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1.
PLoS Comput Biol ; 15(4): e1006937, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30973878

RESUMO

Gestational alcohol exposure causes fetal alcohol spectrum disorder (FASD) and is a prominent cause of neurodevelopmental disability. Whole transcriptome sequencing (RNA-Seq) offer insights into mechanisms underlying FASD, but gene-level analysis provides limited information regarding complex transcriptional processes such as alternative splicing and non-coding RNAs. Moreover, traditional analytical approaches that use multiple hypothesis testing with a false discovery rate adjustment prioritize genes based on an adjusted p-value, which is not always biologically relevant. We address these limitations with a novel approach and implemented an unsupervised machine learning model, which we applied to an exon-level analysis to reduce data complexity to the most likely functionally relevant exons, without loss of novel information. This was performed on an RNA-Seq paired-end dataset derived from alcohol-exposed neural fold-stage chick crania, wherein alcohol causes facial deficits recapitulating those of FASD. A principal component analysis along with k-means clustering was utilized to extract exons that deviated from baseline expression. This identified 6857 differentially expressed exons representing 1251 geneIDs; 391 of these genes were identified in a prior gene-level analysis of this dataset. It also identified exons encoding 23 microRNAs (miRNAs) having significantly differential expression profiles in response to alcohol. We developed an RDAVID pipeline to identify KEGG pathways represented by these exons, and separately identified predicted KEGG pathways targeted by these miRNAs. Several of these (ribosome biogenesis, oxidative phosphorylation) were identified in our prior gene-level analysis. Other pathways are crucial to facial morphogenesis and represent both novel (focal adhesion, FoxO signaling, insulin signaling) and known (Wnt signaling) alcohol targets. Importantly, there was substantial overlap between the exomes themselves and the predicted miRNA targets, suggesting these miRNAs contribute to the gene-level expression changes. Our novel application of unsupervised machine learning in conjunction with statistical analyses facilitated the discovery of signaling pathways and miRNAs that inform mechanisms underlying FASD.


Assuntos
Éxons/genética , Transtornos do Espectro Alcoólico Fetal/genética , MicroRNAs/genética , Aprendizado de Máquina não Supervisionado , Animais , Big Data , Embrião de Galinha , Análise por Conglomerados , Biologia Computacional , Bases de Dados de Ácidos Nucleicos/estatística & dados numéricos , Modelos Animais de Doenças , Etanol/toxicidade , Feminino , Perfilação da Expressão Gênica/estatística & dados numéricos , Humanos , Gravidez , Análise de Componente Principal , Aprendizado de Máquina não Supervisionado/estatística & dados numéricos
2.
Epigenetics Chromatin ; 12(1): 9, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670059

RESUMO

BACKGROUND: Although clinical data support an association between paternal alcohol use and deficits in child neurocognitive development, the relationship between paternal drinking and alcohol-induced growth phenotypes remains challenging to define. Using an established mouse model of chronic exposure, previous work by our group has linked preconception paternal alcohol use to sex-specific patterns of fetal growth restriction and placental dysfunction. The aim of the present study was to investigate the long-term impact of chronic preconception paternal alcohol use on offspring growth and metabolic programming. RESULTS: Preconception paternal alcohol exposure induced a prolonged period of fetal gestation and an increased incidence of intrauterine growth restriction, which affected the male offspring to a greater extent than the females. While the female offspring of ethanol-exposed males were able to match the body weights of the controls within the first 2 weeks of postnatal life, male offspring continued to display an 11% reduction in weight at 5 weeks of age and a 6% reduction at 8 weeks of age. The observed growth deficits associated with insulin hypersensitivity in the male offspring, while in contrast, females displayed a modest lag in their glucose tolerance test. These metabolic defects were associated with an up-regulation of genes within the pro-fibrotic TGF-ß signaling pathway and increased levels of cellular hydroxyproline within the livers of the male offspring. We observed suppressed cytokine profiles within the liver and pancreas of both the male and female offspring, which correlated with the up-regulation of genes in the LiverX/RetinoidX/FarnesoidX receptor pathways. However, patterns of gene expression were highly variable between the offspring of alcohol-exposed sires. In the adult offspring of alcohol-exposed males, we did not observe any differences in the allelic expression of Igf2 or any other imprinted genes. CONCLUSIONS: The impact of paternal alcohol use on child development is poorly explored and represents a significant gap in our understanding of the teratogenic effects of ethanol. Our studies implicate paternal exposure history as an additional and important modifier of alcohol-induced growth phenotypes and challenge the current maternal-centric exposure paradigm.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Desenvolvimento Embrionário , Epigênese Genética , Transtornos do Espectro Alcoólico Fetal/genética , Metaboloma , Exposição Paterna , Consumo de Bebidas Alcoólicas/genética , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Herança Paterna , Fatores Sexuais
3.
Biochem Cell Biol ; 97(4): 431-436, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30605356

