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1.
Biomolecules ; 14(5)2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38785976

RESUMO

Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2-5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or understood. In this study, using a candidate gene approach, we performed a genetic variant analysis of retinoic acid (RA) metabolic and developmental signaling pathway genes on whole exome sequencing data of 23 FASD-diagnosed individuals. We found risk and resilience alleles in ADH and ALDH genes known to normally be involved in alcohol detoxification at the expense of RA production, causing RA deficiency, following PAE. Risk and resilience variants were also identified in RA-regulated developmental pathway genes, especially in SHH and WNT pathways. Notably, we also identified significant variants in the causative genes of rare neurodevelopmental disorders sharing comorbidities with FASD, including STRA6 (Matthew-Wood), SOX9 (Campomelic Dysplasia), FDG1 (Aarskog), and 22q11.2 deletion syndrome (TBX1). Although this is a small exploratory study, the findings support PAE-induced RA deficiency as a major etiology underlying FASD and suggest risk and resilience variants may be suitable biomarkers to determine the risk of FASD outcomes following PAE.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Tretinoína , Humanos , Feminino , Tretinoína/metabolismo , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Gravidez , Masculino , Predisposição Genética para Doença , Sequenciamento do Exoma
2.
Free Radic Biol Med ; 208: 272-284, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37541454

RESUMO

The breast cancer 1 (Brca1) susceptibility gene regulates the repair of reactive oxygen species (ROS)-mediated DNA damage, which is implicated in neurodevelopmental disorders. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), including abnormal brain function, associated with enhanced ROS-initiated DNA damage. Herein, oxidative DNA damage in fetal brains and neurodevelopmental disorders were enhanced in saline-exposed +/- vs. +/+ Brca1 littermates. A single EtOH exposure during gestation further enhanced oxidative DNA damage, altered the expression of developmental/DNA damage response genes in fetal brains, and resulted in neurodevelopmental disorders, all of which were BRCA1-dependent. Pretreatment with the ROS inhibitor phenylbutylnitrone (PBN) blocked DNA damage and some neurodevelopmental disorders in both saline- and EtOH-exposed progeny, corroborating a ROS-dependent mechanism. Fetal BRCA1 protects against altered gene expression and neurodevelopmental disorders caused by both physiological and EtOH-enhanced levels of ROS formation. BRCA1 deficiencies may enhance the risk for FASD.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Neoplasias , Transtornos do Neurodesenvolvimento , Gravidez , Humanos , Feminino , Espécies Reativas de Oxigênio/metabolismo , Etanol/toxicidade , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/genética , Expressão Gênica , Proteína BRCA1/genética
3.
Alcohol ; 110: 65-81, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36898643

RESUMO

INTRODUCTION: Prenatal alcohol exposure can impair placentation and cause intrauterine growth restriction (IUGR), fetal demise, and fetal alcohol spectrum disorder (FASD). Previous studies showed that ethanol's inhibition of placental insulin and insulin-like growth factor, type 1 (IGF-1) signaling compromises trophoblastic cell motility and maternal vascular transformation at the implantation site. Since soy isolate supports insulin responsiveness, we hypothesized that dietary soy could be used to normalize placentation and fetal growth in an experimental model of FASD. METHODS: Pregnant Long-Evans rat dams were fed with isocaloric liquid diets containing 0% or 8.2% ethanol (v/v) from gestation day (GD) 6. Dietary protein sources were either 100% soy isolate or 100% casein (standard). Gestational sacs were harvested on GD19 to evaluate fetal resorption, fetal growth parameters, and placental morphology. Placental insulin/IGF-1 signaling through Akt pathways was assessed using commercial bead-based multiplex enzyme-linked immunosorbent assays. RESULTS: Dietary soy markedly reduced or prevented the ethanol-associated fetal loss, IUGR, FASD dysmorphic features, and impairments in placentation/maturation. Furthermore, ethanol's inhibitory effects on the placental glycogen cell population at the junctional zone, invasive trophoblast populations at the implantation site, maternal vascular transformation, and signaling through the insulin and IGF1 receptors, Akt and PRAS40 were largely abrogated by co-administration of soy. CONCLUSION: Dietary soy may provide an economically feasible and accessible means of reducing adverse pregnancy outcomes linked to gestational ethanol exposure.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Efeitos Tardios da Exposição Pré-Natal , Ratos , Animais , Humanos , Gravidez , Feminino , Placentação , Placenta/metabolismo , Insulina/metabolismo , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/prevenção & controle , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Transtornos do Espectro Alcoólico Fetal/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Long-Evans , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Etanol/efeitos adversos , Morte Fetal , Dieta
4.
Life Sci ; 310: 121102, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36270428

