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ALCOHOL RESEARCH: Current Reviews ALCOHOL RESEARCH: Current Reviews In Utero Alcohol Exposure, Epigenetic Changes, and Their Consequences Michelle Ungerer; Jaysen Knezovich, M.Sc.; and Michele Ramsay, Ph.D. Exposure to alcohol has serious consequences for the developing fetus, leading to a Michelle Ungerer is a Masters range of conditions collectively known as fetal alcohol spectrum disorders (FASD). student and Jaysen Knezovich, Most importantly, alcohol exposure affects the development of the brain during critical M.Sc., is a Ph.D. student and periods of differentiation and growth, leading to cognitive and behavioral deficits. The molecular mechanisms and processes underlying the teratogenic effects of alcohol lecturer in the Division of Human exposure remain poorly understood and are complex, because the specific effects Genetics, School of Pathology, depend on the timing, amount, and duration of exposure as well as genetic Faculty of Health Sciences, susceptibility. Accumulating evidence from studies on DNA methylation and histone University of the Witwatersrand modification that affect chromatin structure, as well as on the role of microRNAs in and the National Health Laboratory regulating mRNA levels supports the contribution of epigenetic mechanisms to the Service in Johannesburg, development of FASD. These epigenetic effects are difficult to study, however, because South Africa. they often are cell-type specific and transient in nature. Rodent models play an important role in FASD research. Although recent studies using these models have Michele Ramsay, Ph.D., is a yielded some insight into epigenetic mechanisms affecting brain development, they professor in the Division of have generated more questions than they have provided definitive answers. Human Genetics, National Health Researchers are just beginning to explore the intertwined roles of different epigenetic Laboratory Service, School of mechanisms in neurogenesis and how this process is affected by exposure to alcohol, Pathology, Faculty of Health causing FASD. KEY WORDS: Prenatal alcohol exposure; fetal alcohol spectrum Sciences, and Interim Director disorders; epigenetics; epigenetic mechanisms; epigenetic modifications; brain development; cognitive deficits; behavioral deficits; DNA methylation; histone of the Syndey Brenner Institute modification; chromatin; microRNAs; rodent models for Molecular Bioscience at the University of the Witwatersrand, Johannesburg, South Africa. lcohol exposure of the developing tant role in these processes. This article FASD embryo and fetus in utero can reviews the current knowledge regard- Ahave a wide range of detrimental ing the contributions of epigenetic FASD can be associated with a variety effects collectively referred to as fetal modifications to the manifestations of symptoms that differ widely in alcohol spectrum disorders (FASD). of FASD, much of which has been severity depending on the specific Researchers are intensively investigating obtained using rodent models in which conditions of alcohol exposure. The the mechanisms that may contribute to the timing, frequency, duration, and most severe outcome is fetal alcohol alcohol’s effects on the developing amount of alcohol exposure can be syndrome (FAS), which can manifest organism and to the resulting conse- tightly controlled. This discussion also variably with diverse combinations of quences, particularly with respect to touches on the concepts of develop- craniofacial, growth, central nervous the cognitive and behavioral deficits mental reprogramming, the role of system (CNS), and neurobehavioral associated with FASD. These studies preconception alcohol exposure, and abnormalities (Jones et al. 1973; Sampson have yielded increasing evidence that transgenerational transmission of the et al. 1997). Associated psychosocial epigenetic mechanisms play an impor- effects of alcohol exposure. problems include learning difficulties, In Utero Alcohol Exposure, Epigenetic Changes, and Their Consequences 37 attention deficit–hyperactivity disorder the ADH1B locus that result in an maintained through two mechanisms; (ADHD), and mental retardation altered amino acid sequence and function structural chromatin modifications (Burd et al. 2003; O’Leary 2004). of the encoded enzyme can influence (i.e., DNA methylation and histone Given that alcohol consumption is the severity of the adverse effects on modifications) and RNA interactions voluntary, FASD is said to be the the developing fetus (i.e., teratogenesis) (i.e., the actions of non-coding RNAs most preventable cause of birth defects in different ethnic populations (for a [ncRNAs]). In eukaryotes, the genome and mental retardation. FASD is a review see Ramsay 2010). However, is present in the cell nucleus in the global health