RESUMO

Fetal alcohol spectrum disorder (FASD) is caused by prenatal exposure to ethanol and has been linked to neurodevelopmental impairments. Alcohol has the potential to alter some of the epigenetic components that play a critical role during development. Previous studies have provided evidence that prenatal exposure to ethanol results in abnormal epigenetic patterns (i.e., hypomethylation) of the genome. The aim of this study was to determine how prenatal exposure to ethanol in rats affects the hippocampal levels of expression of two important brain epigenetic transcriptional regulators involved in synaptic plasticity and memory consolidation: methyl CpG-binding protein 2 (MeCP2) and histone variant H2A.Z. Unexpectedly, under the conditions used in this work we were not able to detect any changes in MeCP2. Interestingly, however, we observed a significant decrease in H2A.Z, accompanied by its chromatin redistribution in both female and male FASD rat pups. Moreover, the data from reverse-transcription qPCR later confirmed that this decrease in H2A.Z is mainly due to down-regulation of its H2A.Z-2 isoform gene expression. Altogether, these data provide strong evidence that prenatal exposure to ethanol alters histone variant H2A.Z during neurogenesis of rat hippocampus.


Assuntos
Transtornos do Espectro Alcoólico Fetal/metabolismo , Hipocampo/metabolismo , Histonas/genética , Histonas/metabolismo , Animais , Feminino , Transtornos do Espectro Alcoólico Fetal/genética , Perfilação da Expressão Gênica , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Ratos , Ratos Sprague-Dawley
4.
Mol Psychiatry ; 24(1): 10-17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29892052

RESUMO

Alcohol exposure during pregnancy affects the development of the fetus in various ways and may lead to Fetal Alcohol Spectrum Disorders (FASD). FASD is one of the leading preventable forms of neurodevelopmental disorders. In the light of prevention and early intervention, knowledge on how ethanol exposure induces fetal damage is urgently needed. Besides direct ethanol and acetaldehyde toxicity, alcohol increases oxidative stress, and subsequent general effects (e.g., epigenetic imprinting, gene expression, and metabolite levels). The current review provides an overview of the existing knowledge about specific downstream pathways for FASD that affects e.g., the SHH pathway, cholesterol homeostasis, neurotransmitter signaling, and effects on the cytoskeleton. Available human data vary greatly, while animal studies with controlled ethanol exposition are only to a certain limit transferable to humans. The main deficits in knowledge about FASD are the lack of pathophysiological understanding and dose-response relationships, together with the lack of reliable biomarkers for either FASD detection or estimation of susceptibility. In addition to single outcome experiments, omics data should be generated to overcome this problem. Therefore, for future studies we recommend holistic data driven analysis, which allows integrative analyses over multiple levels of genetic variation, transcriptomics and metabolomics data to investigate the whole image of FASD development and to provide insight in potential drug targets for intervention.


Assuntos
Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Animais , Modelos Animais de Doenças , Etanol/efeitos adversos , Feminino , Feto/metabolismo , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
5.
Appl Physiol Nutr Metab ; 44(7): 744-750, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30521352

RESUMO

Prenatal ethanol (EtOH) exposure is known to induce adverse effects on fetal brain development. Docosahexaenoic acid (DHA) has been shown to alleviate these effects by up-regulating antioxidant mechanisms in the brain. The liver is the first organ to receive enriched blood after placental transport. Therefore, it could be negatively affected by EtOH, but no studies have assessed the effects of DHA on fetal liver. This study examined the effects of maternal DHA intake on DHA status and gene expression of key enzymes of the glutathione antioxidant system in the fetal liver after prenatal EtOH exposure. Pregnant Sprague-Dawley dams were intubated with EtOH for the first 10 days of pregnancy, while being fed a control or DHA-supplemented diet. Fetal livers were collected at gestational day 20, and free fatty acids and phospholipid profile, as well as glutathione reductase (GR) and glutathione peroxidase-1 (GPx1) gene expressions, were assessed. Prenatal EtOH exposure increased fetal liver weight, whereas maternal DHA supplementation decreased fetal liver weight. DHA supplementation increased fetal liver free fatty acid and phospholipid DHA independently of EtOH. GR and GPx1 messenger RNA (mRNA) expressions were significantly increased and decreased, respectively, in the EtOH-exposed group compared with all other groups. Providing DHA normalized GR and GPx1 mRNA expression to control levels. This study shows that maternal DHA supplementation alters the expression of fetal liver genes involved in the glutathione antioxidative system during prenatal EtOH exposure. The fetal liver may play an important role in mitigating the signs and symptoms of fetal alcohol spectrum disorders in affected offspring.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Etanol/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Fígado/metabolismo , Animais , Antioxidantes/metabolismo , Dieta , Suplementos Nutricionais , Ácidos Graxos não Esterificados/metabolismo , Feminino , Transtornos do Espectro Alcoólico Fetal/genética , Glutationa Peroxidase/biossíntese , Glutationa Peroxidase/genética , Fígado/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Sprague-Dawley
6.
Alcohol ; 73: 73-78, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30312858