RESUMO

One of the most common causes of fetal alcohol spectrum disease (FASD) characterized with neurodevelopmental disorder and growth retardation, is the postnatal alcohol consumption. Since studies in literature are mainly focused on alcohol-induced effects on brain tissues, the molecular effects of postnatal alcohol consumption on fetal liver are not clarified yet. The aim of this study is to determine the postnatal alcohol consumption-induced structural and compositional changes on liver tissue and the antioxidant capacity of liver. Newborn mice were divided into 3 groups as control group without any treatment, alcohol group treated with 3.0 g/kg of ethanol in 0.02 ml/g of artificially enriched milk between Postnatal Days (PD) 3-20 and intragastric intubation control group which was intragastrically intubated in the same method as the alcohol group but without ethanol/milk. These postnatal days in mice refers prenatal period (third trimester) of gestation in human. The biomolecular changes were determined by ATR-FTIR spectral analysis of the samples, besides the biochemical measurement of total protein content and antioxidant capacity of liver tissue. The result of the current study shows that while there was a slight increase in total lipid content, significant decrease in unsaturated lipid and total protein contents and total antioxidant capacity of liver were observed in alcohol-treated group. Thus, it is concluded that postnatal alcohol treatment causes significant changes in tissue proteins and lipids by inducing lipid peroxidation and changes in protein conformations of the liver tissue. In addition to that alcohol consumption also reduce the antioxidant capacity of liver tissue.


Assuntos
Antioxidantes , Transtornos do Espectro Alcoólico Fetal , Gravidez , Feminino , Humanos , Animais , Camundongos , Animais Recém-Nascidos , Etanol/toxicidade , Fígado/metabolismo , Lipídeos , Transtornos do Espectro Alcoólico Fetal/metabolismo
5.
Alcohol Clin Exp Res ; 46(11): 1953-1966, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36109176

RESUMO

BACKGROUND: Fetal alcohol spectrum disorders (FASD) occur in children who were exposed to alcohol in utero and are manifested in a wide range of neurocognitive deficits. These deficits could be caused by alterations to the cortical microvasculature that are controlled by post-transcriptional regulators such as microRNAs. METHODS: Using an established mouse model of moderate prenatal alcohol exposure (PAE), we isolated cortices (CTX) and brain microvascular endothelial cells (BMVECs) at embryonic day 18 (E18) and examined the expression of miR-150-5p and potential downstream targets. Cellular transfections and intrauterine injections with LNA™ mimics or inhibitors were used to test miR-150-5p regulation of novel target vascular endothelial zinc finger 1 (Vezf1). Dual-luciferase assays were used to assess the direct binding of miR-150-5p to the Vezf1 3'UTR. The effects of miR-150-5p and Vezf1 on endothelial cell function were determined by in vitro migration and tube formation assays. RESULTS: We found that miR-150-5p was upregulated and Vezf1 was downregulated during PAE in the E18 CTX and BMVECs. Transfection with miR-150-5p mimics resulted in decreased Vezf1 expression in BMVECs, while miR-150-5p inhibition did the opposite. Dual-luciferase assays revealed direct binding of miR-150-5p with the Vezf1 3'UTR. Intrauterine injections showed that miR-150-5p regulates the expression of Vezf1 in vivo during PAE. miR-150-5p overexpression decreased BMVEC migration and tube formation, while miR-150-5p inhibition enhanced migration and tube formation. Vezf1 overexpression rescued the effects of the miR-150-5p mimic. Alcohol treatment of BMVECs increased miR-150-5p expression and inhibited migration and tube formation. Finally, miR-150-5p inhibition and Vezf1 overexpression rescued the negative effects of alcohol on migration and tube formation. CONCLUSIONS: miR-150-5p regulation of Vezf1 results in altered endothelial cell function during alcohol exposure. Further, miR-150-5p inhibition of Vezf1 may adversely alter the development of the cortical microvasculature during PAE and contribute to deficits seen in patients with FASD.


Assuntos
Transtornos do Espectro Alcoólico Fetal , MicroRNAs , Efeitos Tardios da Exposição Pré-Natal , Humanos , Animais , Camundongos , Feminino , Gravidez , Indutores da Angiogênese/metabolismo , Indutores da Angiogênese/farmacologia , Regiões 3' não Traduzidas , Células Endoteliais/fisiologia , Neovascularização Fisiológica/fisiologia , Transtornos do Espectro Alcoólico Fetal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , MicroRNAs/metabolismo , Encéfalo/metabolismo , Microvasos , Luciferases/metabolismo , Luciferases/farmacologia , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo
6.
Neurotox Res ; 40(2): 605-613, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35386022

