Maternal drinking during pregnancy can result in a wide spectrum of cognitive and behavioral abnormalities termed fetal alcohol spectrum disorders (FASD). The heterogeneity observed in FASD-related phenotypes can be a...Maternal drinking during pregnancy can result in a wide spectrum of cognitive and behavioral abnormalities termed fetal alcohol spectrum disorders (FASD). The heterogeneity observed in FASD-related phenotypes can be attributed to a number of environmental and genetic factors;however, ethanol dose and timing of exposure may have significant influences. Here, we report the behavioral effects of acute, binge-like ethanol exposure at three neurodevelopmental times corresponding to the first, second, and third trimester of human development in C57BL/6J mice. Results show that developmental ethanol exposure consistently delays the development of basic motor skill reflexes and coordination as well as impairs spatial learning and memory. Observed changes in activity and anxiety-related behaviors, however, appear to be dependent on timing of alcohol exposure. The variability in behaviors between different treatment models suggests that these may be useful in evaluating the mechanisms disrupted by ethanol at specific neurodevelopmental times. The results provide further evidence that, regardless of developmental stage, the developing brain is acutely sensitive to alcohol exposure.展开更多
Background: Fetal Alcohol Spectrum Disorders (FASDs) are a global public health concern with lifelong consequences for affected individuals. Recent prevalence studies suggest FASD prevalence rates range from 1-5% amon...Background: Fetal Alcohol Spectrum Disorders (FASDs) are a global public health concern with lifelong consequences for affected individuals. Recent prevalence studies suggest FASD prevalence rates range from 1-5% among school age children. Most people with FASD are not correctly diagnosed and inadequate screening to identify patients with increased risk may contribute to under-diagnosis. This study developed a 10-item screening tool for FASD and examined its feasibility. Methods: The sample consisted of 355 children who had been evaluated at an FASD clinic. Data from the 33-item Alcohol Related Neurodevelopmental Disorder Behavioral Checklist was used to develop a brief FASD screen by comparing the changes in Cronbach’s alpha for different combinations of items. The validity of the brief scale was then further examined using receiving operating characteristic analyses. Results: The 10-item screen demonstrated acceptable sensitivity, specificity, and accuracy to identify children at high risk for FASD. The percentage correctly classified was 91.3 and the area under the receiving operating characteristic curve was 0.971. Conclusions: This feasibility study demonstrated that a screen for FASD consisting of 10 items with yes or no responses can be completed in 3 - 4 minutes. The tool is brief, with a low administration burden and has acceptable epidemiologic performance characteristics including accuracy. Future research should examine the performance of this tool when used in larger, community-based populations where screening for FASD would be appropriate.展开更多
Maternal alcohol consumption is the leading known non-genetic cause of mental retardation.Prenatal alcohol exposure can cause a range of structural and functional birth defects,which are defined as Fetal Alcohol Spect...Maternal alcohol consumption is the leading known non-genetic cause of mental retardation.Prenatal alcohol exposure can cause a range of structural and functional birth defects,which are defined as Fetal Alcohol Spectrum Disorders(FASD).Growing evidence suggests that excessive cell death in selected cell populations is a major component of the pathogenesis of FASD.This suggests that a strategy for protecting against ethanol’s teratogenesis by epigenetically regulating the genes involved in the apoptotic pathway is promising for effective intervention and prevention of FASD.We have recently found that treatment with ethanol resulted in a significant decrease in miR-125b expression in neural crest cells(NCCs)and mouse embryos.We also validated that Bcl-2 antagonist killer 1(Bak1)and p53-upregulated modulator of apoptosis(PUMA)are the direct targets of miR-125b in NCCs.In addition,overexpression of miR-125b significantly reduced the ethanol-induced increase in Bak1 and PUMA