RESUMO

Fetal alcohol spectrum disorders (FASD) are associated with social interaction behavior and gastrointestinal (GI) abnormalities. These abnormal behaviors and GI abnormalities overlap with autism spectrum disorder (ASD). We investigated the effect of fetal alcohol exposure (FAE) on social interaction deficits (hallmark of autism) in mice. Evidence indicates that exogenous lipopolysaccharide (LPS) administration during gestation induces autism-like behavior in the offspring. LPS regulates the expression of genes underlying differentiation, immune function, myelination, and synaptogenesis in fetal brain by the LPS receptor, TLR-4-dependent mechanism. In this study, we evaluated the role of TLR-4 in FAE-induced social behavior deficit. WT and TLR4-/- pregnant mice were fed Lieber-DeCarli liquid diet with or without ethanol. The control group was pair-fed with an isocaloric diet. Social behavior was tested in the adult offspring at postnatal day 60. Frontal cortex mRNA expression of autistic candidate genes (Ube3a, Gabrb3, Mecp2) and inflammatory cytokine genes (IL-1ß, IL-6, TNF-α) were measured by RT-qPCR. Adult male offspring of ethanol-fed WT dams showed low birth weight compared to offspring of pair-fed WT dams. However, their body weights at adulthood were greater compared to the body weights of offspring of pair-fed WT dams. There were no body weight differences in offspring of TLR4-/- dams. Social interaction deficit was observed only in male offspring of ethanol-fed WT dams, but it was not observed in both male and female offspring of ethanol-fed TLR4-/- dams. Expressions of autism candidate genes, Gabrb3 and Ube3a, were elevated, while that of the Mecp2 gene was suppressed in the frontal cortex of male, but not female, offspring of ethanol-fed WT mice. The expressions of inflammatory cytokine genes, IL-1ß, IL-6, and TNF-α, were also significantly increased in the frontal cortex of male, but not female, offspring of ethanol-fed dams. The changes in the expression of autistic and cytokine genes were unaffected in the offspring of ethanol-fed TLR4-/- dams. These data also indicate that TLR4 mediates FAE-induced changes in social interactions and gene expression in brain, suggesting that ethanol-induced LPS absorption from the maternal gut may be involved in gene expression changes in the fetal brain.


Assuntos
Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/psicologia , Relações Interpessoais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/fisiologia , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Citocinas/genética , Feminino , Inflamação/induzido quimicamente , Inflamação/genética , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez
7.
Alcohol Clin Exp Res ; 42(11): 2136-2143, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30129265

RESUMO

BACKGROUND: MNS1 (meiosis-specific nuclear structural protein 1) is necessary for motile cilia function, such as sperm flagella or those found in the embryonic primitive node. While little is known regarding the function or expression pattern of MNS1 in the embryo, co-immunoprecipitation experiments in sperm have determined that MNS1 interacts with ciliary proteins, which are also important during development. Establishment of morphogenic gradients is dependent on normal ciliary motion in the primitive node beginning during gastrulation (gestational day [GD] 7 in the mouse, second-third week of pregnancy in humans), a critical window for face, eye, and brain development and particularly susceptible to perturbations of developmental signals. The current study investigates the role of Mns1 in craniofacial defects associated with gastrulation-stage alcohol exposure. METHODS: On GD7, pregnant Mns1+/- dams were administered 2 doses of ethanol (5.8 g/kg total) or vehicle 4 hours apart to target gastrulation. On GD17, fetuses were examined for ocular defects by scoring each eye on a scale from 1 to 7 (1 = normal, 2 to 7 = defects escalating in severity). Craniofacial and brain abnormalities were also assessed. RESULTS: Prenatal alcohol exposure (PAE) significantly increased the rate of defects in wild-type fetuses, as PAE fetuses had an incidence rate of 41.18% compared to a 10% incidence rate in controls. Furthermore, PAE interacted with genotype to significantly increase the defect rate and severity in Mns1+/- (64.29%) and Mns1-/- mice (92.31%). PAE Mns1-/- fetuses with severe eye defects also presented with craniofacial dysmorphologies characteristic of fetal alcohol syndrome and midline tissue loss in the brain, palate, and nasal septum. CONCLUSIONS: These data demonstrate that a partial or complete knockdown of Mns1 interacts with PAE to increase the susceptibility to ocular defects and correlating craniofacial and brain anomalies, likely though interaction of alcohol with motile cilia function. These results further our understanding of genetic risk factors that may underlie susceptibility to teratogenic exposures.