RESUMO

Fetal alcohol exposure has permanent effects on the brain structure, leading to functional deficits in several aspects of behavior, including learning and memory. Alcohol-induced neurocognitive impairment in offsprings is included with activation of oxidative- inflammatory cascade followed with wide apoptotic neurodegeneration in several brain areas, such as the hippocampus. Metformin is the first-line treatment for diabetic patients. It rapidly crosses the blood-brain barrier (BBB) and exerts antioxidant, anti-inflammatory, and neuroprotective effects. In this study, we evaluated the protective effects of metformin on ethanol-related neuroinflammation, as well as neuron apoptosis in the hippocampus of adult male rat in animal model of fetal alcohol spectrum disorders. Treatment with ethanol in milk solution (5.25 and 27.8 g/kg, respectively) was conducted by intragastric intubation at 2-10 days after birth. To examine the antioxidant and anti-inflammatory properties of metformin, an ELISA assay was performed for determining the tumor necrosis factor-α (TNF-α) and antioxidant enzyme concentrations. Immunohistochemical staining was conducted for evaluating the glial fibrillary acidic protein (GFAP) and cleaved caspase-3 expression. Based on the results, metformin caused a significant increase in the superoxide dismutase (SOD) (P < 0.05) and glutathione peroxidase (GSH-Px) (P < 0.01) activities. On the other hand, it reduced the concentrations of TNF-α and malondialdehyde, compared to the ethanol group (P < 0.01). In the metformin group, there was a reduction in cell apoptosis in the hippocampus, as well as GFAP-positive cells (P < 0.01). Overall, apoptotic signaling, regulated by the oxidative inflammatory cascade, can be suppressed by metformin in adult brain rats following animal model of fetal alcohol spectrum disorders.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Metformina , Síndromes Neurotóxicas , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose , Modelos Animais de Doenças , Etanol/toxicidade , Feminino , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/metabolismo , Humanos , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Estresse Oxidativo , Gravidez , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
7.
Neurochem Res ; 47(4): 1001-1011, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35040027

RESUMO

Several experimental and clinical findings suggest that ethanol consumption during pregnancy activates an oxidative-inflammatory cascade followed by wide apoptotic neurodegeneration within several brain areas, including the hippocampus. Crocin can protect neurons because of its antioxidant, anti-inflammatory, and antiapoptotic effects. This study evaluated the crocin protective impact on ethanol-related neuroinflammation and neuronal apoptosis in the hippocampus of rat pups exposed to alcohol over postnatal days. Ethanol (5.25 g/kg) was administrated in milk solution (27.8 ml/kg) by intragastric intubation 2-10 days after birth. The animals received crocin (15, 30, and 45 mg/kg) 2-10 days after birth. The hippocampus-dependent memory and spatial learning were evaluated 36 days after birth using the Morris water maze task. Further, the concentrations of TNF-α and antioxidant enzymes were determined using ELISA assay to examine the antioxidant and anti-inflammatory activities. Also, immunohistochemical staining was performed to evaluate the glial fibrillary acidic protein (GFAP), Ionized calcium binding adaptor molecule 1(Iba-1), and caspase-3 expression. The administration of crocin significantly attenuated spatial memory impairment (P < 0.01) after ethanol neurotoxicity. Also, crocin led to a significant enhancement in SOD (P < 0.05) and GSH-PX (P < 0.01), whereas it caused a reduction in the TNF-α and MDA concentrations compared to the ethanol group (P < 0.01). Moreover, the hippocampal level of caspase-3 (P < 0.01) and the number of GFAP and Iba-1-positive cells decreased in the crocin group (P < 0.001). Crocin suppresses apoptotic signaling mediated by the oxidative-inflammatory cascade in rat pups exposed to ethanol after birth.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Fármacos Neuroprotetores , Animais , Apoptose , Carotenoides , Modelos Animais de Doenças , Etanol/toxicidade , Feminino , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Hipocampo/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Gravidez , Ratos , Ratos Wistar
8.
Alcohol Clin Exp Res ; 45(10): 1965-1979, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34581462