protein expression,caspase-3 activation,and apoptosis in NCCs,indicating that miR-125b can modulate ethanol-induced apoptosis by the regulation of Bcl-2 and p53 pathways.Furthermore,microinjection of miR-125b mimic resulted in a significant increase in miR-125b expression and a decrease in the protein expression of Bak1 and PUMA in ethanol-exposed mouse embryos.Up-regulation of miR-125b also significantly reduced ethanol-induced caspase-3 activation and diminished ethanol-induced growth retardation in mouse embryos.Our studies have also shown that exposure to ethanol resulted in a significant increase in the activities of histone deacetylase(HDAC)and DNA methyltransferase(DNMT),and increased the methylation of Bcl-2 promoter in NCCs.In addition,ChIP-qPCR assay revealed that ethanol exposure significantly decreased acetyl-histone H3 binding to the Bcl-2 promoter and the expression of Bcl-2.Supplementing with sulforaphane(SFN),an isothiocyanate derived from cruciferous vegetables and a dual epigenetic regulator which can inhibit both DNMTs and HDACs,reversed the ethanol-induced hypermethylation of Bcl-2 promoter and reduction in acetyl-histone H3 binding to the Bcl-2 promoter.Treatment with SFN also restored the expression of Bcl-2 in ethanol-exposed NCCs.Furthermore,supplementing with SFN diminished ethanol-induced apoptosis in NCCs and in mouse embryos exposed to ethanol in vivo.These results demonstrate that SFN can epigenetically restore the expression of Bcl-2 and attenuate ethanol-induced apoptosis by decreasing methylation and increasing histone acetylation at the Bcl-2 promoter.These findings support the potential of dietary consumption of SFN or SFN-rich broccoli sprouts to attenuate ethanol-induced apoptosis and confer in vivo protection against FASD through epigenetic regulation of the expression of anti-apoptotic genes.展开更多
In utero exposure to ethanol continues to be a significant public health issue and neonatal healthcare professionals are in need of objective means to identify exposed newborns. The aim of this study was to fully vali...In utero exposure to ethanol continues to be a significant public health issue and neonatal healthcare professionals are in need of objective means to identify exposed newborns. The aim of this study was to fully validate two methods for the detection of two direct alcohol biomarkers, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanol (POPE) and ethyl glucuronide (EtG), in umbilical cord and apply the assays to a group of authentic specimens. The limits of detections were 2 and 1 ng/g for POPE and ETG and the limits of quantitation were 4 and 3 ng/g, respectively. Inter and intra-day precision and accuracy measurements were within 15%. The assays were applied to 308 authentic specimens where we detected POPE in five (1.6%) specimens and EtG in twelve (3.9%) specimens. The mean concentrations were 11.4 ng/g ± 9.4 ng/g and 127.2 ± 227.7 ng/g for POPE and EtG, respectively. This study suggested that umbilical cord was a suitable specimen type for the identification of newborns exposed to ethanol in the womb and the prevalence of POPE and EtG detected in umbilical cord were consistent with the prevalence of self-reported binge drinking reported by the National Birth Defect Prevention Study (NBDPS) and Behavioral Risk Factor Surveillance System (BRFSS). Further studies are required to fully describe the association between the observed concentrations of POPE and EtG in umbilical cord to the level of maternal consumption of ethanol.展开更多
To the Editor:Alcohol-induced heart defect is one of the most important clinical manifestations of fetal alcohol spectrum disorder(FASD),characterized by atrioventricular septal defect and arterial conical deformity.[...To the Editor:Alcohol-induced heart defect is one of the most important clinical manifestations of fetal alcohol spectrum disorder(FASD),characterized by atrioventricular septal defect and arterial conical deformity.[1]Resveratrol,a polyphenol component of the traditional Chinese herb Polygonum cuspidatum,which is mainly extracted from its rhizome,is known to exhibit beneficial effects on the cardiovascular system.For example,resveratrol has beneficial effects on heart dysfunction,myocardial hypertrophy,and pressure overload.Moreover,resveratrol was found to inhibit platelet aggregation,prevent atherosclerosis,and scavenge free radicals.[2]However,the effect of resveratrol on alcohol-induced heart defect during heart formation is still unknown.The unique characteristics of zebrafish embryos,such as their transparent body,in vitro fertilization,and short reproductive cycle,make them an attractive tool for cardiovascular research.Moreover,the immersion-based alcohol delivery method used with zebrafish embryos is non-invasive unlike most of the alcohol administration protocols applied in rodent models.展开更多