concern, and worldwide to date few studies have supported a form of chromatin—a DNA–protein approximately 1 to 3 per 1,000 births role for genetics in the development complex that packages DNA into a is thought to be suffering from FAS. of FASD. highly condensed form. The structural In the United States, FAS prevalence Rodent models have provided a building blocks of chromatin are the ranges between 0.5 and 2.0 per 1,000 valuable tool for investigating genetic nucleosomes, each of which consists live births (Abel 1995; May and Gossage influences on the observable outcomes of 147 base pairs of DNA wrapped 2001). The highest rates of FAS have (i.e., phenotypes) associated with FASD. around a core of 8 histone proteins been reported in mixed-ancestry com- For example, the effects of in utero (Ooi and Henikoff 2007). The octamer munities in the Western Cape of South alcohol exposure differ between inbred core comprises two copies each of his- Africa, where between 68.0 and 89.2 and selectively bred mice. These find- tone proteins H2A, H2B, H3, and per 1,000 school-age children display ings highlight the contribution of a H4. Moreover, the nucleosomes are FAS symptoms (May et al. 2007). genetic predisposition to the suscepti- connected with each other by a linker Between 5 and 10 percent of bility to the detrimental effects of histone H1 that offers stability to the offspring who have been exposed to prenatal ethanol exposure and provide packaged structure. Modifications of alcohol prenatally display alcohol- additional support for the importance the chromatin structure affect the first related developmental anomalies (Abel of genetic factors in the development step of gene expression (i.e., transcrip- 1995), with the severity of the out- of FASD (Boehm et al. 1997; Gilliam tion). ncRNAs, on the other hand, act come determined by the dose, timing, et al. 1989; Ogawa et al. 2005). at the posttranscriptional level. and duration of exposure (Padmanabhan Although studies have investigated and Hameed 1988; Pierce and West the genetic susceptibility to FASD, the Chromatin Remodeling 1986; Sulik 1984). However, the pro- underlying cause(s) of these disorders portion of affected offspring may be still remains unclear. The wide range considerably higher in unfavorable of clinical features observed in people dnA Modifications. Both DNA and circumstances, including instances of affected by in utero alcohol exposure protein components of the nucleosome malnutrition of the mother and thus, underlines the importance of investigat- are subject to a variety of modifications the fetus. The genetic makeup of both ing the mechanisms of alcohol-related that can influence chromatin mother and fetus, in conjunction with teratogenesis at a molecular level. Because conformation and accessibility. The best-characterized epigenetic mark, other factors (e.g., gender, diet, and FASD is a developmental abnormality, DNA methylation, involves the social environment), also plays an impor- disruptions in normal cellular differen- covalent addition of a methyl (CH ) tant role in the manifestation of FASD tiation driven by changes in gene 3 group to one of the four DNA (Chernoff 1980; Ogawa et al. 2005). expression that in turn are regulated The effects of prenatal alcohol expo- nucleotides (i.e., cytosine [C]) to by epigenetic mechanisms are most form 5-methylcytosine (5mC). In sure are more similar in identical (i.e., likely involved in FASD pathogenesis. monozygotic) twins than in fraternal eukaryotes, methylation usually affects (i.e., dizygotic) twins, suggesting a her- C that are followed by the nucleotide itable component (Abel 1988; Chasnoff Epigenetic Modifications guanine (G) (i.e., that are part of a 1985; Streissguth and Dehaene 1993). CpG dinucleotide) (Rodenhiser and Genetic studies have shown that differ- The term epigenetics, first defined by Mann, 2006). At these sites, enzymes ent variants of the genes encoding Waddington in 1942 (as reprinted in called DNA methyltransferases various alcohol-metabolizing enzymes— Waddington 2012), refers to the changes (DNMTs) mediate the methylation such as alcohol dehydrogenases (ADHs), in gene expression that occur without 1 genomic imprinting is a genetic phenomenon in which only a aldehyde dehydrogenases (ALDHs), changes in the DNA sequence itself. gene copy inherited from one parent is expressed in the offspring. and cytochrome P450 2E1 (CYP2E1)— Epigenetics plays a vital role in regulat- each person inherits two copies of each gene, one inherited from the mother and one inherited from the father. in general, both of in the mother and their offspring can ing key developmental events, allowing these gene copies can be active in the offspring. For some genes, affect alcohol metabolism and con- for tissue-specific
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