RESUMO

BACKGROUND: Alcohol exposure during the gastrulation stage of development causes the craniofacial and brain malformations that define fetal alcohol syndrome. These malformations, such as a deficient philtrum, are exemplified by a loss of midline tissue and correspond, at least in part, to regionally selective cell death in the embryo. The tumor suppressor protein Tp53 is an important mechanism for cell death, but the role of Tp53 in the consequences of alcohol exposure during the gastrulation stage has yet to be examined. The current studies used mice and zebrafish to test whether genetic loss of Tp53 is a conserved mechanism to protect against the effects of early developmental stage alcohol exposure. METHODS: Female mice, heterozygous for a mutation in the Tp53 gene, were mated with Tp53 heterozygous males, and the resulting embryos were exposed during gastrulation on gestational day 7 (GD 7) to alcohol (two maternal injections of 2.9 g/kg, i.p., 4 h apart) or a vehicle control. Zebrafish mutants or heterozygotes for the tp53zdf1  M214K mutation and their wild-type controls were exposed to alcohol (1.5% or 2%) beginning 6 h postfertilization (hpf), the onset of gastrulation. RESULTS: Examination of GD 17 mice revealed that eye defects were the most common phenotype among alcohol-exposed fetuses, occurring in nearly 75% of the alcohol-exposed wild-type fetuses. Tp53 gene deletion reduced the incidence of eye defects in both the heterozygous and mutant fetuses (to about 35% and 20% of fetuses, respectively) and completely protected against alcohol-induced facial malformations. Zebrafish (4 days postfertilization) also demonstrated alcohol-induced reductions of eye size and trabeculae length that were less common and less severe in tp53 mutants, indicating a protective effect of tp53 deletion. CONCLUSIONS: These results identify an evolutionarily conserved role of Tp53 as a pathogenic mechanism for alcohol-induced teratogenesis.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Craniofaciais/etiologia , Etanol/efeitos adversos , Transtornos do Espectro Alcoólico Fetal/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Anormalidades Induzidas por Medicamentos/metabolismo , Animais , Anormalidades Craniofaciais/metabolismo , Feminino , Masculino , Camundongos , Gravidez , Teratogênese , Peixe-Zebra
9.
Alcohol Clin Exp Res ; 45(2): 329-337, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33296097

RESUMO

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is characterized by severe clinical impairment, considerable social burden, and high mortality and morbidity, which are due to various malformations, sepsis, and cancer. As >50% of deaths from FASD occur during the first year of life, we hypothesized that there is the acceleration of biological aging in FASD. Several recent studies have established genome-wide DNA methylation (DNAm) profiles as "epigenetic clocks" that can estimate biological aging, and FASD has been associated with differential DNAm patterns. Therefore, we tested this hypothesis using epigenetic clocks. METHODS: We investigated 5 DNAm-based measures of epigenetic age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge) and telomere length (DNAmTL) using 4 independent publicly available DNAm datasets; 2 datasets were derived from buccal epithelium, and the other 2 datasets were derived from peripheral blood. RESULTS: Compared with controls, children with FASD exhibited an acceleration of GrimAge in 1 buccal and 2 blood datasets. No significant difference was found in other DNAm ages and DNAmTL. Meta-analyses showed a significant acceleration of GrimAge in the blood samples but not in the buccal samples. CONCLUSIONS: This study provides novel evidence regarding accelerated epigenetic aging in children with FASD.


Assuntos
Envelhecimento/genética , Envelhecimento/metabolismo , Epigênese Genética/fisiologia , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Adolescente , Criança , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Masculino , Mucosa Bucal/metabolismo , Gravidez
10.
Neurotoxicol Teratol ; 83: 106946, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33340653

RESUMO

Prenatal alcohol exposure (PAE) continues to be a serious public health problem, yet no reliable clinical tools are available for assessing levels of drinking during pregnancy. Fatty acid ethyl esters (FAEEs), the nonoxidative metabolites of ethanol measured in meconium, are potential biomarkers to quantify the level of PAE. The association between the concentrations of FAEEs from meconium and adolescent substance use and related problems was examined in a prospective birth-cohort of adolescents exposed to alcohol and drugs in utero. FAEEs were quantified with gas chromatography via a flame ionization detector. Meconium was analyzed for FAEEs in 216 newborns; 183 of them (81 boys, 102 girls) were assessed at age 15 for alcohol, tobacco, and marijuana use using biologic assays and self-report. Substance use problems were assessed using the Problem Oriented Screening Instrument for Teenagers. Findings from multivariable logistic regression analyses indicated that, after controlling for other prenatal drug exposure and covariates, higher concentrations of FAEEs (ethyl myristate, ethyl palmitate, ethyl oleate, ethyl linoleate, ethyl linolenate, and ethyl arachidonate) were related to a greater likelihood of marijuana use and experiencing substance use problems, but not tobacco or alcohol use, at age 15. Elevated levels of FAEEs in meconium may be promising markers for PAE, identifying newborns at risk for early substance use and developing substance use problems.


