Maternal Ethanol Consumption Alters the Epigenotype and the Phenotype of Offspring in a Mouse Model
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{"title"=>"Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model", "type"=>"journal", "authors"=>[{"first_name"=>"Nina", "last_name"=>"Kaminen-Ahola", "scopus_author_id"=>"14040594400"}, {"first_name"=>"Arttu", "last_name"=>"Ahola", "scopus_author_id"=>"35733186800"}, {"first_name"=>"Murat", "last_name"=>"Maga", "scopus_author_id"=>"54908259500"}, {"first_name"=>"Kylie Ann", "last_name"=>"Mallitt", "scopus_author_id"=>"35069963100"}, {"first_name"=>"Paul", "last_name"=>"Fahey", "scopus_author_id"=>"7006775369"}, {"first_name"=>"Timothy C.", "last_name"=>"Cox", "scopus_author_id"=>"53979641500"}, {"first_name"=>"Emma", "last_name"=>"Whitelaw", "scopus_author_id"=>"7003350178"}, {"first_name"=>"Suyinn", "last_name"=>"Chong", "scopus_author_id"=>"7201660964"}], "year"=>2010, "source"=>"PLoS Genetics", "identifiers"=>{"sgr"=>"76749151467", "scopus"=>"2-s2.0-76749151467", "doi"=>"10.1371/journal.pgen.1000811", "isbn"=>"1553-7404 (Electronic)\\n1553-7390 (Linking)", "pui"=>"358308128", "issn"=>"15537390", "pmid"=>"20084100"}, "id"=>"86f8d5b0-32da-3d18-9311-cfb01acdf2c6", "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 (A(vy)), 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 A(vy). 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 A(vy) mice. These findings suggest that moderate ethanol exposure in utero is capable of inducing changes in the expression of genes other than A(vy), 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 A(vy) allele. 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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/430804", "https://ndownloader.figshare.com/files/430828", "https://ndownloader.figshare.com/files/430865", "https://ndownloader.figshare.com/files/430978", "https://ndownloader.figshare.com/files/430996"], "description"=>"<div><p>Recent studies have shown that exposure to some nutritional supplements and chemicals <em>in utero</em> 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 <em>ad libitum</em> ingestion of 10% (v/v) ethanol between gestational days 0.5–8.5 and observed changes in the expression of an epigenetically-sensitive allele, <em>Agouti viable yellow</em> (<em>A<sup>vy</sup></em>), 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 <em>A<sup>vy</sup></em>. 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 <em>a/a</em> siblings of the <em>A<sup>vy</sup></em> mice. These findings suggest that moderate ethanol exposure <em>in utero</em> is capable of inducing changes in the expression of genes other than <em>A<sup>vy</sup></em>, 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 <em>A<sup>vy</sup></em> 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.</p></div>", "links"=>[], "tags"=>["maternal", "ethanol", "alters", "epigenotype", "phenotype", "offspring"], "article_id"=>145018, "categories"=>["Genetics", "Molecular Biology", "Developmental Biology"], "users"=>["Nina Kaminen-Ahola", "Arttu Ahola", "Murat Maga", "Kylie-Ann Mallitt", "Paul Fahey", "Timothy C. Cox", "Emma Whitelaw", "Suyinn Chong"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000811.s001", "https://dx.doi.org/10.1371/journal.pgen.1000811.s002", "https://dx.doi.org/10.1371/journal.pgen.1000811.s003", "https://dx.doi.org/10.1371/journal.pgen.1000811.s004", "https://dx.doi.org/10.1371/journal.pgen.1000811.s005"], "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Maternal_Ethanol_Consumption_Alters_the_Epigenotype_and_the_Phenotype_of_Offspring_in_a_Mouse_Model/145018", "title"=>"Maternal Ethanol Consumption Alters the Epigenotype and the Phenotype of Offspring in a Mouse Model", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-01-15 01:23:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/867564"], "description"=>"<p>(A) Output of the CVA on the procrustes coordinates. Two components account for more than 90% of the total variation. CV1 clearly discriminates ethanol treated female specimens from the rest of the samples. Both male and female ethanol specimens have CV2 values close to (and above) 0, whereas controls span the entire