Elsevier

Experimental Neurology

Volume 347, January 2022, 113919
Experimental Neurology

Review article
Potential roles of imprinted genes in the teratogenic effects of alcohol on the placenta, somatic growth, and the developing brain

https://doi.org/10.1016/j.expneurol.2021.113919Get rights and content

Abstract

Despite several decades of research and prevention efforts, fetal alcohol spectrum disorders (FASD) remain the most common preventable cause of neurodevelopmental disabilities worldwide. Animal and human studies have implicated fetal alcohol-induced alterations in epigenetic programming as a chief mechanism in FASD. Several studies have demonstrated fetal alcohol-related alterations in methylation and expression of imprinted genes in placental, brain, and embryonic tissue. Imprinted genes are epigenetically regulated in a parent-of-origin-specific manner, in which only the maternal or paternal allele is expressed, and the other allele is silenced. The chief functions of imprinted genes are in placental development, somatic growth, and neurobehavior—three domains characteristically affected in FASD. In this review, we summarize the growing body of literature characterizing prenatal alcohol-related alterations in imprinted gene methylation and/or expression and discuss potential mechanistic roles for these alterations in the teratogenic effects of prenatal alcohol exposure. Future research is needed to examine potential physiologic mechanisms by which alterations in imprinted genes disrupt development in FASD, which may, in turn, elucidate novel targets for intervention. Furthermore, mechanistic alterations in imprinted gene expression and/or methylation in FASD may inform screening assays that identify individuals with FASD neurobehavioral deficits who may benefit from early interventions.

Introduction

Despite extensive prevention efforts and more than five decades of research demonstrating teratogenic effects of alcohol, prenatal alcohol exposure remains the most common preventable cause of neurodevelopmental disabilities worldwide, with prevalence estimates of 1.1–5.0% in the US and Western Europe (May et al., 2018) and as much as 13.6–20.9% in endemic regions, such as Cape Town, South Africa (May et al., 2013). In a recent Centers for Disease Control analysis of National Survey on Drug Use and Health data (2015–2018) in the US, approximately 10% of pregnant women disclosed alcohol use in the past 30 days, with almost half of these women reporting binge drinking (i.e., 4 or more drinks per occasion) (England et al., 2020). Fetal alcohol spectrum disorders (FASD) are manifest by growth restriction and a broad range of cognitive and behavioral deficits, and teratogenic effects of alcohol have been documented in every organ system (Hoyme et al., 2016; Hoyme et al., 2005). Children with fetal alcohol syndrome (FAS), the most severe form of FASD, have a characteristic pattern of facial dysmorphology, growth restriction, and central nervous system (CNS) abnormalities, including structural brain abnormalities and neurobehavioral deficits (Hoyme et al., 2016; Hoyme et al., 2005). Numerous studies in animal models have implicated alcohol-induced alterations in epigenetic programming as a chief mechanism in FASD (Kobor and Weinberg, 2011; Lunde et al., 2016; Lussier et al., 2017). A large proportion of studies examining methylation and gene expression in FASD have found prenatal alcohol-related changes in imprinted genes, particularly in placental and brain tissue (Haycock and Ramsay, 2009; Laufer et al., 2013; Liu et al., 2009; Sathyan et al., 2007; Sittig et al., 2011; Stouder et al., 2011). Imprinted genes are a subset of genes that are epigenetically regulated in a parent-of-origin-specific manner, in which only the maternal or paternal allele is expressed, and the other allele is silenced. The purpose of this review is to examine evidence demonstrating prenatal alcohol-related alterations in imprinted gene expression and methylation—the imprintome—and their potential mechanistic roles in the teratogenic effects of alcohol. We first introduce imprinted genes and review literature demonstrating prenatal alcohol-related changes in the imprintome. We then discuss potential mechanisms underlying these changes, as well as potential interactions with methyl donor/one-carbon nutrients. We describe the striking similarities between the chief functional roles of imprinted genes and FASD growth and neurobehavioral deficits and review research demonstrating mechanistic roles of imprintome disruptions in FASD. We conclude with a discussion of potential clinical applications of imprintome disruptions in FASD and areas for future research.

