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Early maternal alcohol consumption alters hippocampal DNA methylation, gene expression and volume in a mouse model.

Marjonen H, Sierra A, Nyman A, Rogojin V, Gröhn O, Linden AM, Hautaniemi S, Kaminen-Ahola N - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

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.

No MeSH data available.


Related in: MedlinePlus

Altered volumes of left and right hippocampi, olfactory bulbs, and lateral ventricles of ethanol-exposed offspring.Wilcoxon test was used to access left-right differences within the same animals (#) and Mann-Whitney test to compare control and ethanol-exposed (EtOH) mice (*). #/*p<0.05 and ###p<0.001. Each dot represents an individual adult male mouse (P60). Control mice are illustrated in black and ethanol-exposed offspring in grey. Bars are averaged values ± SD.
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pone.0124931.g007: Altered volumes of left and right hippocampi, olfactory bulbs, and lateral ventricles of ethanol-exposed offspring.Wilcoxon test was used to access left-right differences within the same animals (#) and Mann-Whitney test to compare control and ethanol-exposed (EtOH) mice (*). #/*p<0.05 and ###p<0.001. Each dot represents an individual adult male mouse (P60). Control mice are illustrated in black and ethanol-exposed offspring in grey. Bars are averaged values ± SD.

Mentions: Examples of increase in ventricular volume are shown in Fig 6. Control mice showed small lateral ventricular volume as compared to ethanol-exposed mice (Fig 6A and 6D), which varied between animals (Fig 6B,6C and 6E,6F). The most relevant volumetric findings are presented in Fig 7. Left hippocampal volume in ethanol-exposed mice was significantly higher as compared to that in control mice (p<0.05, Mann-Whitney) and to the right hippocampus in the same animals (p<0.001, Wilcoxon test) (Fig 7A). Left olfactory bulb volume was found to be significantly lower as compared to that in control mice (p<0.05, Mann-Whitney) (Fig 7B). The ventricular volumes of both hemispheres appeared slightly larger than those in control mice, however, no significant differences were found (Fig 7C).


Early maternal alcohol consumption alters hippocampal DNA methylation, gene expression and volume in a mouse model.

Marjonen H, Sierra A, Nyman A, Rogojin V, Gröhn O, Linden AM, Hautaniemi S, Kaminen-Ahola N - PLoS ONE (2015)

Altered volumes of left and right hippocampi, olfactory bulbs, and lateral ventricles of ethanol-exposed offspring.Wilcoxon test was used to access left-right differences within the same animals (#) and Mann-Whitney test to compare control and ethanol-exposed (EtOH) mice (*). #/*p<0.05 and ###p<0.001. Each dot represents an individual adult male mouse (P60). Control mice are illustrated in black and ethanol-exposed offspring in grey. Bars are averaged values ± SD.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430308&req=5

pone.0124931.g007: Altered volumes of left and right hippocampi, olfactory bulbs, and lateral ventricles of ethanol-exposed offspring.Wilcoxon test was used to access left-right differences within the same animals (#) and Mann-Whitney test to compare control and ethanol-exposed (EtOH) mice (*). #/*p<0.05 and ###p<0.001. Each dot represents an individual adult male mouse (P60). Control mice are illustrated in black and ethanol-exposed offspring in grey. Bars are averaged values ± SD.
Mentions: Examples of increase in ventricular volume are shown in Fig 6. Control mice showed small lateral ventricular volume as compared to ethanol-exposed mice (Fig 6A and 6D), which varied between animals (Fig 6B,6C and 6E,6F). The most relevant volumetric findings are presented in Fig 7. Left hippocampal volume in ethanol-exposed mice was significantly higher as compared to that in control mice (p<0.05, Mann-Whitney) and to the right hippocampus in the same animals (p<0.001, Wilcoxon test) (Fig 7A). Left olfactory bulb volume was found to be significantly lower as compared to that in control mice (p<0.05, Mann-Whitney) (Fig 7B). The ventricular volumes of both hemispheres appeared slightly larger than those in control mice, however, no significant differences were found (Fig 7C).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

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.

No MeSH data available.


Related in: MedlinePlus