文摘Maternal drinking during pregnancy can result in a wide spectrum of cognitive and behavioral abnormalities termed fetal alcohol spectrum disorders (FASD). The heterogeneity observed in FASD-related phenotypes can be attributed to a number of environmental and genetic factors;however, ethanol dose and timing of exposure may have significant influences. Here, we report the behavioral effects of acute, binge-like ethanol exposure at three neurodevelopmental times corresponding to the first, second, and third trimester of human development in C57BL/6J mice. Results show that developmental ethanol exposure consistently delays the development of basic motor skill reflexes and coordination as well as impairs spatial learning and memory. Observed changes in activity and anxiety-related behaviors, however, appear to be dependent on timing of alcohol exposure. The variability in behaviors between different treatment models suggests that these may be useful in evaluating the mechanisms disrupted by ethanol at specific neurodevelopmental times. The results provide further evidence that, regardless of developmental stage, the developing brain is acutely sensitive to alcohol exposure.
文摘Background: Fetal Alcohol Spectrum Disorders (FASDs) are a global public health concern with lifelong consequences for affected individuals. Recent prevalence studies suggest FASD prevalence rates range from 1-5% among school age children. Most people with FASD are not correctly diagnosed and inadequate screening to identify patients with increased risk may contribute to under-diagnosis. This study developed a 10-item screening tool for FASD and examined its feasibility. Methods: The sample consisted of 355 children who had been evaluated at an FASD clinic. Data from the 33-item Alcohol Related Neurodevelopmental Disorder Behavioral Checklist was used to develop a brief FASD screen by comparing the changes in Cronbach’s alpha for different combinations of items. The validity of the brief scale was then further examined using receiving operating characteristic analyses. Results: The 10-item screen demonstrated acceptable sensitivity, specificity, and accuracy to identify children at high risk for FASD. The percentage correctly classified was 91.3 and the area under the receiving operating characteristic curve was 0.971. Conclusions: This feasibility study demonstrated that a screen for FASD consisting of 10 items with yes or no responses can be completed in 3 - 4 minutes. The tool is brief, with a low administration burden and has acceptable epidemiologic performance characteristics including accuracy. Future research should examine the performance of this tool when used in larger, community-based populations where screening for FASD would be appropriate.
文摘Maternal alcohol consumption is the leading known non-genetic cause of mental retardation.Prenatal alcohol exposure can cause a range of structural and functional birth defects,which are defined as Fetal Alcohol Spectrum Disorders(FASD).Growing evidence suggests that excessive cell death in selected cell populations is a major component of the pathogenesis of FASD.This suggests that a strategy for protecting against ethanol’s teratogenesis by epigenetically regulating the genes involved in the apoptotic pathway is promising for effective intervention and prevention of FASD.We have recently found that treatment with ethanol resulted in a significant decrease in miR-125b expression in neural crest cells(NCCs)and mouse embryos.We also validated that Bcl-2 antagonist killer 1(Bak1)and p53-upregulated modulator of apoptosis(PUMA)are the direct targets of miR-125b in NCCs.In addition,overexpression of miR-125b significantly reduced the ethanol-induced increase in Bak1 and PUMA protein expression,caspase-3 activation,and apoptosis in NCCs,indicating that miR-125b can modulate ethanol-induced apoptosis by the regulation of Bcl-2 and p53 pathways.Furthermore,microinjection of miR-125b