Assuntos
Depressores do Sistema Nervoso Central/toxicidade , Anormalidades Craniofaciais/induzido quimicamente , Anormalidades Craniofaciais/genética , Etanol/toxicidade , Transtornos do Espectro Alcoólico Fetal/genética , Gastrulação/efeitos dos fármacos , Proteínas Nucleares/genética , Animais , Proteínas de Ciclo Celular , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/patologia , Anormalidades Craniofaciais/epidemiologia , Anormalidades do Olho/induzido quimicamente , Anormalidades do Olho/epidemiologia , Anormalidades do Olho/patologia , Feminino , Transtornos do Espectro Alcoólico Fetal/epidemiologia , Transtornos do Espectro Alcoólico Fetal/patologia , Feto/patologia , Técnicas de Silenciamento de Genes , Incidência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez
8.
Alcohol Clin Exp Res ; 42(9): 1627-1639, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29957842

RESUMO

BACKGROUND: Alcohol exposure during pregnancy can kill developing neurons and lead to fetal alcohol spectrum disorder (FASD). However, affected individuals differ in their regional patterns of alcohol-induced neuropathology. Because neuroprotective genes are expressed in spatially selective ways, their mutation could increase the vulnerability of some brain regions, but not others, to alcohol teratogenicity. The objective of this study was to determine whether a null mutation of neuronal nitric oxide synthase (nNOS) can increase the vulnerability of some brain regions, but not others, to alcohol-induced neuronal losses. METHODS: Immunohistochemistry identified brain regions in which nNOS is present or absent throughout postnatal development. Mice genetically deficient for nNOS (nNOS-/- ) and wild-type controls received alcohol (0.0, 2.2, or 4.4 mg/g/d) over postnatal days (PD) 4 to 9. Mice were sacrificed in adulthood (~PD 115), and surviving neurons in the olfactory bulb granular layer and brain stem facial nucleus were quantified stereologically. RESULTS: nNOS was expressed throughout postnatal development in olfactory bulb granule cells but was never expressed in the facial nucleus. In wild-type mice, alcohol reduced neuronal survival to similar degrees in both cell populations. However, null mutation of nNOS more than doubled alcohol-induced cell death in the olfactory bulb granule cells, while the mutation had no effect on the facial nucleus neurons. As a result, in nNOS-/- mice, alcohol caused substantially more cell loss in the olfactory bulb than in the facial nucleus. CONCLUSIONS: Mutation of the nNOS gene substantially increases vulnerability to alcohol-induced cell loss in a brain region where the gene is expressed (olfactory bulb), but not in a separate brain region, where the gene is not expressed (facial nucleus). Thus, differences in genotype may explain why some individuals are vulnerable to FASD, while others are not, and may determine the specific patterns of neuropathology in children with FASD.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Etanol/toxicidade , Transtornos do Espectro Alcoólico Fetal/genética , Neurônios/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/genética , Bulbo Olfatório/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/patologia , Animais , Animais Recém-Nascidos , Feminino , Transtornos do Espectro Alcoólico Fetal/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Óxido Nítrico Sintase Tipo I/deficiência , Bulbo Olfatório/metabolismo , Bulbo Olfatório/patologia , Gravidez , Distribuição Aleatória
9.
Prog Mol Biol Transl Sci ; 157: 299-342, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29933954

RESUMO

Early developmental exposure to ethanol, a known teratogen, can result in a range of neurodevelopmental disorders, collectively referred to as Fetal Alcohol Spectrum Disorders (FASDs). Changes in the environment, including exposure to teratogens, can result in long term alterations to the epigenetic landscape of a cell, thereby altering gene expression. Noncoding RNAs (ncRNAs) can affect transcription and translation of networks of genes. ncRNAs are dynamically expressed during development and have been identified as a target of alcohol. ncRNAs therefore make for attractive targets for novel therapeutics to address the developmental deficits associated with FASDs.


