GABA receptor density alterations revealed in a mouse model of early moderate prenatal ethanol exposure using [F]AH114726.

Introduction: Prenatal ethanol exposure (PEE) has been shown to alter the level and function of receptors in the brain, one of which is GABA receptors (GABAR), the major inhibitory ligand gated ion channels that mediate neuronal inhibition. High dose PEE in animals resulted in the upregulation of GABAR, but the effects of low and moderate dose PEE at early gestation have not been investigated. This study aimed at examining GABAR density in the adult mouse brain following PEE during a period equivalent to the first 3 to 4 weeks in human gestation.

Magnetic Resonance Imaging and Micro-Computed Tomography reveal brain morphological abnormalities in a mouse model of early moderate prenatal ethanol exposure.

Background: This study investigated the effects of early moderate prenatal ethanol exposure (PEE) on the brain in a mouse model that mimics a scenario in humans, whereby moderate daily drinking ceases after a woman becomes aware of her pregnancy.

Methods: C57BL/6J pregnant mice were given 10% v/v ethanol from gestational day 0-8 in the drinking water. The male offspring were used for imaging.

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.

Effects of periconceptional maternal alcohol intake and a postnatal high-fat diet on obesity and liver disease in male and female rat offspring.

The effects of maternal alcohol consumption around the time of conception on offspring are largely unknown and difficult to determine in a human population. This study utilized a rodent model to examine if periconceptional alcohol (PC:EtOH) consumption, alone or in combination with a postnatal high-fat diet (HFD), resulted in obesity and liver dysfunction. Sprague-Dawley rats were fed a control or an ethanol-containing [12.

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.

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 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], [4].

Prenatal ethanol exposure alters adult hippocampal VGLUT2 expression with concomitant changes in promoter DNA methylation, H3K4 trimethylation and miR-467b-5p levels.

Background: Maternal consumption of alcohol during pregnancy is associated with a range of physical, cognitive and behavioural outcomes in the offspring which are collectively called foetal alcohol spectrum disorders. We and others have proposed that epigenetic modifications, such as DNA methylation and post-translational histone modifications, mediate the effects of prenatal alcohol exposure on gene expression and, ultimately, phenotype. Here we use an inbred C57BL/6J mouse model of early gestational ethanol exposure equivalent, developmentally, to the first 3-4 weeks of pregnancy in humans to examine the long-term effects on gene expression and epigenetic state in the hippocampus.

Non-telomeric epigenetic and genetic changes are associated with the inheritance of shorter telomeres in mice.

Studies using human and mouse cells have revealed some changes to non-telomeric chromatin and gene expression in response to abnormally short telomeres. To investigate this further, we studied the effect of inheriting shorter telomeres on transcription and genetic stability at non-telomeric sites in the mouse. Using multiple generations of Terc knockout mice, we show that inheriting shorter telomeres from one parent increases the likelihood of transcriptional silencing at a non-telomeric green fluorescent protein (GFP) transgene inherited from the other parent.

Early gestational exposure to moderate concentrations of ethanol alters adult behaviour in C57BL/6J mice.

Alcohol consumption during pregnancy has deleterious effects on the developing foetus ranging from subtle physical deficits to severe behavioural abnormalities and is encompassed under a broad umbrella term, foetal alcohol spectrum disorders (FASD). High levels of exposure show distinct effects, whereas the consequences of moderate exposures have been less well studied. The aim of this study was to examine the effects of a moderate dose ethanol exposure using an ad libitum drinking procedure during the first eight days of gestation in mice on the behavioural phenotype of adult offspring.

No evidence for cumulative effects in a Dnmt3b hypomorph across multiple generations.

Observations of inherited phenotypes that cannot be explained solely through genetic inheritance are increasing. Evidence points to transmission of non-DNA molecules in the gamete as mediators of the phenotypes. However, in most cases it is unclear what the molecules are, with DNA methylation, chromatin proteins, and small RNAs being the most prominent candidates.

Reduced dosage of the modifiers of epigenetic reprogramming Dnmt1, Dnmt3L, SmcHD1 and Foxo3a has no detectable effect on mouse telomere length in vivo.

