med Genet. 2002; 112, 31–37.CrossRefGoogle ScholarPubMed
24. Kubota, T, Furuumi, H, Kamoda, T, et al. ICF syndrome in a girl with DNA hypomethylation but without detectable DNMT3B mutation. Am J Med Genet. A. 2004; 129, 290–293.Google Scholar
25. Tatton-Brown, K, Seal, S, Ruark, E, et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014; 46, 385–388.Google Scholar
26. Amir, RE, Van den Veyver, IB, Wan, M, et al. Rett syndrome is caused by mutations in X-linked MECP2 encoding methyl-CpG-binding protein 2. Nat Genet. 1999; 23, 185–188.Google Scholar
27. Chunshu, Y, Endoh, K, Soutome, M, et al. A patient with classic Rett syndrome with a novel mutation in MECP2 exon 1. Clin Genet. 2006; 70, 530–531.Google Scholar
28. Miyake, K, Hirasawa, T, Soutome, M, et al. The protocadherins, PCDHB1 and PCDH7, are regulated by MeCP2 in neuronal cells and brain tissues: implication for pathogenesis of Rett syndrome. BMC Neurosci. 2011; 12, 81.Google Scholar
29. Lumey, LH. Decreased birthweights in infants after maternal in utero exposure to the Dutch famine of 1944-1945. Paediatr Perinat Epidemiol. 1992; 6, 240–253.CrossRefGoogle Scholar
30. Painter, RC, de Rooij, SR, Bossuyt, PM, et al. Early onset of coronary artery disease after prenatal exposure to the Dutch famine. Am J Clin Nutr. 2006; 84, 322–327.Google Scholar
31. St Clair, D, Xu, M, Wang, P, et al. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959–1961. JAMA. 2005; 294, 557–562.Google Scholar
32. Gluckman, PD, Seng, CY, Fukuoka, H, Beedle, AS, Hanson, MA. Low birthweight and subsequent obesity in Japan. Lancet. 2007; 369, 1081–1082.Google Scholar
33. Tobi, EW, Lumey, LH, Talens, RP, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009; 18, 4046–4053.Google Scholar
34. Lim, D, Bowdin, SC, Tee, L. Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies. Hum Reprod. 2009; 24, 741–747.CrossRefGoogle ScholarPubMed
35. Tee, L, Lim, DH, Dias, RP, et al. Epimutation profiling in Beckwith-Wiedemann syndrome: relationship with assisted reproductive technology. Clin Epigenetics. 2013; 5, 23.Google Scholar
36. McGowan, PO, Sasaki, A, D’Alessio, AC, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009; 12, 342–348.Google Scholar
37. Murgatroyd, C, Patchev, AV, Wu, Y, et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci. 2009; 12, 1559–1566.Google Scholar
38. Kim, YS, Leventhal, BL, Koh, YJ, et al. Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry. 2011; 168, 904–912.Google Scholar
39. Tsankova, NM, Berton, O, Renthal, W, et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci. 2006; 9, 519–525.Google Scholar
40. Jessberger, S, Nakashima, K, Clemenson, GD Jr, et al. Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. J Neurosci. 2007; 27, 5967–5975.Google Scholar
41. Dong, E, Nelson, M, Grayson, DR, Costa, E, Guidotti, A. Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proc Natl Acad Sci USA. 2008; 105, 13614–13619.Google Scholar
42. Dong, E, Chen, Y, Gavin, DP, Grayson, DR, Guidotti, A. Valproate induces DNA demethylation in nuclear extracts from adult mouse brain. Epigenetics. 2010; 5, 730–735.Google Scholar
43. Wang, Q, Xu, X, Li, J, et al. Lithium, an anti-psychotic drug, greatly enhances the generation of induced pluripotent stem cells. Cell Res. 2011; 21, 1424–1435.CrossRefGoogle ScholarPubMed
44. Ma, DK, Jang, MH, Guo, JU, et al. Neuronal activity–induced gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science. 2009; 323, 1074–1077.Google Scholar
45. Breitling, LP, Yang, R, Korn, B, Burwinkel, B, Brenner, H. Tobacco-smoking-related differential DNA methylation: 27 K discovery and replication. Am J Hum Genet. 2011; 88, 450–457.Google Scholar
46. Shenker, NS, Polidoro, S, van Veldhoven, K, et al. Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking. Hum Mol Genet. 2013; 22, 843–851.Google Scholar
47. Waterland, RA, Jirtle, RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003; 23, 5293–5300.Google Scholar
48. Rimland, B. Controversies in the treatment of autistic children: vitamin and drug therapy. J Child Neurol. 1988; 3(Suppl.), S68–S72.CrossRefGoogle ScholarPubMed
49. James, SJ, Cutler, P, Melnyk, S, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004; 80, 1611–1617.Google Scholar
50. Moretti, P, Sahoo, T, Hyland, K, et al. Cerebral folate deficiency with developmental delay; autism; and response to folinic acid. Neurology. 2005; 64, 1088–1090.Google Scholar
51. Kucharski, R, Maleszka, J, Foret, S, Maleszka, R. Nutritional control of reproductive status in honeybees via DNA methylation. Science. 2008; 319, 1827–1830.Google Scholar
52. Yaoi, T, Itoh, K, Nakamura, K, et al. Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A. Biochem Biophys Res Commun. 2008; 376, 563–567.Google Scholar
53. Gore, AC, Walker, DM, Zama, AM, Armenti, AE, Uzumcu, M. Early life exposure to endocrine-disrupting chemicals causes lifelong molecular reprogramming of the hypothalamus and premature reproductive aging. Mol Endocrinol. 2011; 25, 2157–2168.Google Scholar
