Gene expression in teratogenic exposures: a new approach to understanding individual risk
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50600 | GEO | 2013/12/31
SECONDARY ACCESSION(S): PRJNA218063
REPOSITORIES: GEO
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Project description:The phenomenon of partial or incomplete penetrance is common to many paradigms of exposure to teratogens, where only some of the exposed individuals exhibit developmental defects. We here argue that the most widely used experimental approaches in reproductive toxicology do not take partial penetrance into account, and are thus likely to miss differences between affected and unaffected individuals that contribute to susceptibility for teratogenesis. We propose that focus on the variation between exposed individuals could help to discover factors that may play a causative role for abnormal developmental processes that occur with incomplete penetrance. Total RNA was extracted from individual embryos E10.5 derived from normal and diabetic pregnancies. A total of 8 sample pools were created, 4 resultiing from normal (C1-C4) and 4 from diabetic (E1-E4) pregnancies. Each pool consisted of RNA from 4 embryos obtained from 4 different pregnancies. Samples E5-E8 consisted of individual embryos with NT defects obtained from diabetic pregnancies.
2013-12-31 | E-GEOD-50600 | biostudies-arrayexpress
Project description:In vitro prediction of developmental toxicity during early discovery phases of drug development has the potential to guide decision-making toward prioritizing candidate drugs that are less likely to later show teratogenicity in vivo. Such screening would reduce animal use in preclinical studies, including full-scale regulatory reproductive toxicology. we evaluate an assay format based on short-term toxicogenomic responses in pluripotent embryonic stem cells (ESC). We exposed attached undifferentiated cells of the mouse ESC cell line R1 for 6h to 10 known teratogenic and 9 non-teratogenic pharmaceutical drugs . We used microarry to access genome-wide gene expression response and identify gene signatures to classify teratogens and non-teratogens.
2015-12-01 | GSE57639 | GEO
Project description:Inbred individuals reared in controlled environments display considerable variance in many complex traits. The underlying cause of this variability has been an enigma, hence the term intangible variation. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process. Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28), show greater coefficients of variance in body weight than their wildtype littermates. Inbred mice carrying a mutation in Trim28 develop metabolic syndrome and abnormal behaviour with incomplete penetrance. These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans. Liver gene expression in Trim28MommeD9 heterozygotes compared to wildtype littermates.
2010-11-15 | E-GEOD-23512 | biostudies-arrayexpress
Project description:Animal studies for embryotoxicity evaluation of potential therapeutics and environmental factors are complex, costly, and time-consuming. Often, studies are not of human relevance because of species differences. In the present study, we recapitulated the process of cardiomyogenesis in human induced pluripotent stem cells (hiPSCs) by modulation of the Wnt signaling pathway to identify a key cardiomyogenesis gene signature that can be applied to identify compounds and/or stress factors compromising the cardiomyogenesis process. Among the 23 tested teratogens and 16 non-teratogens, we identified three retinoids including 13-cis-retinoic acid that completely block the process of cardiomyogenesis in hiPSCs. Moreover, we have identified an early gene signature consisting of 31 genes and associated biological processes that are severely affected by the retinoids. To predict the inhibitory potential of teratogens and non-teratogens in the process of cardiomyogenesis we established the “Developmental Cardiotoxicity Index” (DCI_31g) that accurately differentiates teratogens and non-teratogens to do or do not affect the differentiation of hiPSCs to functional cardiomyocytes.
2023-06-06 | GSE233925 | GEO
Project description:Animal studies for embryotoxicity evaluation of potential therapeutics and environmental factors are complex, costly, and time-consuming. Often, studies are not of human relevance because of species differences. In the present study, we recapitulated the process of cardiomyogenesis in human induced pluripotent stem cells (hiPSCs) by modulation of the Wnt signaling pathway to identify a key cardiomyogenesis gene signature that can be applied to identify compounds and/or stress factors compromising the cardiomyogenesis process. Among the 23 tested teratogens and 16 non-teratogens, we identified three retinoids including 13-cis-retinoic acid that completely block the process of cardiomyogenesis in hiPSCs. Moreover, we have identified an early gene signature consisting of 31 genes and associated biological processes that are severely affected by the retinoids. To predict the inhibitory potential of teratogens and non-teratogens in the process of cardiomyogenesis we established the “Developmental Cardiotoxicity Index” (DCI_31g) that accurately differentiates teratogens and non-teratogens to do or do not affect the differentiation of hiPSCs to functional cardiomyocytes.
2023-06-06 | GSE233924 | GEO
Project description:Stem cell-based tests for developmental toxicity are currently intensively studied. Here, we used a protocol that differentiates human induced pluripotent stem cells (hiPSCs) to neural ectodermal progenitor cells (UKN1) and exposed them to 23 teratogens and 16 non-teratogens at human relevant concentrations. Substance-induced, genome-wide expression profiles were analyzed by two procedures that classified the compounds either based on the number of significantly deregulated genes or on a classification technique with cross-validation. Both procedures demonstrated a high performance with accuracy, sensitivity and specificity of 0.90, 0.83 and 1.0, as well as 0.87, 0.92 and 0.80, respectively. Comparing the present findings with the UKN1 test to those from our recently published UKK2 test that instead recapitulates cardiomyogenic differentiation showed a high congruence in compound classification. This may be explained by the fact that the same pathways, such as PI3K-Akt, P53, TGF-beta, MAPK, EGFR and Hippo were overrepresented among the differentially expressed genes for both tests. However, for some teratogens discrepant results were obtained, such as atorvastatin and thalidomide. In conclusion, UKN1 identifies teratogens with high sensitivity and specificity, and combined interpretation analysis with other tests that differentiate hiPSCs into otherdifferent cell types may further improve the results in the future.