Studies carried out in cultured cells have implicated modifiers of epigenetic reprogramming in the regulation of telomere length, reporting elongation in cells that were null for DNA methyltransferase DNA methyltransferase 1 (Dnmt1), both de novo DNA methyltransferases, Dnmt3a and Dnmt3b or various histone methyltransferases. To investigate this further, we assayed telomere length in whole embryos or adult tissue from mice carrying mutations in four different modifiers of epigenetic reprogramming: Dnmt1, DNA methyltransferase 3-like, structural maintenance of chromosomes hinge domain containing 1, and forkhead box O3a. Terminal restriction fragment analysis was used to compare telomere length in homozygous mutants, heterozygous mutants and wild-type littermates.

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.

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.

Tuning in to noise: epigenetics and intangible variation.

In this special issue of Developmental Cell, we discuss the role of chromatin in phenotypic variation as a counterpoint to the reviews on chromatin dynamics in development and cancer. We highlight some recent work on the role of chromatin in transcriptional noise in yeast and Caenorhabditis elegans and consider the implications in understanding intangible variation or developmental noise in mammals.

Postnatal growth restriction and gene expression changes in a mouse model of fetal alcohol syndrome.

Growth restriction, craniofacial dysmorphology, and central nervous system defects are the main diagnostic features of fetal alcohol syndrome. Studies in humans and mice have reported that the growth restriction can be prenatal or postnatal, but the underlying mechanisms remain unknown.We recently described a mouse model of moderate gestational ethanol exposure that produces measurable phenotypes in line with fetal alcohol syndrome (e.

Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model.

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.

Epigenetic regulation in male germ cells.

In recent years, it has become increasingly clear that epigenetic regulation of gene expression is critical during spermatogenesis. In this review, the epigenetic regulation and the consequences of its aberrant regulation during mitosis, meiosis and spermiogenesis are described. The current knowledge on epigenetic modifications that occur during male meiosis is discussed, with special attention on events that define meiotic sex chromosome inactivation.

Modifiers of epigenetic reprogramming show paternal effects in the mouse.

There is increasing evidence that epigenetic information can be inherited across generations in mammals, despite extensive reprogramming both in the gametes and in the early developing embryo. One corollary to this is that disrupting the establishment of epigenetic state in the gametes of a parent, as a result of heterozygosity for mutations in genes involved in reprogramming, could affect the phenotype of offspring that do not inherit the mutant allele. Here we show that such effects do occur following paternal inheritance in the mouse.

Epigenetic germline inheritance.

Our increased knowledge of epigenetic reprogramming supports the idea that epigenetic marks are not always completely cleared between generations. Incomplete erasure at genes associated with a measurable phenotype can result in unusual patterns of inheritance from one generation to the next. It is also becoming clear that the establishment of epigenetic marks during development can be influenced by environmental factors.

How the mouse got its spots.

One's ultimate phenotype is the result of a combination of genotype and environment, and includes a poorly understood component termed "developmental noise". This "developmental noise", also known as "intangible variation", is rarely discussed even though it appears to make a significant contribution to the variance of quantitative traits within a species. The molecular basis of developmental noise remains unknown, but it appears to be established in embryonic development and to be retained for the life of the organism.

Dynamic reorganization of chromatin structure and selective DNA demethylation prior to stable enhancer complex formation during differentiation of primary hematopoietic cells in vitro.

In order to gain insights in the true molecular mechanisms involved in cell fate decisions, it is important to study the molecular details of gene activation where such decisions occur, which is at the level of the chromatin structure of individual genes. In the study presented here we addressed this issue and examined the dynamic development of an active chromatin structure at the chicken lysozyme locus during the differentiation of primary myeloid cells from transgenic mouse bone marrow. Using in vivo footprinting we found that stable enhancer complex assembly and high-level gene expression are late events in cell differentiation.

Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission.

Phenotypic variation that cannot be explained by genetic or environmental heterogeneity has intrigued geneticists for decades. The molecular basis of this phenomenon, however, is largely a mystery. Axin-fused (Axin(Fu)), first identified in 1937, is a classic example of a mammalian allele displaying extremely variable expression states.

A Functional chromatin domain does not resist X chromosome inactivation: silencing of cLys correlates with methylation of a dual promoter-replication origin.

To investigate the molecular mechanism(s) involved in the propagation and maintenance of X chromosome inactivation (XCI), the 21.4-kb chicken lysozyme (cLys) chromatin domain was inserted into the Hprt locus on the mouse X chromosome. The inserted fragment includes flanking matrix attachment regions (MARs), an origin of bidirectional replication (OBR), and all the cis-regulatory elements required for correct tissue-specific expression of cLys.