Fetal Sex Does Not Influence Rates of Gastrulation-Stage Alcohol-Induced Craniofacial Malformations in C57BL/6J Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE239355 | GEO | 2024/03/19
REPOSITORIES: GEO
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Project description:Prevailing dogma maintains that Fetal Alcohol Syndrome (FAS) craniofacial and neurological birth defects are the sole consequence of maternal alcohol use during pregnancy. Using a physiologically relevant mouse model, we contrasted the incidence of alcohol-related growth and craniofacial defects between offspring derived from maternal, paternal, and dual parental alcohol exposures. Geometric morphometric analyses reveal that maternal, paternal, and dual parental exposures each induce unique craniofacial malformations and program dose-dependent increases in microcephaly, particularly in male offspring. Notably, dual parental exposures do not exhibit additive or synergistic effects; instead, our transcriptomic analyses demonstrate that each treatment programs distinct sex-specific changes in gene expression within the developing brain. Our data are the first to demonstrate that male drinking is a plausible driver of alcohol- related birth defects and that epidemiological examination of male alcohol consumption may help explain the enormous variation in FAS clinical presentations and severity.
2024-06-30 | GSE218362 | GEO
Project description:EXPERIMENT: Microarray expression profiles derived from the cranial neural folds (headfold) of neurulation-stage mouse embryos 3.0h after maternal alcohol exposure on 8 d.p.c. ANIMAL MODEL: Pregnancies from 2 substrains of C57BL/6 mice that differ in relative risk of Fetal Alcohol Syndrome (FAS): C57BL/6J (B6J) high-risk condition, and C57BL/6NCrl (B6N) low-risk condition. EXPOSURE: Dams dosed with ethanol (EtOH) by intraperitoneal injection at 2.9 g EtOH per kg body weight. Controls received vehicle (saline) alone. A third group of dams received EtOH + 4.0 mg/kg PK11195, a specific high-affinity ligand to the 18 KDa mitochondrial peripheral benzodiazepine receptor site. INTERVAL: High blood alcohol content must be sustained in dams for several hours to invoke FAS and is traditionally accomplished by a double injection of EtOH 4.0h apart. Since these embryos were harvested for genetic analysis 1h before dams would have gotten the second alcohol injection, the interval represents a snapshot of the critical response, prior to the second maternal injection that invokes greater risk. Counter-exposure to PK11195 significantly lowers the adverse response of B6J embryos to EtOH. PLATFORM: Two independent assays run. The first dataset (PE), run April 2002 â January 2003, used samples pooled from 2 litters (PE) and the platform was a two-channel MPS621 array (http://www.lifesciences.perkinelmer.com/). This platform has 4800 sequence-verified gene elements derived from over 50 different human cDNA libraries reflecting a variety of well-annotated cellular processes and disease pathways. The second dataset (AF), run between May 2005 â November 2005, used samples pooled from 1 litter and the platform was Affymetrix GeneChip® Mouse Genome 430A 2.0 Array (http://www.affymetrix.com/). The MG430A 2.0 platform has 45,102 oligonucleotide probe cells representing approximately 14,000 well-characterized genes in the draft mouse genome assembly. The corresponding GEO samples are GSM12218 - GSM12227 for the two-channel PE arrays, and GSM136067 - GSM136078 for the one-channel AF arrays. Keywords = fetal alcohol syndrome Keywords = alcohol-related birth defects Keywords = EtOH Keywords = PK11195 Keywords = embryo Keywords = strain differences Keywords: Ordered Assay of early mouse embryos during pathogenesis of Fetal Alcohol Syndrome (FAS). Replicate RNA samples were arrayed by one-channel oligonucleotide (Affymetrix) or two-channel cDNA (Perkin-Elmer) platforms.
2010-06-09 | E-GEOD-1074 | biostudies-arrayexpress
Project description:Mouse model for Fetal Alcohol Syndrome. Embryos exposed to alcohol in controlled environment to assess teratogenic effects. Fetal Alcohol Syndrome (FAS) is a leading developmental disorder. To date, a holistic view of molecular gene changes is largely unexplored. Using microarray analysis of whole embryo mouse culture with strict-control over alcohol-level, we found, directly related alcohol-metabolism, a reduction of retinol binding protein 1(Rbp1), and a, de novo expression of aldehyde dehydrogenase 1B1 (ALDH1B1). Remarkably, four key hemopoiesis genes (glycophorin A, adducin 2, beta-2 microglobulin, and ceruloplasmin) became absent, and many histone variants genes were reduced. Hypothesis-driven informatics analysis and intersection analysis of two independent experiments indicated that the altered genes are involved in cell growth, hemopoiesis, histone modification, eye and heart development, and a collective reduction in expression of growth factor genes (Igf1, Efemp1, Tieg, and Edil3) and neural specification genes (neurogenin, Sox 5, bHLHb5). Down-regulated neural specification phenotypes further supported the above findings. Further more, the gene expression profile indicated distinct subgroups which overlapped with the teratogenesis of the open- and the closed-neural tubes known in FAS. In summary, our data reveal genes alteration with causal potential for dysmorpology (e.g. retinoic acid, neuronal specification, and neurotrophic factors, and epigenetics related histone genes) and those downstream responsive genes related to alcohol metabolism, and developmental teratogenesis. Experiment Overall Design: Comparison of whole embryo gene expression after exposure to ethanol for 46 hours. Note 2 independent experiments completed.