54. Ma, DK, Jang, MH, Guo, JU, et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science. 2009; 323, 1074–1077.Google Scholar
55. Ling, C, Rönn, T. Epigenetic adaptation to regular exercise in humans. Drug Discov Today. 2014; 19, 1015–1018.Google Scholar
56. Kondo, M, Gray, LJ, Pelka, GJ, et al. Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndrome-Mecp2 gene dosage effects and BDNF expression. Eur J Neurosci. 2008; 27, 3342–3350.Google Scholar
57. Lonetti, G, Angelucci, A, Morando, L, et al. Early environmental enrichment moderates the behavioral and synaptic phenotype of MeCP2 null mice. Biol Psychiatry. 2010; 67, 657–665.Google Scholar
58. Nag, N, Moriuchi, JM, Peitzman, CG, et al. Environmental enrichment alters locomotor behaviour and ventricular volume in MeCP2 1lox mice. Behav Brain Res. 2009; 196, 44–48.CrossRefGoogle ScholarPubMed
59. Kerr, B, Silva, PA, Walz, K, Young, JI. Unconventional transcriptional response to environmental enrichment in a mouse model of Rett syndrome. PLoS One. 2010; 5, e11534.Google Scholar
60. Luikenhuis, S, Giacometti, E, Beard, CF, Jaenisch, R. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc Natl Acad Sci USA. 2004; 101, 6033–6038.Google Scholar
61. Guy, J, Gan, J, Selfridge, J, Cobb, S, Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science. 2007; 315, 1143–1147.Google Scholar
62. Lioy, DT, Garg, SK, Monaghan, CE, et al. A role for glia in the progression of Rett’s syndrome. Nature. 2011; 475, 497–500.Google Scholar
63. Vecsler, M, Simon, AJ, Amariglio, N, Rechavi, G, Gak, E. MeCP2 deficiency downregulates specific nuclear proteins that could be partially recovered by valproic acid in vitro. Epigenetics. 2010; 5, 61–67.Google Scholar
64. Abel, T, Zukin, RS. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol. 2008; 8, 57–64.Google Scholar
65. Cassel, S, Carouge, D, Gensburger, C, et al. Fluoxetine and cocaine induce the epigenetic factors MeCP2 and MBD1 in adult rat brain. Mol Pharmacol. 2006; 70, 487–492.Google Scholar
66. Popp, C, Dean, W, Feng, S, et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature. 2011; 463, 1101–1105.CrossRefGoogle Scholar
67. Daxinger, L, Whitelaw, E. Transgenerational epigenetic inheritance: more questions than answers. Genome Res. 2010; 20, 1623–1628.CrossRefGoogle ScholarPubMed
68. Horsthemke, B. Heritable germline epimutations in humans. Nat Genet. 2007; 39, 573–574.Google Scholar
69. Rakyan, VK, Chong, S, Champ, ME, et al. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci USA. 2003; 100, 2538–2543.Google Scholar
70. Relton, CL, Davey Smith, G. Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. Int J Epidemiol. 2012; 41, 161–176.Google Scholar
71. Kappeler, L, Meaney, MJ. Epigenetics and parental effects. Bioessays. 2010; 32, 818–827.Google Scholar
72. Waterland, RA, Travisano, M, Tahiliani, KG. Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J. 2007; 21, 3380–3385.Google Scholar
73. Anway, MD, Cupp, AS, Uzumcu, M, Skinner, MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005; 308, 1466–1469, Erratum in: Science. 2010; 328, 690.Google Scholar
74. Manikkam, M, Tracey, R, Guerrero-Bosagna, C, Skinner, MK. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One. 2013; 8, e55387.CrossRefGoogle ScholarPubMed
75. Seong, KH, Li, D, Shimizu, H, Nakamura, R, Ishii, S. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell. 2011; 145, 1049–1061.Google Scholar
76. Franklin, TB, Russig, H, Weiss, IC, et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry. 2010; 68, 408–415.Google Scholar
77. Champagne, FA, Weaver, IC, Diorio, J, et al. Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology. 2006; 147, 2909–2915.Google Scholar
78. Martínez, D, Pentinat, T, Ribó, S, et al. In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered lxra DNA methylation. Cell Metab. 2014; 19, 941–951.Google Scholar
79. Jones, B. Epigenetics: transgenerational effects of in utero malnutrition. Nat Rev Genet. 2014; 15, 364.Google Scholar
80. Xu, C, Spragni, E, Jacques, V, Rsche, JR, Gottesfeld, JM. Improved histone deacetylase inhibitors as therapeutics for the neurodegenerative disease Friedreich’s ataxia: a new synthetic route. Pharmaceuticals. 2011; 4, 1578–1590.Google Scholar
81. leiman, SF, Berlin, J, Basso, M, et al. Histone deacetylase inhibitors and mitramycin a impact a similar neuroprotective pathway at a crossroad between cancer and neurodegeneration. Pharmaceuticals. 2011; 4, 1183–1185.Google Scholar
82. Wiers, CE. Methylation and the human brain: towards a new discipline of imaging epigenetics. Eur Arch Psychiatry Clin Neurosci. 2012; 262, 271–273.Google Scholar
83. Lista, S, Garaci, FG, Toschi, N, Hampel, H. Imaging epigenetics in Alzheimer’s disease. Curr Pharm Des. 2013; 19, 6393–6415.Google Scholar
84. Wang, Y, Zhang, YL, Hennig, K, et al. Class I HDAC imaging using [(3)H]CI-994 autoradiography. Epigenetics. 2013; 8, 756–764.Google Scholar
85. Wang, C, Schroeder, FA, Hooker, JM. Visualizing epigenetics: current advances and advantages in HDAC PET imaging techniques. Neuroscience. 2014; 264, 186–197.Google Scholar
Figure 0