Section snippets

Prenatal alcohol exposure leads to alterations in imprinted gene methylation and expression

Although only ~1% of genes are believed to be imprinted in the human genome, the functions of imprinted genes cluster in placental development, somatic growth, and neurobehavior, three domains that are strongly affected in FASD. The expression of imprinted genes can be altered by the intrauterine environment and, thus, potentially by prenatal alcohol exposure (Cassidy and Charalambous, 2018; Kappil et al., 2015a; Monk et al., 2019). Parent-of-origin allele-specific expression of many imprinted

Potential epigenetic mechanisms underlying prenatal alcohol-related imprintome alterations and potential interaction with one-carbon nutrients

A chief mechanism by which prenatal alcohol exposure leads to alterations in imprinted gene expression may be through disruptions in imprinting methylation patterns. Indeed, a growing body of research has demonstrated prenatal alcohol-related changes in methylation and expression of genes with roles in growth, metabolism, and neurodevelopment (Haycock and Ramsay, 2009; Laufer et al., 2013; Liu et al., 2009; Marjonen et al., 2018; Kobor and Weinberg, 2011; Lunde et al., 2016; Lussier et al., 2017

Potential roles of imprinted genes and placental, fetal, and postnatal growth restriction in FASD

Prenatal alcohol exposure characteristically leads to placental, fetal, and postnatal growth restriction (Carter et al., 2021; Carter et al., 2016a; Carter et al., 2012; Carter et al., 2013; Carter et al., 2016b; Fuller et al., 2005; Wang et al., 2014), all three of which are associated with imprinted gene dysregulation in experimental animal models (Plasschaert and Bartolomei, 2014). Imprinted genes play important roles in determining the placental phenotype: size, structure/morphology, and

Potential roles of imprinted genes in FASD neurobehavioral deficits

To examine the potential interplay between alcohol-related growth restriction and FASD neurobehavioral deficits, we stratified our original Cape Town cohort by child growth trajectory and examined the relations of alcohol exposure to a range of neurocognitive outcomes within each stratum (Carter et al., 2016a). Effect sizes among children with both fetal and postnatal growth restriction were markedly stronger—among the strongest in the literature to date—than those seen among children with

Conclusions and future research directions

As discussed above, a growing body of literature has demonstrated alterations in imprinted gene expression in the placenta and brain that likely play mechanistic roles in the teratogenic effects of alcohol. Table 1 lists all imprinted genes previously shown to be affected by prenatal alcohol exposure described in this review, with summaries of their roles in growth and neurobehavior and evidence of their potential importance in FASD. Animal and human studies have demonstrated prenatal

Funding

This work was funded by grants from NIH/National Institute on Alcohol Abuse and Alcoholism (R01AA016781, R21AA022203, R01AA027916) and National Institute of Environmental Health Sciences (P30ES023515) and from the Lycaki-Young Fund from the State of Michigan. The funding sources had no involvement in the decision to write this manuscript or in its content.

Declaration of Competing Interest

The authors have no conflicts to disclose.

References (185)

  • A.L. Fowden et al.

    Imprinted genes and the epigenetic regulation of placental phenotype

    Prog. Biophys. Mol. Biol.

    (2011)
  • E.M. Gårdebjer et al.

    Periconceptional alcohol consumption causes fetal growth restriction and increases glycogen accumulation in the late gestation rat placenta

    Placenta

    (2014)
  • K.P. Giese et al.

    Hippocampus-dependent learning and memory is impaired in mice lacking the ras-guanine-nucleotide releasing factor 1 (Ras-Grf1)

    Neuropharmacology

    (2001)
  • D.A. Hamilton et al.

    Children with fetal alcohol syndrome are impaired at place learning but not cued-navigation in a virtual morris water task

    Behav. Brain Res.

    (2003)
  • X. Joya et al.

    Prenatal ethanol exposure and placental Hcg and Igf2 expression

    Placenta

    (2015)
  • E. Keating et al.

    Acute and chronic effects of some dietary bioactive compounds on folic acid uptake and on the expression of folic acid transporters by the human trophoblast cell line bewo

    J. Nutr. Biochem.

    (2008)
  • E. Keating et al.

    Folic acid uptake by the human syncytiotrophoblast: interference by pharmacotherapy, drugs of abuse and pathological conditions

    Reprod. Toxicol.

    (2009)
  • N. Kikyo et al.

    Genetic and functional analysis of neuronatin in mice with maternal or paternal duplication of distal Chr 2

    Dev. Biol.

    (1997)
  • Y.I. Kim et al.

    Severe folate deficiency causes secondary depletion of choline and phosphocholine in rat liver

    J. Nutr.

    (1994)
  • H.M.A. Labib

    Alteration Of Cyp2e1, Dbn1, Dnmt1, Mirna-335, Mirna-21, C-Fos and Cox-2 gene expression in prefrontal cortex of rats’ offspring submitted to prenatal ethanol exposure during their neurodevelopment and the preventive role of nancocurcumin administration: a histological, ultrastructural and molecular Study

    J. Chem. Neuroanat.

    (2021)
  • L. Lambertini et al.

    Imprinted gene expression in fetal growth and development

    Placenta

    (2012)
  • C.W. Abbott et al.