Assuntos
Transtornos do Espectro Alcoólico Fetal/genética , RNA não Traduzido/genética , Biomarcadores/metabolismo , Epigênese Genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Nucleolar Pequeno/genética , RNA Nucleolar Pequeno/metabolismo
10.
Biochem Cell Biol ; 96(2): 161-166, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29533680

RESUMO

Fetal alcohol spectrum disorder (FASD) is characterized by a combination of neurological, developmental, and congenital defects that may occur as a consequence of prenatal alcohol exposure. Earlier reports showed that large chromosomal anomalies may link to FASD. Here, we examined the prevalence and types of copy number variations (CNVs) in FASD cases previously diagnosed by a multidisciplinary FASD team in sites across Canada. We genotyped 95 children with FASD and 87 age-matched, typically developing controls on the Illumina Human Omni2.5 SNP (single nucleotide polymorphisms) array platform. We compared their CNVs with those of 10 851 population controls to identify rare CNVs (<0.1% frequency), which may include large unbalanced chromosomal abnormalities, that might be relevant to FASD. In 12/95 (13%) of the FASD cases, rare CNVs were found that impact potentially clinically relevant developmental genes, including the CACNA1H involved in epilepsy and autism, the 3q29 deletion disorder, and others. Our results show that a subset of children diagnosed with FASD have chromosomal deletions and duplications that may co-occur or explain the neurodevelopmental impairments in a diagnosed cohort of FASD individuals. Children suspected to have FASD with or without sentinel facial features of fetal alcohol syndrome and neurodevelopmental delays should potentially be evaluated by a clinical geneticist and possibly have genetic investigations as appropriate to exclude other etiologies.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Transtornos do Espectro Alcoólico Fetal/genética , Dosagem de Genes , Polimorfismo de Nucleotídeo Único , Criança , Pré-Escolar , Feminino , Humanos , Masculino
11.
J Pediatr ; 196: 270-274.e1, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29398060

RESUMO

OBJECTIVE: To study the utility of genetic evaluation and testing in patients with suspected fetal alcohol spectrum disorder (FASD). STUDY DESIGN: We performed a retrospective chart review of all patients (n = 36) referred for evaluation for suspected FASD to the genetics clinic at Boston Children's Hospital between January 2006 and January 2013. Records of all patients were reviewed to obtain the medical history, family history, examination findings, and investigations, including genetic testing. RESULTS: Of the 36 patients, definite prenatal exposure was documented in 69%. Eight patients did not fulfill clinical criteria for FASD. Chromosomal microarray analysis (CMA) detected 19 copy number variants (CNVs) in 14 patients. Among patients who fulfilled criteria for FASD and underwent CMA, pathogenic CNVs were detected in 3 patients (2q37del, 22q11.22dup, and 4q31.21del syndromes), giving a yield of 14.3%. All 3 patients had overlapping features between FASD and the genetic syndrome. CONCLUSION: Genetic testing, especially CMA, should be considered in patients referred for evaluation of FASD, as a significant proportion have a clinically significant CNV even when they fulfill diagnostic criteria for FASD spectrum.


Assuntos
Transtornos do Espectro Alcoólico Fetal/genética , Testes Genéticos/métodos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adolescente , Boston , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Feminino , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Estudos Retrospectivos
12.
Clin Epigenetics ; 10: 5, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29344313

RESUMO

Background: Fetal alcohol spectrum disorder (FASD) is a developmental disorder that manifests through a range of cognitive, adaptive, physiological, and neurobiological deficits resulting from prenatal alcohol exposure. Although the North American prevalence is currently estimated at 2-5%, FASD has proven difficult to identify in the absence of the overt physical features characteristic of fetal alcohol syndrome. As interventions may have the greatest impact at an early age, accurate biomarkers are needed to identify children at risk for FASD. Building on our previous work identifying distinct DNA methylation patterns in children and adolescents with FASD, we have attempted to validate these associations in a different clinical cohort and to use our DNA methylation signature to develop a possible epigenetic predictor of FASD. Methods: Genome-wide DNA methylation patterns were analyzed using the Illumina HumanMethylation450 array in the buccal epithelial cells of a cohort of 48 individuals aged 3.5-18 (24 FASD cases, 24 controls). The DNA methylation predictor of FASD was built using a stochastic gradient boosting model on our previously published dataset FASD cases and controls (GSE80261). The predictor was tested on the current dataset and an independent dataset of 48 autism spectrum disorder cases and 48 controls (GSE50759). Results: We validated findings from our previous study that identified a DNA methylation signature of FASD, replicating the altered DNA methylation levels of 161/648 CpGs in this independent cohort, which may represent a robust signature of FASD in the epigenome. We also generated a predictive model of FASD using machine learning in a subset of our previously published cohort of 179 samples (83 FASD cases, 96 controls), which was tested in this novel cohort of 48 samples and resulted in a moderately accurate predictor of FASD status. Upon testing the algorithm in an independent cohort of individuals with autism spectrum disorder, we did not detect any bias towards autism, sex, age, or ethnicity. Conclusion: These findings further support the association of FASD with distinct DNA methylation patterns, while providing a possible entry point towards the development of epigenetic biomarkers of FASD.