Fig. 1 Erasure and establishment of genomic imprinting. Inherited maternal and paternal imprints are erased and new imprinting is established according to the individual’s sex during the processes of spermatogenesis and oogenesis.

Figure 1

Fig. 2 Neurodevelopmental disorders caused by epigenetic abnormalities. (a) Abnormal suppression of the active allele of imprinted genes causes genomic imprinting disorders. (b) Abnormal activation of the inactive X chromosome in females causes X-chromosome inactivation disorders. (c) Mutations in genes encoding a DNA methyltransferase produces a deficiency resulting in insufficient DNA methylation, which in turn leads to aberrant expression of the target genes. (d) Mutations in genes encoding methyl-CpG binding proteins causes abnormal regulation of the target genes.

Figure 2

Fig. 3 Epigenetic basis of the linkage between maternal nutrition and predicting future neurodevelopmental outcomes in the offspring. Maternal malnutrition (especially folic acid deficiency, a methylation residue) induces a low DNA methylation status of metabolic genes in the liver of the fetus, which causes overexpression of the target genes and development of an origin of obese in the fetus. This status is good for survival of the fetus in the malnutritional environment, but if it then nurtured in a well-fed society after birth, it will develop obesity and diabetes mellitus during its adult period. A recent report demonstrated that the in utero malnutrition-programmed liver lipid metabolism can be inherited by the second generation, suggesting that the nutritional environment-induced ‘DOHaD nature’ can be transmitted to the descendants.

Figure 3

Fig. 4 Epigenetic mechanism that bridges mental stress and neuronal gene function. Environmental factors (e.g. maternal separation-stress during the 1st week of life) can alter the epigenetic status (e.g. DNA methylation) in a neuronal gene (e.g. the glucocorticoid receptor gene promoter) in the rat brain, which leads to persistent gene expression changes, that result in abnormal behavior throughout the lifespan of the individual.

Figure 4

Fig. 5 Current understanding of extrinsic mechanisms of acquired neurodevelopmental disorders. Acquired neurodevelopmental disorders may be caused by dysregulations of epigenetic mechanisms due to harmful environmental factors; these failures might be reversed by favorable factors that restore the normal epigenetic mechanism.

Figure 5

Fig. 6 Epigenetic-based preemptive treatment of neurodevelopmental disorders. Early detection, via blood analyses or neuroimaging, of epigenomic signatures induced by environmental stresses during fetal and infant periods opens a path for early intervention in neurodevelopmental disorders by offering an appropriate environment, nutrition or drugs to restore normal epigenetic patterns.