title: Early maternal alcohol consumption alters hippocampal DNA methylation, gene expression and volume in a mouse model.
abstract: The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first 8 days of gestation (GD 0.5-8.5). Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P) 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60): we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in different tissue types later in life.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Marjonen
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Sierra
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Nyman
authors.affiliation: Institute of Biomedicine & Genome-Scale Biology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Rogojin
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Gröhn
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
authors.forename: Anni-Maija
authors.initials: AM
authors.lastname: Linden
authors.affiliation: Institute of Biomedicine & Genome-Scale Biology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Kaminen-Ahola
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D054444:Immunoglobulin Light Chains, Surrogate / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D054261:Neurulation / Q000187:drug effects / Q000235:genetics; D009830:Olfactory Bulb / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018035:Receptors, Odorant / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D054444:Immunoglobulin Light Chains, Surrogate; D035683:MicroRNAs; D018035:Receptors, Odorant; C515638:pre-B lymphocyte gene 2 protein, mouse; D000431:Ethanol