2009-09-05 | E-GEOD-9545 | biostudies-arrayexpress
Project description:Gene expression of embryonic eye (e13.5) in Ftx KO females, Ftx KO males, WT females and WT males.
2018-07-29 | GSE100700 | GEO
Project description:Ethanol is the most common substance of abuse in the US, and abuse can lead to physical dependence, addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. As a complex brain disorder, there is evidence for both a genetic contribution to risk and sexually-dimorphic responses in alcoholism, but an overall understanding of the biological contributions and the neuroadaptive underpinnings of alcohol addiction is limited. Utilizing novel genetic animal models with highly divergent withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) selected lines of mice and by examining both sexes, the distinct or common contributions of response to alcohol genotype/phenotype and of sex to addiction stages over time were characterized. Transcriptional profiling was performed to identify neuroadaptive changes as a consequence of chronic intoxication in the medial prefrontal cortex (mPFC). Significant expression differences were identified for each line and tracked over a behaviorally-relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more responsive to ethanol with higher fold expression differences. Data structure was analyzed by bioinformatics, which showed a strong effect of sex with high similarity of male vs. female expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, striking differences were observed instead between the lines/phenotypes irrespective of sex. Because sex was the strongest influence on neuroadaptive changes overall, confirmation analysis compared males vs. females. Notably, results revealed distinct inflammatory signaling between males and females at peak withdrawal, with a pro-inflammatory inflammotoxic phenotype in females but in contrast overall suppression of immune signaling in males. Thus, the early response to chronic intoxication is strongly influenced by sex while pathways that are altered during a period of abstinence are dependent on genotype. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of distinct translational targets for stage- and sex-specific therapies for the treatment of alcohol withdrawal and the maintenance of sobriety.
2014-09-17 | GSE56247 | GEO
Project description:Gestating F0 generational female rats were transiently exposed to DDT during fetal gonadal sex determination and the incidence of adult onset pathologies was assessed in the subsequent F1, F2, and F3 generations. In addition, sperm differential DNA methylation regions (DMRs) that were associated with specific pathologies in the F3 generation males were investigated. No pathology was observed in the F1 generation DDT lineage males or females compared with F1 generation controls (vehicle exposure). There was an increase of testis disease and early onset puberty in the F2 generation DDT lineage males. The F3 generation DDT males had significant increases in testis disease, prostate disease, and late onset puberty. The F3 generation DDT females had significant increases in ovarian and kidney disease. Both the F3 generation males and females had significant increases in the frequency of obesity and multiple disease. The F3 generation sperm was collected to examine DMRs for the ancestrally exposed DDT male population. Unique sets of DMRs were associated with late onset puberty, kidney disease, and multiple disease pathologies.
2018-07-31 | GSE114032 | GEO
Project description:Preimplantation alcohol exposure can negatively impact embryonic development through disruption of molecular profiles and lead to fetal alcohol spectrum disorder (FASD). Despite the central role of the placenta in proper embryonic development and successful pregnancy, studies on the placenta in a FASD context are markedly lacking. Here, preimplantation binge-like alcohol exposure was implemented on pregnant C57BL/6 female mice through subcutaneous injection with two doses of either 2.5 g/kg 50% ethanol or an equivalent volume of saline at 2-h intervals on embryonic day 2.5 corresponding to the 8-cell stage. The placental morphology, DNA methylation and gene expression patterns in male and female late-gestation (E18.5) placentas were assessed. While overall placental morphology was not affected, we found a significant decrease in male ethanol-exposed embryo weights. When looking at molecular profiles, we uncovered numerous differentially methylated regions (DMRs ≥10% difference; 991 in males; 1309 in females) and differentially expressed genes (DEGs; 1046 in males; 340 in females) in the placentas. Remarkably, only 21 DMRs and 54 DEGs were common to both sexes, which were enriched for genes involved in growth factor response pathways. Preimplantation alcohol exposure had a greater impact on imprinted genes expression in male placentas (imprinted DEGs: 18 in males; 1 in females). Finally, by using L1-regularized linear regression, we were able to precisely discriminate control and ethanol-exposed placentas based on their specific DNA methylation patterns. This is the first study demonstrating that preimplantation alcohol exposure alters the DNA methylation and transcriptomic profiles of late-gestation placentas in a sex-specific manner. Importantly, it reveals a placental DNA methylation signature that can detect prenatal alcohol exposure in early life in order to provide appropriate support to attenuate and prevent eventual impact.
