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.
Highlights
Exposure to an adverse environment during pregnancy can harm the developing fetus and have life-long effects on the individual’s health and wellbeing
Gestational ethanol exposure leads to altered gene expression in adolescent hippocampus, bone marrow and main olfactory epithelium
To verify our array results we investigated if similar upregulated expression of Olfr601 and H2-M10.3 can be seen in both, hippocampus and main olfactory epithelium (MOE), and Vpreb2 in hippocampus and bone marrow
Summary
Exposure to an adverse environment during pregnancy can harm the developing fetus and have life-long effects on the individual’s health and wellbeing. Maternal alcohol consumption during pregnancy is a leading cause of nongenetic mental retardation and birth defects in the Western world [1], [2]. It can produce fetal alcohol spectrum disorders (FASD), which is an umbrella term for all alcohol-related neurodevelopmental disorders and birth defects. Fetal alcohol syndrome (FAS) with growth restriction, craniofacial dysmorphology, and central nervous system defects represents the most severe end of the FASD continuum. Alcohol consumption during early embryogenesis, the time frame around gastrulation when pregnancy may be unknown, has been shown to lead to a high FAS incidence [4], [5], [6]
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