Assuntos
Ácidos Graxos/metabolismo , Mecônio/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Transtornos Relacionados ao Uso de Substâncias/etiologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Adolescente , Comportamento do Adolescente , Adulto , Consumo de Bebidas Alcoólicas/metabolismo , Biomarcadores/metabolismo , Cognição , Estudos de Coortes , Esterificação , Ésteres/metabolismo , Etanol/metabolismo , Ácidos Graxos/química , Feminino , Transtornos do Espectro Alcoólico Fetal/etiologia , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/psicologia , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Estudos Prospectivos , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto Jovem
11.
PLoS One ; 15(11): e0242276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33196678

RESUMO

Alcohol (ethanol, EtOH) consumption during pregnancy can result in fetal alcohol spectrum disorders (FASDs), which are characterized by prenatal and postnatal growth restriction and craniofacial dysmorphology. Recently, cell-derived extracellular vesicles, including exosomes and microvesicles containing several species of RNAs (exRNAs), have emerged as a mechanism of cell-to-cell communication. However, EtOH's effects on the biogenesis and function of non-coding exRNAs during fetal development have not been explored. Therefore, we studied the effects of maternal EtOH exposure on the composition of exosomal RNAs in the amniotic fluid (AF) using rat fetal alcohol exposure (FAE) model. Through RNA-Seq analysis we identified and verified AF exosomal miRNAs with differential expression levels specifically associated with maternal EtOH exposure. Uptake of purified FAE AF exosomes by rBMSCs resulted in significant alteration of molecular markers associated with osteogenic differentiation of rBMSCs. We also determined putative functional roles for AF exosomal miRNAs (miR-199a-3p, miR-214-3p and let-7g) that are dysregulated by FAE in osteogenic differentiation of rBMSCs. Our results demonstrate that FAE alters AF exosomal miRNAs and that exosomal transfer of dysregulated miRNAs has significant molecular effects on stem cell regulation and differentiation. Our results further suggest the usefulness of assessing molecular alterations in AF exRNAs to study the mechanisms of FAE teratogenesis that should be further investigated by using an in vivo model.


Assuntos
Líquido Amniótico/metabolismo , Diferenciação Celular/efeitos dos fármacos , Etanol/farmacologia , Exossomos/metabolismo , MicroRNAs/metabolismo , Líquido Amniótico/efeitos dos fármacos , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/patologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteogênese/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley
12.
J Neurodev Disord ; 12(1): 15, 2020 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-32416732

RESUMO

BACKGROUND: Fetal alcohol spectrum disorders (FASD) are common, seen in 1-5% of the population in the USA and Canada. Children diagnosed with FASD are not likely to remain with their biological parents, facing early maternal separation and foster placements throughout childhood. METHODS: We model FASD in mice via prenatal alcohol exposure and further induce early life stress through maternal separation. We use RNA-seq followed by clustering of expression profiles through weighted gene co-expression network analysis (WGCNA) to analyze transcriptomic changes that result from the treatments. We use reverse transcription qPCR to validate these changes in the mouse hippocampus. RESULTS: We report an association between adult hippocampal gene expression and prenatal ethanol exposure followed by postnatal separation stress that is related to behavioral changes. Expression profile clustering using WGCNA identifies a set of transcripts, module 19, associated with anxiety-like behavior (r = 0.79, p = 0.002) as well as treatment group (r = 0.68, p = 0.015). Genes in this module are overrepresented by genes involved in transcriptional regulation and other pathways related to neurodevelopment. Interestingly, one member of this module, Polr2a, polymerase (RNA) II (DNA directed) polypeptide A, is downregulated by the combination of prenatal ethanol and postnatal stress in an RNA-Seq experiment and qPCR validation (q = 2e-12, p = 0.004, respectively). CONCLUSIONS: Together, transcriptional control in the hippocampus is implicated as a potential underlying mechanism leading to anxiety-like behavior via environmental insults. Further research is required to elucidate the mechanism involved and use this insight towards early diagnosis and amelioration strategies involving children born with FASD.


Assuntos
Transtornos do Espectro Alcoólico Fetal/genética , Perfilação da Expressão Gênica , Hipocampo/metabolismo , Privação Materna , Processamento Pós-Transcricional do RNA , Consumo de Bebidas Alcoólicas/genética , Animais , Animais Recém-Nascidos , Ansiedade , Canadá , Modelos Animais de Doenças , Etanol/administração & dosagem , Etanol/metabolismo , Feminino , Transtornos do Espectro Alcoólico Fetal/metabolismo , Regulação da Expressão Gênica , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Transcriptoma
13.
Neurotox Res ; 37(4): 977-986, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31900896

