Gene expression in the mouse brain following early pregnancy exposure to ethanol

Exposure to alcohol during early embryonic or fetal development has been linked with a variety of adverse outcomes, the most common of which are structural and functional abnormalities of the central nervous system [1]. Behavioural and cognitive deficits reported in individuals exposed to alcohol in utero include intellectual impairment, learning and memory difficulties, diminished executive functioning, attention problems, poor motor function and hyperactivity [2]. The economic and social costs of these outcomes are substantial and profound [3] and [4]. Improvement of neurobehavioural outcomes following prenatal alcohol exposure requires greater understanding of the mechanisms of alcohol-induced damage to the brain. Here we use a mouse model of relatively moderate ethanol exposure early in pregnancy and profile gene expression in the hippocampus and caudate putamen of adult male offspring. The effects of offspring sex and age on ethanol-sensitive hippocampal gene expression were also examined. All array data are available at the Gene Expression Omnibus (GEO) repository under accession number GSE87736

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

Fetal Alcohol Spectrum Disorders encompass a wide range of birth defects in children born to mothers who consumed alcohol during pregnancy. Typical mental impairments in FASD include difficulties in life adaptation and learning and memory, deficits in attention, visuospatial skills, language and speech disabilities, mood disorders and motor disabilities. Multimodal imaging methods have enabled in vivo studies of the teratogenic effects of alcohol on the central nervous system, giving more insight into the FASD phenotype. This paper offers an up-to-date comprehensive review of radiological findings in the central nervous system in studies of prenatal alcohol exposure in both humans and translational animal models, including Magnetic Resonance Imaging, Computed Tomography, Positron Emission Tomography, Single Photon Emission Tomography and Ultrasonography. (C) 2017 Elsevier Inc. All rights reserved

Early gestational ethanol exposure in mice : Effects on brain structure, energy metabolism and adiposity in adult offspring

We examined whether an early-life event ethanol exposure in the initial stages of pregnancy affected offspring brain structure, energy metabolism, and body composition in later life. Consumption of 10% (v/v) ethanol by inbred C57BL/6J female mice from 0.5 to 8.5 days post coitum was used to model alcohol exposure during the first 3-4 weeks of gestation in humans, when pregnancy is not typically recognized. At adolescence (postnatal day [P] 28) and adulthood (P64), the brains of male offspring were scanned ex vivo using ultra-high field (16.4 T) magnetic resonance imaging and diffusion tensor imaging. Energy metabolism and body composition were measured in adulthood by indirect calorimetry and dual energy X-ray absorptiometry (DXA), respectively. Ethanol exposure had no substantial impact on white matter organization in the anterior commissure, corpus callosum, hippocampal commissure, internal capsule, optic tract, or thalamus. Whole brain volume and the volumes of the neocortex, cerebellum, and caudate putamen were also unaffected. Subtle, but non-significant, effects were observed on the hippocampus and the hypothalamus in adult ethanol-exposed male offspring. Ethanol exposure was additionally associated with a trend toward decreased oxygen consumption, carbon dioxide production, and reduced daily energy expenditure, as well as significantly increased adiposity, albeit with normal body weight and food intake, in adult male offspring. In summary, ethanol exposure restricted to early gestation had subtle long-term effects on the structure of specific brain regions in male offspring. The sensitivity of the hippocampus to ethanol-induced damage is reminiscent of that reported by other studies despite differences in the level, timing, and duration of exposure and likely contributes to the cognitive impairment that characteristically results from prenatal ethanol exposure. The hypothalamus plays an important role in regulating metabolism and energy homeostasis. Our finding of altered daily energy expenditure and adiposity in adult ethanol-exposed males is consistent with the idea that central nervous system abnormalities also underpin some of the metabolic phenotypes associated with ethanol exposure in pregnancy. (C) 2018 Elsevier Inc. All rights reserved.Peer reviewe

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

Peer reviewe

Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise

Background: Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process.Results: Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals.Conclusions: These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans

DNMT3L Is a Regulator of X Chromosome Compaction and Post-Meiotic Gene Transcription

Previous studies on the epigenetic regulator DNA methyltransferase 3-Like (DNMT3L), have demonstrated it is an essential regulator of paternal imprinting and early male meiosis. Dnmt3L is also a paternal effect gene, i.e., wild type offspring of heterozygous mutant sires display abnormal phenotypes suggesting the inheritance of aberrant epigenetic marks on the paternal chromosomes. In order to reveal the mechanisms underlying these paternal effects, we have assessed X chromosome meiotic compaction, XY chromosome aneuploidy rates and global transcription in meiotic and haploid germ cells from male mice heterozygous for Dnmt3L. XY bodies from Dnmt3L heterozygous males were significantly longer than those from wild types, and were associated with a three-fold increase in XY bearing sperm. Loss of a Dnmt3L allele resulted in deregulated expression of a large number of both X-linked and autosomal genes within meiotic cells, but more prominently in haploid germ cells. Data demonstrate that similar to embryonic stem cells, DNMT3L is involved in an auto-regulatory loop in germ cells wherein the loss of a Dnmt3L allele resulted in increased transcription from the remaining wild type allele. In contrast, however, within round spermatids, this auto-regulatory loop incorporated the alternative non-coding alternative transcripts. Consistent with the mRNA data, we have localized DNMT3L within spermatids and sperm and shown that the loss of a Dnmt3L allele results in a decreased DNMT3L content within sperm. These data demonstrate previously unrecognised roles for DNMT3L in late meiosis and in the transcriptional regulation of meiotic and post-meiotic germ cells. These data provide a potential mechanism for some cases of human Klinefelter's and Turner's syndromes

The chicken lysozyme chromatin domain contains a second, widely expressed gene

The chicken lysozyme (cLys) locus has been shown to contain all of the cis-elements necessary for position-independent and tissue-specific expression entirely within a 24-kb region defined by general DNase I sensitivity and flanked by matrix attachment regions. As such, it has been viewed as an example of a functional chromatin domain, which is structurally and functionally isolated from neighbouring chromatin. We report here the identification and characterisation of the chicken glioma-amplified sequence (cGas41) locus, which though widely expressed, is contained entirely within the lysozyme chromatin domain. The cGas41 transcript encodes a putative transcription factor, starts 207 bp downstream of the cLys polyadenylation site and is preceded by a CpG island with proposed dual promoter/origin function. The location and differential expression of cGas41 compels re-evaluation of the accumulated literature on the lysozyme domain, and represents an example of two unrelated, differentially expressed vertebrate genes coexisting in the same functional chromatin domain