Assuntos
Metilação de DNA , Transtornos do Espectro Alcoólico Fetal/genética , Marcadores Genéticos , Análise de Sequência de DNA/métodos , Adolescente , Criança , Pré-Escolar , Ilhas de CpG , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Aprendizado de Máquina , Masculino , Gravidez
13.
Exp Dermatol ; 27(1): 91-93, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28833556

RESUMO

The precise molecular basis of retinoid embryopathy is yet unknown. This hypothesis predicts that isotretinoin (13-cis retinoic acid), the prodrug of all-trans retinoic acid (ATRA), exaggerates neural crest cell (NCC) apoptosis via upregulation of the pro-apoptotic transcription factor p53, the guardian of the genome. Increased p53 signalling is associated with Treacher Collins-, CHARGE- and fetal alcohol syndrome, which exhibit dysmorphic craniofacial features resembling retinoid embryopathy. In addition, developmental studies of NCC homeostasis in the zebrafish support the pivotal role of p53. Translational evidence implies that isotretinoin-stimulated overactivation of p53 during embryogenesis represents the molecular basis of isotretinoin's teratogenicity.


Assuntos
Isotretinoína/toxicidade , Teratogênios/toxicidade , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Síndrome CHARGE/genética , Modelos Animais de Doenças , Desenvolvimento Embrionário , Transtornos do Espectro Alcoólico Fetal/genética , Homeostase , Humanos , Disostose Mandibulofacial/genética , Crista Neural/citologia , Transdução de Sinais , Pesquisa Médica Translacional , Tretinoína/química , Regulação para Cima , Peixe-Zebra
14.
Biochem Cell Biol ; 96(2): 88-97, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28817785

RESUMO

The term fetal alcohol spectrum disorder (FASD) refers to the entire suite of deleterious outcomes resulting from embryonic exposure to alcohol. Along with other reviews in this special issue, we provide insight into how animal models, specifically the zebrafish, have informed our understanding of FASD. We first provide a brief introduction to FASD. We discuss the zebrafish as a model organism and its strengths for alcohol research. We detail how zebrafish has been used to model some of the major defects present in FASD. These include behavioral defects, such as social behavior as well as learning and memory, and structural defects, disrupting organs such as the brain, sensory organs, heart, and craniofacial skeleton. We provide insights into how zebrafish research has aided in our understanding of the mechanisms of ethanol teratogenesis. We end by providing some relatively recent advances that zebrafish has provided in characterizing gene-ethanol interactions that may underlie FASD.


Assuntos
Modelos Animais de Doenças , Etanol/efeitos adversos , Transtornos do Espectro Alcoólico Fetal , Teratogênese/efeitos dos fármacos , Peixe-Zebra , Animais , Etanol/farmacologia , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/patologia , Humanos , Peixe-Zebra/embriologia , Peixe-Zebra/genética
15.
Pediatr Res ; 83(1-1): 119-127, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28820871

RESUMO

BackgroundFetal alcohol syndrome (FAS) is caused by maternal alcohol consumption during pregnancy; although additional factors might be involved, as development and severity are not directly related to alcohol intake. The abnormal glycosylation caused by alcohol might play a role in FAS according to the clinical similarities shared with congenital disorders of glycosylation (CDG). Thus, mutations underlying CDG, affecting genes involved in glycosylation, could also be involved in FAS.MethodsA panel of 74 genes involved in N-glycosylation was sequenced in 25 FAS patients and 20 controls with prenatal alcohol exposure. Transferrin glycoforms were evaluated by HPLC.ResultsRare (minor allele frequency<0.009) missense/splice site variants were more frequent in FAS than controls (84% vs. 50%; P=0.034, odds ratio: 5.25, 95% confidence interval: 1.3-20.9). Remarkably, three patients, but no controls, carried variants with functional effects identified in CDG patients. Moreover, the patient with the most severe clinical phenotype was the only one carrying two variants with functional effects. Family studies support that the combination of a genetic defect and alcohol consumption during pregnancy might have a role in FAS development.ConclusionsOur study supports that the rare variants of genes involved in N-glycosylation could play a role in the development and severity of FAS under prenatal alcohol exposure.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Transtornos do Espectro Alcoólico Fetal/genética , Predisposição Genética para Doença , Mutação , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Defeitos Congênitos da Glicosilação/complicações , Feminino , Variação Genética , Glicosilação , Humanos , Lactente , Masculino , Exposição Materna , Pessoa de Meia-Idade , Mães , Razão de Chances , Gravidez , Estudos Retrospectivos , Análise de Sequência de DNA , Transferrina/química
16.
Biochem Cell Biol ; 96(2): 231-236, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28746809

