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