RESUMO

Fetal alcohol spectrum disorder (FASD), which is caused by prenatal alcohol exposure, can result in cell death in specific brain regions. Alcohol-induced neurocognitive defects offspring's are included with activation of oxidative-inflammatory cascade followed with wide apoptotic neurodegeneration in many brain's regions such as hippocampus. According to the latest studies, H2S (hydrogen sulfide) can protect neuronal cells via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms in different animal models. Therefore, we aimed to evaluate the protective effects of H2S on ethanol-induced neuroinflammation and neuronal apoptosis in pup hippocampus with postnatal alcohol exposure. Administration of ethanol (5.27 g/kg) in milk solution (27.8 mL/kg) for each rat pups was performed through intragastric intubation on 2 to 10 postnatal days and NaHS as H2S donor (1 mg/kg) was injected on similar time, subcutaneously. For examining the antioxidant and anti-inflammatory effects, ELISA assay was performed to determine the levels of TNF-α, IL1ß, and antioxidant enzymes. Immunohistochemical staining was performed to evaluate the expression levels of GFAP and caspase-3 also Nissl staining was done for necrotic cell death evaluation. H2S treatment could significantly increase the activity of total superoxide dismutase, catalase, and glutathione (P < 0.05). It also decreased the levels of TNF-α, IL1ß, and malondialdehyde, compared with the ethanol group (P < 0.05). Moreover, the number of hippocampal caspase-3, GFAP-positive cells, and necrotic cells death reduced in the H2S group (P < 0.01). Based on the findings, H2S can inhibit apoptotic signaling that is mediated by the oxidative-inflammatory cascade following ethanol exposure of rat pups on postnatal period.


Assuntos
Etanol/toxicidade , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Sulfeto de Hidrogênio/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Animais , Animais Recém-Nascidos , Concentração Alcoólica no Sangue , Etanol/administração & dosagem , Feminino , Gasotransmissores/farmacologia , Gasotransmissores/uso terapêutico , Sulfeto de Hidrogênio/farmacologia , Masculino , Gravidez , Ratos , Ratos Wistar
14.
Sci Rep ; 9(1): 16057, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690747

RESUMO

We tested whether cannabinoids (CBs) potentiate alcohol-induced birth defects in mice and zebrafish, and explored the underlying pathogenic mechanisms on Sonic Hedgehog (Shh) signaling. The CBs, Δ9-THC, cannabidiol, HU-210, and CP 55,940 caused alcohol-like effects on craniofacial and brain development, phenocopying Shh mutations. Combined exposure to even low doses of alcohol with THC, HU-210, or CP 55,940 caused a greater incidence of birth defects, particularly of the eyes, than did either treatment alone. Consistent with the hypothesis that these defects are caused by deficient Shh, we found that CBs reduced Shh signaling by inhibiting Smoothened (Smo), while Shh mRNA or a CB1 receptor antagonist attenuated CB-induced birth defects. Proximity ligation experiments identified novel CB1-Smo heteromers, suggesting allosteric CB1-Smo interactions. In addition to raising concerns about the safety of cannabinoid and alcohol exposure during early embryonic development, this study establishes a novel link between two distinct signaling pathways and has widespread implications for development, as well as diseases such as addiction and cancer.


Assuntos
Canabinoides/toxicidade , Transtornos do Espectro Alcoólico Fetal/metabolismo , Proteínas Hedgehog/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Teratogênese/efeitos dos fármacos , Animais , Etanol/efeitos adversos , Etanol/farmacologia , Feminino , Transtornos do Espectro Alcoólico Fetal/patologia , Camundongos , Receptor Smoothened/metabolismo
15.
Alcohol Clin Exp Res ; 43(9): 1887-1897, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31329297

RESUMO

BACKGROUND: We have recently shown that binge or heavy levels of alcohol drinking increase deoxyribonucleic acid (DNA) methylation and reduce gene expression of proopiomelanocortin (POMC) and period 2 (PER2) in adult human subjects (Gangisetty et al., Alcohol Clin Exp Res, 43, 2019, 212). One hypothesis would be that methylation of these 2 genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of prenatal alcohol exposure (PAE). Results of the present study provided some support for this hypothesis. METHODS: We conducted a series of studies to determine DNA methylation changes in stress regulatory genes proopiomelanocortin (POMC) and period 2 (PER2) using biological samples from 3 separate cohorts of patients: (i) pregnant women who consumed moderate-to-high levels of alcohol or low/unexposed controls, (ii) children with PAE and non-alcohol-exposed controls, and (iii) children with PAE treated with or without choline. RESULTS: We found pregnant women who consumed moderate-to-high levels of alcohol and gave birth to PAE children had higher DNA methylation of POMC and PER2. PAE children also had increased methylation of POMC and PER2. The differences in the gene methylation of PER2 and POMC between PAE and controls did not differ by maternal smoking status. PAE children had increased levels of stress hormone cortisol and adrenocorticotropic hormone. Choline supplementation reduced DNA hypermethylation and increased expression of POMC and PER2 in children with PAE. CONCLUSIONS: These data suggest that PAE significantly elevates DNA methylation of POMC and PER2 and increases levels of stress hormones. Furthermore, these results suggest the possibility that measuring DNA methylation levels of PER2 and POMC in biological samples from pregnant women or from children may be useful for identification of a woman or a child with PAE.