    Prenatal ethanol exposure and neocortical development: a transgenerational model of fasd

    Cereb. Cortex

    (2018)
  • M.D.S. Ainsworth et al.

    Patterns of Attachment: A Psychological Study of the Strange Situation

    (1978)
  • S.L. Archibald et al.

    Brain dysmorphology in individuals with severe prenatal alcohol exposure

    Dev. Med. Child Neurol.

    (2001)
  • S. Aros et al.

    Effects Of prenatal ethanol exposure on postnatal growth and the insulin-like growth factor axis

    Horm. Res. Paediatr.

    (2011)
  • S. Astley et al.

    Magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders

    Alcohol. Clin. Exp. Res.

    (2009)
  • S. Balaraman et al.

    Plasma mirna profiles in pregnant women predict infant outcomes following prenatal alcohol exposure

    PLoS One

    (2016)
  • R.A. Bekdash et al.

    Gestational choline supplementation normalized fetal alcohol-induced alterations in histone modifications, dna methylation, and proopiomelanocortin (pomc) gene expression in β-endorphin-producing pomc neurons of the hypothalamus

    Alcohol. Clin. Exp. Res.

    (2013)
  • D. Bergman et al.

    Insulin-like growth factor 2 in development and disease: a mini-review

    Gerontology

    (2013)
  • D. Bhattacharya et al.

    Impaired Ilk function is associated with deficits in hippocampal based memory and synaptic plasticity in a fasd rat model

    PLoS One

    (2015)
  • D.J. Bonthius et al.

    Alcohol-induced neuronal loss in developing rats: increased brain damage with binge exposure

    Alcohol. Clin. Exp. Res.

    (1990)
  • R. Brambilla et al.

    A role for the ras signalling pathway in synaptic transmission and long-term memory

    Nature

    (1997)
  • K.D. Broad et al.

    Placental protection of the fetal brain during short-term food deprivation

    Proc. Natl. Acad. Sci. U. S. A.

    (2011)
  • R.C. Carter et al.

    Effects of heavy prenatal alcohol exposure and iron deficiency anemia on child growth and body composition through age 9 years

    Alcohol. Clin. Exp. Res.

    (2012)
  • R.C. Carter et al.

    Fetal alcohol-related growth restriction from birth through young adulthood and moderating effects of maternal prepregnancy weight

    Alcohol. Clin. Exp. Res.

    (2013)
  • R.C. Carter et al.

    Fetal Alcohol Growth Restriction And Cognitive Impairment

    Pediatrics

    (2016)
  • R.C. Carter et al.

    Alcohol, methamphetamine, and marijuana exposure have distinct effects on the human placenta

    Alcohol. Clin. Exp. Res.

    (2016)
  • R.C. Carter et al.

    Maternal alcohol use and nutrition during pregnancy: diet and anthropometry

    Alcohol. Clin. Exp. Res.

    (2017)
  • R.C. Carter et al.

    Alcohol-related alterations in placental imprinted gene expression in humans mediate effects of prenatal alcohol exposure on postnatal growth

    Alcohol. Clin. Exp. Res.

    (2018)
  • F.C. Cassidy et al.

    Genomic imprinting, growth and maternal–fetal interactions

    J. Exp. Biol.

    (2018)
  • B.M. Cattanach et al.

    Interactions between imprinting effects in the mouse

    Genetics

    (2004)
  • S.Y. Chan et al.

    The role of the placenta in thyroid hormone delivery to the fetus

    Nat. Clin. Pract. Endocrinol. Metab.

    (2009)
  • M. Charalambous et al.

    Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • M. Charalambous et al.

    Genomic imprinting, growth control and the allocation of nutritional resources: consequences for postnatal life

    Curr. Opin. Endocrinol. Diabetes Obes.

    (2007)
  • M. Chen et al.

    Alternative gnas gene products have opposite effects on glucose and lipid metabolism

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • D.Y. Chen et al.

    A critical role for Igf-Ii In memory consolidation and enhancement

    Nature

    (2011)
  • Hisafumi Chikamori et al.

    Distinctive expression pattern of peg10 in the mouse brain

    Eur. J. Anat.

    (2019)
  • M.A. Cleaton et al.

    Fetus-derived Dlk1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction

    Nat. Genet.

    (2016)
  • M. Constância et al.

    Placental-specific Igf-Ii is a major modulator of placental and fetal growth

    Nature

    (2002)
  • A. Cordova-Palomera et al.

    Birth weight, working memory and epigenetic signatures in Igf2 and related genes: a Mz twin study

    PLoS One

    (2014)
  • Cited by (0)

    View full text