2024-02-07 | GSE254846 | GEO
Project description:Preimplantation alcohol exposure can negatively impact embryonic development through disruption of molecular profiles and lead to fetal alcohol spectrum disorder (FASD). Despite the central role of the placenta in proper embryonic development and successful pregnancy, studies on the placenta in a FASD context are markedly lacking. Here, preimplantation binge-like alcohol exposure was implemented on pregnant C57BL/6 female mice through subcutaneous injection with two doses of either 2.5 g/kg 50% ethanol or an equivalent volume of saline at 2-h intervals on embryonic day 2.5 corresponding to the 8-cell stage. The placental morphology, DNA methylation and gene expression patterns in male and female late-gestation (E18.5) placentas were assessed. While overall placental morphology was not affected, we found a significant decrease in male ethanol-exposed embryo weights. When looking at molecular profiles, we uncovered numerous differentially methylated regions (DMRs ≥10% difference; 991 in males; 1309 in females) and differentially expressed genes (DEGs; 1046 in males; 340 in females) in the placentas. Remarkably, only 21 DMRs and 54 DEGs were common to both sexes, which were enriched for genes involved in growth factor response pathways. Preimplantation alcohol exposure had a greater impact on imprinted genes expression in male placentas (imprinted DEGs: 18 in males; 1 in females). Finally, by using L1-regularized linear regression, we were able to precisely discriminate control and ethanol-exposed placentas based on their specific DNA methylation patterns. This is the first study demonstrating that preimplantation alcohol exposure alters the DNA methylation and transcriptomic profiles of late-gestation placentas in a sex-specific manner. Importantly, it reveals a placental DNA methylation signature that can detect prenatal alcohol exposure in early life in order to provide appropriate support to attenuate and prevent eventual impact.
2024-02-07 | GSE254845 | GEO
Project description:Alcohol-associated liver disease (ALD) is a major cause of alcohol related mortality. Recently we identified hepatic demethylases KDM5B and KDM5C as important sex-specific epigenetic regulators of alcohol response in the liver. In this study we aimed to study the molecular mechanisms of KDM5-dependent ALD development and resolution. We found that alcohol induces pathological changes in cell-cell communication in the liver that are in part mediated by epigenetic changes in hepatocytes mediated by histone demethylase KDM5B. Using cell type specific knockout mice, we found that KDM5B histone demethylase was a key regulator of alcohol-induced epigenetic changes in hepatocytes. Moreover, it regulated hepatocytes-non-parenchymal cell crosstalk that promoted inflammation and fibrosis development in ALD. This mechanism was specific to females. In males KDM5B deficiency was not sufficient to prevent fibrosis development. In contrast KDM5B demethylase loss promoted fibrosis resolution in both males and females. This mechanism involved changes in hepatocyte-macrophage crosstalk and LXRα activation, which we identified to be critical for the fibrosis resolution process. CONCLUSION: In summary, KDM5B demethylase is a regulator of cell-cell crosstalk involved in disease progression in females and in disease resolution in both sexes.
2023-10-07 | GSE244240 | GEO
Project description:We sought to investigate the scope of cellular and molecular changes within a mouse’s olfactory system as a function of its exposure to odors emitted from members of the opposite sex. To this end, we housed mice either separated from members of the opposite sex (sex-separated) or together with members of the opposite sex (sex-combined) until six months of age and then profiled transcript levels within the main olfactory epithelium (MOE), vomeronasal organ (VNO), and olfactory bulb (OB) of the mice via RNA-seq. For each tissue type, we then analyzed gene expression differences between sex-separated males and sex-separated females (SM v SF), sex-combined males and sex-combined females (CM v CF), sex-separated females and sex-combined females (SF v CF), and sex-separated males and sex-combined males (SM v CM). Within both the MOE and VNO, we observed significantly more numerous gene expression differences between males and females when mice were sex-separated as compared to sex-combined. Chemoreceptors were highly enriched among the genes differentially expressed between males and females in sex-separated conditions, and these expression differences were found to reflect differences in the abundance of the corresponding sensory neurons.
2018-11-01 | GSE112352 | GEO