RESUMO

This paper discusses the current state of knowledge and practice for diagnosing fetal alcohol spectrum disorder (FASD). The strengths and challenges of different models of diagnosis are compared. Some models require a team approach for evaluation, while other approaches assume that a clinician in his or her office provides a diagnosis based on a review of the patient's medical and social history, behaviour, and physical examination. The author reviews the emergence of new information from recent advances in genetics, imaging, and electrophysiology that has the potential to lead to changes in practice and improved reliability of an FASD diagnosis.


Assuntos
Transtornos do Espectro Alcoólico Fetal/diagnóstico , Animais , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Humanos
17.
Biochem Cell Biol ; 96(2): 213-221, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29091739

RESUMO

Ethanol is the most important teratogen agent in humans. Prenatal alcohol exposure can lead to a wide range of adverse effects, which are broadly termed as fetal alcohol spectrum disorder (FASD). The most severe consequence of maternal alcohol abuse is the development of fetal alcohol syndrome, defined by growth retardation, facial malformations, and central nervous system impairment expressed as microcephaly and neurodevelopment abnormalities. These alterations generate a broad range of cognitive abnormalities such as learning disabilities and hyperactivity and behavioural problems. Socioeconomic status, ethnicity, differences in genetic susceptibility related to ethanol metabolism, alcohol consumption patterns, obstetric problems, and environmental influences like maternal nutrition, stress, and other co-administered drugs are all factors that may influence FASD manifestations. Recently, much attention has been paid to the role of nutrition as a protective factor against alcohol teratogenicity. There are a great number of papers related to nutritional treatment of nutritional deficits due to several factors associated with maternal consumption of alcohol and with eating and social disorders in FASD children. Although research showed the clinical benefits of nutritional interventions, most of work was in animal models, in a preclinical phase, or in the prenatal period. However, a minimum number of studies refer to postnatal nutrition treatment of neurodevelopmental deficits. Nutritional supplementation in children with FASD has a dual objective: to overcome nutritional deficiencies and to reverse or improve the cognitive deleterious effects of prenatal alcohol exposure. Further research is necessary to confirm positive results, to determine optimal amounts of nutrients needed in supplementation, and to investigate the collective effects of simultaneous multiple-nutrient supplementation.


Assuntos
Transtornos do Espectro Alcoólico Fetal/dietoterapia , Transtornos Neurocognitivos/dietoterapia , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Etanol/efeitos adversos , Etanol/metabolismo , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/patologia , Predisposição Genética para Doença , Humanos , Transtornos Neurocognitivos/genética , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/patologia
18.
Int J Biol Sci ; 13(9): 1100-1108, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29104501

RESUMO

Ethanol is well known for its teratogenic effects during fetal development. Maternal alcohol consumption allows the developing fetus to experience the detrimental effects of alcohol exposure. Alcohol-mediated teratogenic effects can vary based on the dosage and the length of exposure. The specific mechanism of action behind this teratogenic effect is still unknown. Previous reports demonstrated that alcohol participates in epigenetic alterations, especially histone modifications during fetal development. Additional research is necessary to understand the correlation between major epigenetic events and alcohol-mediated teratogenesis such as that observed in fetal alcohol spectrum disorder (FASD). Here, we attempted to collect all the available information concerning alcohol-mediated histone modifications during gestational fetal development. We hope that this review will aid researchers to further examine the issues associated with ethanol exposure.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Epigênese Genética/genética , Código das Histonas/efeitos dos fármacos , Código das Histonas/genética , Exposição Materna/efeitos adversos , Animais , Modelos Animais de Doenças , Feminino , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/patologia , Feto/metabolismo , Humanos , Masculino , Camundongos , Ratos , Fatores de Risco
19.
Clin Epigenetics ; 9: 117, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29075360

