Maternal Ethanol Consumption Alters the Epigenotype and the Phenotype of Offspring in a Mouse Model

Abstract

Recent studies have shown that exposure to some nutritional supplements and chemicals in utero can affect the epigenome of the developing mouse embryo, resulting in adult disease. Our hypothesis is that epigenetics is also involved in the gestational programming of adult phenotype by alcohol. We have developed a model of gestational ethanol exposure in the mouse based on maternal ad libitum ingestion of 10% (v/v) ethanol between gestational days 0.5–8.5 and observed changes in the expression of an epigenetically-sensitive allele, Agouti viable yellow (Avy), in the offspring. We found that exposure to ethanol increases the probability of transcriptional silencing at this locus, resulting in more mice with an agouti-colored coat. As expected, transcriptional silencing correlated with hypermethylation at Avy. This demonstrates, for the first time, that ethanol can affect adult phenotype by altering the epigenotype of the early embryo. Interestingly, we also detected postnatal growth restriction and craniofacial dysmorphology reminiscent of fetal alcohol syndrome, in congenic a/a siblings of the Avy mice. These findings suggest that moderate ethanol exposure in utero is capable of inducing changes in the expression of genes other than Avy, a conclusion supported by our genome-wide analysis of gene expression in these mice. In addition, offspring of female mice given free access to 10% (v/v) ethanol for four days per week for ten weeks prior to conception also showed increased transcriptional silencing of the Avy allele. Our work raises the possibility of a role for epigenetics in the etiology of fetal alcohol spectrum disorders, and it provides a mouse model that will be a useful resource in the continued efforts to understand the consequences of gestational alcohol exposure at the molecular level.

Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa

“…If these chromatin states also escaped reprogramming during gametogenesis, the inheritance program would function transgenerationally 13 . An increasing number of studies point to inter-or transgenerational transmission of acquired phenotypic traits that are related to temporal exposure of (grand-)parents to alternative instructive environmental cues [14][15][16][17][18] . Mechanistically, such phenotypic changes may be related to (transient) alterations of an intrinsic inheritance program.…”

Radiological studies of fetal alcohol spectrum disorders in humans and animal models: An updated comprehensive review

“…CT imaging revealed alterations in skull shape at PD28, including leftward deviation of the frontal bone (observed in one specimen), a smaller centroid area (Fig.8), wider inter-orbital distance and shorter midface [167]. At PD60, ex vivo MRI revealed asymmetric changes in the hippocampus and olfactory bulb, in which significant increase in hippocampal volume and decrease in olfactory bulb volume were both observed in the left hemisphere [168].…”

“…Moderate PAE (10% v/v provided ad libitum) from GD0-8 in C57Bl/6J mice, encompassing pre-implantation, implantation and the first two days of gastrulation, equivalent to the first 3 -4 weeks of human gestation [167], resulted in growth retardation (indicated by body weight) observable at the weaning (PD21) and extended into adulthood [167]. CT imaging revealed alterations in skull shape at PD28, including leftward deviation of the frontal bone (observed in one specimen), a smaller centroid area (Fig.8), wider inter-orbital distance and shorter midface [167].…”

Transgenerational epigenetic effects on animal behaviour

“…In one study, mice were given alcohol during the first part of gestation, and the effect on offspring methylation was assessed by the expression of the epigenetically regulated allele Agouti Viable Yellow (Kaminen-Ahola et al, 2010). Prenatal alcohol exposure caused hypermethylation and a substantial transcriptional silencing of the allele, leading to a higher number of mice with agouti-coloured fur.…”

“…Different forms of stressful challenges have been used as experimental treatments to induce such effect, for example maternal isolation and chemical exposure of various kinds (Banerjee, Arterbery, Fergus, & Adkins-Regan, 2011;16 Champagne & Curley, 2008;Kaminen-Ahola et al, 2010). Is this just a matter of experimental convenience, or is there something particular about the stress response, which makes it more likely than other physiological reactions to cause epigenetic changes relevant for behaviour?…”