2022-11-03 | GSE209962 | GEO
Project description:Inbred individuals reared in controlled environments display considerable variance in many complex traits. The underlying cause of this variability has been an enigma, hence the term intangible variation. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process. Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28), show greater coefficients of variance in body weight than their wildtype littermates. Inbred mice carrying a mutation in Trim28 develop metabolic syndrome and abnormal behaviour with incomplete penetrance. These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans.
2010-11-15 | GSE23512 | GEO
Project description:There is a great need for in vitro tests that identify developmental toxicants in relation to human oral doses and blood concentrations. In the present study, we used the hiPSC-based UKK-24h-test and analyzed genome-wide expression profiles of 23 known teratogens and 16 non-teratogens. All compounds were analyzed at the maximal plasma concentration (Cmax) and the 20-fold Cmax for a 24 h incubation period in three independent experiments. Using the 1,000 probe sets with the highest variability and including information on cytotoxicity, a penalized logistic regression based classifier (top-1,000 classifier) reached an AUC, accuracy, sensitivity, and specificity of 0.96, 0.92, 0.96 and 0.88, respectively to correctly classify the compounds as teratogens or non-teratogens. This top-1,000 classifier reached a higher AUC, accuracy and sensitivity than a second classifier (SPS-classifier), which used the number of significant probe sets to classify the compounds. At least, the SPS-classifier had a specificity of 1. Classification at 20-fold Cmax did not lead to better performance metrics than testing at 1-fold Cmax. Finally, inclusion of cytotoxicity information into the classifier clearly improved the performance metrics. In conclusion, although further optimization by additional readouts and inclusion of cell systems that model different developmental processes is required, the UKK-24h-test will support the early discovery-phase detection of human developmental toxicants already in its present form.
2022-06-24 | GSE187001 | GEO
Project description:Parkinson’s disease (PD) has a neuro-developmental component with multiple genetic predispositions. The most prevalent mutation, LRRK2-G2019S is linked to familial and sporadic PD. Based on the multiple origins of PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patient genetic background act as susceptibility factors for developing PD. To assess the developmental component of LRRK2-G2019S pathogenesis, we used 19 human iPSC-derived neuroepithelial stem cell lines (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal. Within patients, phenotypes were only partly LRRK2-G2019S dependent, suggesting Parkinson’s disease (PD) has a neuro-developmental component with multiple genetic predispositions. The most prevalent mutation, LRRK2-G2019S is linked to familial and sporadic PD. Based on the multiple origins of PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patient genetic background act as susceptibility factors for developing PD. To assess the developmental component of LRRK2-G2019S pathogenesis, we used 19 human iPSC-derived neuroepithelial stem cell lines (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal. Within patients, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. We identified Serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the abberant phenotypes. Its enzymatic product, D-Serine, rescued altered NESC renewal. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment.
2018-03-07 | GSE101534 | GEO
Project description:Congenital malformations are a prevalent cause of infant mortality in the United States and their induction has been linked to a variety of factors, including exposure to teratogens. However, the molecular mechanisms of teratogenicity are not fully understood. MicroRNAs are an important group of small, non-coding RNAs that regulate mRNA expression. MicroRNA roles in early embryonic development are well established, and their disruption during development can cause abnormalities. We hypothesized that developmental exposure to teratogens such as valproic acid alters microRNA expression profiles in developing embryos. Valproic acid is an anticonvulsant and mood-stabilizing drug used to treat epilepsy, bipolar disorder and migraines. To examine the effects of valproic acid on microRNA expression during development, we used zebrafish embryos as a model vertebrate developmental system. Zebrafish embryos were continuously exposed to valproic acid (1 mM) or vehicle control (ethanol) starting from 4 hours post-fertilization (hpf) and sampled at 48 and 96 hpf to determine the miRNA expression profiles prior to and after the onset of developmental defects. At 96 hpf, 95% of the larvae showed skeletal deformities, abnormal swimming behavior, and pericardial effusion. Microarray expression profiling was done using Agilent zebrafish miRNA microarrays. Microarray results revealed changes in miRNA expression at both the time points. Thirteen miRNAs were differentially expressed at 48 hpf and 22 miRNAs were altered at 96 hpf. Among them, six miRNAs (miR-16a, 18c, 122, 132, 457b, and 724) were common to both time points. Bioinformatic target prediction and examination of published literature revealed that these miRNAs target several genes involved in the normal functioning of the central nervous system. These results suggest that the teratogenic effects of valproic acid could involve altered miRNA expression. Small RNA profiles were deteremined in valproic acid exposed zebrafish embryos using Agilent miRNA microarrays
2013-06-19 | E-GEOD-48054 | biostudies-arrayexpress