range. Changes in the skull morphology were visualized by using the loadings of the first two canonical variates. Negative values of CV1 indicate a relatively wider skull and relatively longer rostrum. Positive values of CV2 indicates relatively wider orbits (as measured by landmarks 7–11), and shorter rostrum. (B) Output of the EDMA form difference matrix. Out of the possible 561 interlandmark distances, the top and bottom 20 are shown. Values are reported as the proportion of ethanols to controls for each interlandmark distance. None of the confidence intervals for the reported distances crosses 1.0, indicating that all the dimensions are significantly lower in the ethanol specimens. The higher values at the bottom of the graph indicate relatively expanded dimensions for ethanols. 90% confidence intervals were estimated by the non-parametric bootstrap method. For landmark descriptions and positions, see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000811#pgen.1000811.s005\" target=\"_blank\">Text S1</a> and <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000811#pgen.1000811.s003\" target=\"_blank\">Figure S3</a>. (C) Mean relative size of selected linear dimensions in ethanol and control groups. Tails indicate the observed range. Measurements are divided by the centroid size to remove the size effect. Cranial width is measured as the distance between landmarks 15 and 17; rostrum length is measured as the distance between landmark 9 and center of landmarks 1 and 2; orbital width is measured by the distance between landmark 7 and 11. Abbreviations: FC, female control; MC, male control; FE, female ethanol; ME, male ethanol. Goodall's F test was used to test for statistical significance of mean shape differences among groups.</p>", "links"=>[], "tags"=>["gestational", "ethanol"], "article_id"=>538019, "categories"=>["Genetics", "Molecular Biology", "Developmental Biology"], "users"=>["Nina Kaminen-Ahola", "Arttu Ahola", "Murat Maga", "Kylie-Ann Mallitt", "Paul Fahey", "Timothy C. Cox", "Emma Whitelaw", "Suyinn Chong"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000811.g005", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantitative_analysis_of_the_effects_of_gestational_exposure_to_ethanol_on_skull_shape_/538019", "title"=>"Quantitative analysis of the effects of gestational exposure to ethanol on skull shape.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-15 02:13:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/867388"], "description"=>"<p>All were <i>a/a</i> pups from first litters. Pups were weighed at 3 weeks of age and came from litter sizes of 4 and 5. The graph shows mean±SEM.</p>", "links"=>[], "tags"=>["gestational", "ethanol"], "article_id"=>537844, "categories"=>["Genetics", "Molecular Biology", "Developmental Biology"], "users"=>["Nina Kaminen-Ahola", "Arttu Ahola", "Murat Maga", "Kylie-Ann Mallitt", "Paul Fahey", "Timothy C. Cox", "Emma Whitelaw", "Suyinn Chong"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000811.g003", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Offspring_in_the_gestational_ethanol_exposure_group_have_a_statistically_significantly_lower_mean_weight_than_the_control_group_Student_s_t_test_p_/537844", "title"=>"Offspring in the gestational ethanol exposure group have a statistically significantly lower mean weight than the control group (Student's <i>t</i>-test, p<0.05).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-15 02:10:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/867225"], "description"=>"<p>Only mice with 100% yellow and 100% pseudoagouti coats were assayed. Control yellow (CY) offspring are numbered 1–6, control pseudoagouti (CP) offspring are numbered 1–6, ethanol yellow (EY) offspring are numbered 1–6 and ethanol pseudoagouti (EP) offspring are numbered 1–6. Methylation was analyzed by sequencing individual clones of PCR-amplified, bisulfite-converted tail genomic DNA. Each circle represents an individual CpG. Open circles indicate an unmethylated CpG, and closed circles represent a methylated CpG. Each line represents an individual clone and the methylation pattern of one allele in one cell. Each block of lines comprises clones derived from one bisulfite conversion. The total percentage of methylated CpGs is shown above each individual and group. There are more hypermethylated clones in yellow ethanol exposed mice (Pearson's chi-square tests. p<0.01). There is no effect of ethanol exposure on the methylation of <i>A<sup>vy</sup></i> in pseudoagouti mice (Student's <i>t</i>-test, p = 0.27).