Assuntos
Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Proteínas Circadianas Period/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Pró-Opiomelanocortina/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Colina/farmacologia , Colina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Suplementos Nutricionais , Epigênese Genética/efeitos dos fármacos , Feminino , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipotrópicos/farmacologia , Lipotrópicos/uso terapêutico , Masculino , Gravidez
16.
Life Sci Alliance ; 2(2)2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833415

RESUMO

Prenatal alcohol exposure (PAE), like other pregnancy complications, can result in placental insufficiency and fetal growth restriction, although the linking causal mechanisms are unclear. We previously identified 11 gestationally elevated maternal circulating miRNAs (HEamiRNAs) that predicted infant growth deficits following PAE. Here, we investigated whether these HEamiRNAs contribute to the pathology of PAE, by inhibiting trophoblast epithelial-mesenchymal transition (EMT), a pathway critical for placental development. We now report for the first time that PAE inhibits expression of placental pro-EMT pathway members in both rodents and primates, and that HEamiRNAs collectively, but not individually, mediate placental EMT inhibition. HEamiRNAs collectively, but not individually, also inhibited cell proliferation and the EMT pathway in cultured trophoblasts, while inducing cell stress, and following trophoblast syncytialization, aberrant endocrine maturation. Moreover, a single intravascular administration of the pooled murine-expressed HEamiRNAs, to pregnant mice, decreased placental and fetal growth and inhibited the expression of pro-EMT transcripts in the placenta. Our data suggest that HEamiRNAs collectively interfere with placental development, contributing to the pathology of PAE, and perhaps also, to other causes of fetal growth restriction.


Assuntos
MicroRNA Circulante/metabolismo , Etanol/efeitos adversos , Transtornos do Espectro Alcoólico Fetal/metabolismo , Placentação/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Alcoolismo/complicações , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Etanol/administração & dosagem , Feminino , Transtornos do Espectro Alcoólico Fetal/etiologia , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/metabolismo , Humanos , Macaca mulatta , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Ratos , Ratos Sprague-Dawley , Trofoblastos/metabolismo
17.
Neuropeptides ; 74: 88-94, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30642580

RESUMO

Clinical and experimental evidence have demonstrated that, use of alcohol during pregnancy can interrupt brain development. Alcohol-induced neurocognitive deficits in offspring's are involved with activation of oxidative-inflammatory cascade joined with extensive apoptotic neurodegeneration in different brain regions such as hippocampus. Obestatin is a newly discovered peptide with anti-inflammatory, antioxidant, activities in different animal models. In this study, we aimed to evaluate the protective effects of obestatin on alcohol-induced neuronal apoptosis and neuroinflammation in rat pups with postnatal ethanol exposure. Through intragastric intubation, ethanol (5/27 g/kg/day) was administered in male Wistar rat pups on postnatal days 2-10 (third trimester in humans). The animals received Obestatin (1 and 5 µg/kg, S.C.) on postnatal days 2-10. Thirty-six days after birth, the spatial memory test was performed using Morris water maze test, and then, antioxidant enzymes and TNF-α levels were measured by ELISA assay. The expression level of GFAP and caspase-3 proteins was determined via immunohistochemical staining after the behavioral test. Obestatin significantly improved spatial memory deficits (P < .01), and obestatin treatment could significantly increase glutathione and total superoxide dismutase activity (P < .05), reduce level of malondialdehyde (P < .05) and TNF-α in comparison with the ethanol group (P < .01). It's also reduced caspase-3 level, and decreased GFAP-positive cells in the hippocampus of ethanol-exposed rat pups (P < .01). The result of this study shows the potential involvement of oxidative-inflammatory cascade-mediated apoptotic signaling in cognitive deficits due to postnatal ethanol exposure, the results also indicated the neuroprotective effects of Obestatin on alcohol-related behavioral, biochemical and molecular deficits.


Assuntos
Apoptose/efeitos dos fármacos , Encefalite/prevenção & controle , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Hormônios Peptídicos/administração & dosagem , Memória Espacial/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Encefalite/etiologia , Encefalite/metabolismo , Etanol/administração & dosagem , Transtornos do Espectro Alcoólico Fetal/metabolismo , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
18.
Sci Rep ; 8(1): 7720, 2018 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29769550