RESUMO

BACKGROUND: Alcohol consumption during pregnancy is a significant public health problem and can result in a continuum of adverse outcomes to the fetus known as fetal alcohol spectrum disorders (FASD). Subjects with FASD show significant neurological deficits, ranging from microencephaly, neurobehavioral, and mental health problems to poor social adjustment and stress tolerance. Neurons are particularly sensitive to alcohol exposure. The neurotoxic action of alcohol, i.e., through ROS production, induces DNA damage and neuronal cell death by apoptosis. In addition, epigenetics, including DNA methylation, histone posttranslational modifications (PTMs), and non-coding RNA, play an important role in the neuropathology of FASD. However, little is known about the temporal dynamics and kinetics of histones and their PTMs in FASD. RESULTS: We examined the effects of postnatal alcohol exposure (PAE), an animal model of human third-trimester equivalent, on the kinetics of various histone proteins in two distinct brain regions, the frontal cortex, and the hypothalamus, using in vivo 2H2O-labeling combined with mass spectrometry-based proteomics. We show that histones have long half-lives that are in the order of days. We also show that H3.3 and H2Az histone variants have faster turnovers than canonical histones and that acetylated histones, in general, have a faster turnover than unmodified and methylated histones. Our work is the first to show that PAE induces a differential reduction in turnover rates of histones in both brain regions studied. These alterations in histone turnover were associated with increased DNA damage and decreased cell proliferation in postnatal rat brain. CONCLUSION: Alterations in histone turnover might interfere with histone deposition and chromatin stability, resulting in deregulated cell-specific gene expression and therefore contribute to the development of the neurological disorders associated with FASD. Using in vivo 2H2O-labeling and mass spectrometry-based proteomics might help in the understanding of histone turnover following alcohol exposure and could be of great importance in enabling researchers to identify novel targets and/or biomarkers for the prevention and management of fetal alcohol spectrum disorders.


Assuntos
Transtornos do Espectro Alcoólico Fetal/metabolismo , Variação Genética , Histonas/genética , Histonas/metabolismo , Proteômica/métodos , Acetilação , Animais , Proliferação de Células , Dano ao DNA , Modelos Animais de Doenças , Epigênese Genética , Feminino , Transtornos do Espectro Alcoólico Fetal/genética , Humanos , Gravidez , Processamento de Proteína Pós-Traducional , Ratos , Ratos Sprague-Dawley
20.
Epigenetics ; 12(10): 841-853, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28816587

RESUMO

The preconception environment is a significant modifier of dysgenesis and the development of environmentally-induced disease. To date, fetal alcohol spectrum disorders (FASDs) have been exclusively associated with maternal exposures, yet emerging evidence suggests male-inherited alterations in the developmental program of sperm may be relevant to the growth-restriction phenotypes of this condition. Using a mouse model of voluntary consumption, we find chronic preconception male ethanol exposure associates with fetal growth restriction, decreased placental efficiency, abnormalities in cholesterol trafficking, sex-specific alterations in the genetic pathways regulating hepatic fibrosis, and disruptions in the regulation of imprinted genes. Alterations in the DNA methylation profiles of imprinted loci have been identified in clinical studies of alcoholic sperm, suggesting the legacy of paternal drinking may transmit via heritable disruptions in the regulation of imprinted genes. However, the capacity of sperm-inherited changes in DNA methylation to broadly transmit environmentally-induced phenotypes remains unconfirmed. Using bisulphite mutagenesis and second-generation deep sequencing, we find no evidence to suggest that these phenotypes or any of the associated transcriptional changes are linked to alterations in the sperm-inherited DNA methylation profile. These observations are consistent with recent studies examining the male transmission of diet-induced phenotypes and emphasize the importance of epigenetic mechanisms of paternal inheritance beyond DNA methylation. This study challenges the singular importance of maternal alcohol exposures and suggests paternal alcohol abuse is a significant, yet overlooked epidemiological factor complicit in the genesis of alcohol-induced growth defects, and may provide mechanistic insight into the failure of FASD children to thrive postnatally.


Assuntos
Metilação de DNA/genética , Transtornos do Espectro Alcoólico Fetal/genética , Retardo do Crescimento Fetal/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Consumo de Bebidas Alcoólicas/efeitos adversos , Animais , Criança , Metilação de DNA/efeitos dos fármacos , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Etanol/toxicidade , Feminino , Transtornos do Espectro Alcoólico Fetal/patologia , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/patologia , Humanos , Masculino , Camundongos , Fenótipo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia
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