</p>", "links"=>[], "tags"=>["methylation", "offspring", "exposed", "ethanol"], "article_id"=>537674, "categories"=>["Genetics", "Molecular Biology", "Developmental Biology"], "users"=>["Nina Kaminen-Ahola", "Arttu Ahola", "Murat Maga", "Kylie-Ann Mallitt", "Paul Fahey", "Timothy C. Cox", "Emma Whitelaw", "Suyinn Chong"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000811.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_vy_methylation_in_control_offspring_and_offspring_exposed_to_ethanol_in_utero_/537674", "title"=>"<i>A<sup>vy</sup></i> methylation in control offspring and offspring exposed to ethanol <i>in utero</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-15 02:07:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/867144"], "description"=>"<p>In each pedigree, the black square represents the <i>a/a</i> dam and the diamonds represent her <i>A<sup>vy</sup>/a</i> offspring. <i>A<sup>vy</sup>/a</i> sires and all <i>a/a</i> offspring have been excluded from the pedigrees. White diamonds represent yellow offspring, light gray diamonds represent mottled offspring and dark gray diamonds represent pseudoagouti offspring. The percentage of offspring in each coat color category is indicated. The gestational ethanol exposure group and the preconceptional ethanol exposure group were statistically significantly different to the control group using Pearson's chi-square test (p<0.05).</p>", "links"=>[], "tags"=>["preconceptional", "ethanol", "produced", "higher", "pseudoagouti"], "article_id"=>537591, "categories"=>["Genetics", "Molecular Biology", "Developmental Biology"], "users"=>["Nina Kaminen-Ahola", "Arttu Ahola", "Murat Maga", "Kylie-Ann Mallitt", "Paul Fahey", "Timothy C. Cox", "Emma Whitelaw", "Suyinn Chong"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000811.g001", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gestational_and_preconceptional_ethanol_exposure_produced_a_higher_proportion_of_pseudoagouti_A_vy_mice_/537591", "title"=>"Gestational and preconceptional ethanol exposure produced a higher proportion of pseudoagouti <i>A<sup>vy</sup></i> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-15 02:06:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/867470"], "description"=>"<p>The top panel shows 3D reconstructions of skull microCT data from 28–30 day old mice. (A) Control female. (B) Ethanol-exposed male showing marked leftward deviation of the midface. (C) Ethanol-exposed female showing an almost absent interfrontal bone that is normally characteristic of untreated C57BL6/J mice. (D) Graph of centroid size (used as an estimate of overall cranial size) against body weight for control (n = 10) and ethanol exposed (n = 7) mice at 28–30 days old. Centroid size was determined by summing the distances from each landmark to the centroid for each individual. Centroid size is highly correlated with body weight in both treatment groups, but those in the ethanol group are on average smaller than those in the controls (ANOVA, p<0.05).</p>", "links"=>[], "tags"=>["midfacial", "dysmorphism", "microcephaly", "offspring", "mothers", "consumed", "ethanol"], "article_id"=>537921, "categories"=>["Genetics", "Molecular Biology", "Developmental Biology"], "users"=>["Nina Kaminen-Ahola", "Arttu Ahola", "Murat Maga", "Kylie-Ann Mallitt", "Paul Fahey", "Timothy C. Cox", "Emma Whitelaw", "Suyinn Chong"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000811.g004", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Variable_midfacial_dysmorphism_and_microcephaly_in_a_a_offspring_of_mothers_that_consumed_ethanol_during_gestation_/537921", "title"=>"Variable midfacial dysmorphism and microcephaly in <i>a/a</i> offspring of mothers that consumed ethanol during gestation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-15 02:12:01"}

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