RESUMO

Excess alcohol use is known to promote development of aggressive tumors in various tissues in human patients, but the cause of alcohol promotion of tumor aggressiveness is not clearly understood. We used an animals model of fetal alcohol exposure that is known to promote tumor development and determined if alcohol programs the pituitary to acquire aggressive prolactin-secreting tumors. Our results show that pituitaries of fetal alcohol-exposed rats produced increased levels of intra-pituitary aromatase protein and plasma estrogen, enhanced pituitary tissue growth, and upon estrogen challenge developed prolactin-secreting tumors (prolactinomas) that were hemorrhagic and often penetrated into the surrounding tissue. Pituitary tumors of fetal alcohol-exposed rats produced higher levels of hemorrhage-associated genes and proteins and multipotency genes and proteins. Cells of pituitary tumor of fetal alcohol exposed rat grew into tumor spheres in ultra-low attachment plate, expressed multipotency genes, formed an increased number of colonies, showed enhanced cell migration, and induced solid tumors following inoculation in immunodeficient mice. These data suggest that fetal alcohol exposure programs the pituitary to develop aggressive prolactinoma after estrogen treatment possibly due to increase in stem cell niche within the tumor microenvironment.


Assuntos
Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Transtornos do Espectro Alcoólico Fetal/etiologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Prolactinoma/etiologia , Animais , Biomarcadores/metabolismo , Feminino , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Prolactinoma/metabolismo , Prolactinoma/patologia , Ratos , Ratos Endogâmicos F344
19.
Toxicol Sci ; 164(1): 179-190, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29617878

RESUMO

Based on our previous findings that prenatal ethanol exposure in offspring increased susceptibility to adult osteoarthritis, this study aimed to further investigate the direct toxicity of ethanol on fetal articular cartilage development. Rat bone marrow-derived stroma cells were capsulated in alginate beads, incubated in a chondrogenic differentiation medium, and cultured for 4 weeks with ethanol treatment at concentrations of 0, 4, 20, and 100 mM. Pregnant rats were treated with ethanol (4 g/kg/day) from gestational days (GDs) 9 to 20. At GD20 and postnatal weeks 2, 6, and 12, 8 male offspring were sacrificed, and 8 male offspring rats of 8-weeks old in each group were treated with or without intraarticular injection of papain for 4 weeks to verify the susceptibility of adult osteoarthritis. Ethanol treatment resulted in poor differentiation of bone marrow-derived stroma cells to chondrocytes and suppressed the expression of the transforming growth factor-ß (TGFß)-smad2/3-Sox9 signaling pathway. In animal experiments, the shape of articular cartilage in the ethanol treatment group was more disordered than that of the control group, the matrix was not deep, and the cartilage was thin, which showed poor cartilage development. The TGFß signaling pathway in the ethanol treatment group was persistently low at all time points. After intraarticular injection of papain, histological analyses, and the Mankin score revealed increased cartilage destruction in the ethanol treatment group. Ethanol caused articular cartilage dysplasia that was programmed in adulthood via a low-functional TGFß signaling pathway, and the tolerance of this articular cartilage to external stimuli was significantly decreased.


Assuntos
Cartilagem Articular/efeitos dos fármacos , Transtornos do Espectro Alcoólico Fetal , Desenvolvimento Fetal/efeitos dos fármacos , Osteoartrite/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fator de Crescimento Transformador beta/metabolismo , Animais , Cartilagem Articular/embriologia , Etanol/efeitos adversos , Feminino , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/patologia , Masculino , Exposição Materna , Osteoartrite/metabolismo , Osteoartrite/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos
20.
Life Sci ; 194: 177-184, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29225110

RESUMO

The adverse effects of prenatal nicotine and alcohol exposure on human reproductive outcomes are a major scientific and public health concern. In the United States, substantial percentage of women (20-25%) of childbearing age currently smoke cigarettes and consume alcohol, and only a small percentage of these individuals quit after learning of their pregnancy. However, there are very few scientific reports on the effect of nicotine in prenatal alcohol exposure on the cerebellum of the offspring. Therefore, this study was conducted to investigate the cerebellar neurotoxic effects of nicotine in a rodent model of Fetal Alcohol Spectrum Disorder (FASD). In this study, we evaluated the behavioral changes, biochemical markers of oxidative stress and apoptosis, mitochondrial functions and the molecular mechanisms associated with nicotine in prenatal alcohol exposure on the cerebellum. Prenatal nicotine and alcohol exposure induced oxidative stress, did not affect the mitochondrial functions, increased the monoamine oxidase activity, increased caspase expression and decreased ILK, PSD-95 and GLUR1 expression without affecting the GSK-3ß. Thus, our current study of prenatal alcohol and nicotine exposure on cerebellar neurotoxicity may lead to new scientific perceptions and novel and suitable therapeutic actions in the future.


Assuntos
Cerebelo/efeitos dos fármacos , Cerebelo/embriologia , Transtornos do Espectro Alcoólico Fetal/patologia , Neurotoxinas/toxicidade , Nicotina/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Feminino , Transtornos do Espectro Alcoólico Fetal/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Sprague-Dawley
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