mimic resulted in a significant increase in miR-125b expression and a decrease in the protein expression of Bak1 and PUMA in ethanol-exposed mouse embryos.Up-regulation of miR-125b also significantly reduced ethanol-induced caspase-3 activation and diminished ethanol-induced growth retardation in mouse embryos.Our studies have also shown that exposure to ethanol resulted in a significant increase in the activities of histone deacetylase(HDAC)and DNA methyltransferase(DNMT),and increased the methylation of Bcl-2 promoter in NCCs.In addition,ChIP-qPCR assay revealed that ethanol exposure significantly decreased acetyl-histone H3 binding to the Bcl-2 promoter and the expression of Bcl-2.Supplementing with sulforaphane(SFN),an isothiocyanate derived from cruciferous vegetables and a dual epigenetic regulator which can inhibit both DNMTs and HDACs,reversed the ethanol-induced hypermethylation of Bcl-2 promoter and reduction in acetyl-histone H3 binding to the Bcl-2 promoter.Treatment with SFN also restored the expression of Bcl-2 in ethanol-exposed NCCs.Furthermore,supplementing with SFN diminished ethanol-induced apoptosis in NCCs and in mouse embryos exposed to ethanol in vivo.These results demonstrate that SFN can epigenetically restore the expression of Bcl-2 and attenuate ethanol-induced apoptosis by decreasing methylation and increasing histone acetylation at the Bcl-2 promoter.These findings support the potential of dietary consumption of SFN or SFN-rich broccoli sprouts to attenuate ethanol-induced apoptosis and confer in vivo protection against FASD through epigenetic regulation of the expression of anti-apoptotic genes.
文摘In utero exposure to ethanol continues to be a significant public health issue and neonatal healthcare professionals are in need of objective means to identify exposed newborns. The aim of this study was to fully validate two methods for the detection of two direct alcohol biomarkers, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanol (POPE) and ethyl glucuronide (EtG), in umbilical cord and apply the assays to a group of authentic specimens. The limits of detections were 2 and 1 ng/g for POPE and ETG and the limits of quantitation were 4 and 3 ng/g, respectively. Inter and intra-day precision and accuracy measurements were within 15%. The assays were applied to 308 authentic specimens where we detected POPE in five (1.6%) specimens and EtG in twelve (3.9%) specimens. The mean concentrations were 11.4 ng/g ± 9.4 ng/g and 127.2 ± 227.7 ng/g for POPE and EtG, respectively. This study suggested that umbilical cord was a suitable specimen type for the identification of newborns exposed to ethanol in the womb and the prevalence of POPE and EtG detected in umbilical cord were consistent with the prevalence of self-reported binge drinking reported by the National Birth Defect Prevention Study (NBDPS) and Behavioral Risk Factor Surveillance System (BRFSS). Further studies are required to fully describe the association between the observed concentrations of POPE and EtG in umbilical cord to the level of maternal consumption of ethanol.
基金the National Natural Science Foundations of China(No.81771632)the National Key Research and Development Program(No.2016YFC1000500)the Shanghai Key Laboratory of Birth Defect(No.13DZ2260600).
文摘To the Editor:Alcohol-induced heart defect is one of the most important clinical manifestations of fetal alcohol spectrum disorder(FASD),characterized by atrioventricular septal defect and arterial conical deformity.[1]Resveratrol,a polyphenol component of the traditional Chinese herb Polygonum cuspidatum,which is mainly extracted from its rhizome,is known to exhibit beneficial effects on the cardiovascular system.For example,resveratrol has beneficial effects on heart dysfunction,myocardial hypertrophy,and pressure overload.Moreover,resveratrol was found to inhibit platelet aggregation,prevent atherosclerosis,and scavenge free radicals.[2]However,the effect of resveratrol on alcohol-induced heart defect during heart formation is still unknown.The unique characteristics of zebrafish embryos,such as their transparent body,in vitro fertilization,and short reproductive cycle,make them an attractive tool for cardiovascular research.Moreover,the immersion-based alcohol delivery method used with zebrafish embryos is non-invasive unlike most of the alcohol administration protocols applied in rodent models.
