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A rat toxicogenomics study with Calcium Sensitizer EMD 82571 reveals a pleiotropic cause in teratogenicity

ABSTRACT: The aim of reprotoxicity testing is to reveal adverse effects of chemicals and drugs on reproduction and on pre and postnatal fetal development. There is very limited data available on gene expression profiling for elucidation of the teratogenic effects of nongenotoxic teratogens. Therefore, research was undertaken to obtain knowledge on the molecular effects of MSC1096199 (previously known as EMD 82571), a calcium sensitizer that was abandoned in the preclinical development phase due to its teratogenic effects in some foetuses. Pregnant wistar rats were dose daily with either MSC1096199 (50 or 150 mg/kg) or Retinoic acid (10 mg/kg) on gestational days 6-17. Microarray experiment were performed using four different tissues (maternal liver, embryo liver (GD20), embryo bone (GD20), and whole embryo (GD12)) under four different conditions (vehicle, low dose and high dose of MSC1096199 and Retinoic acid) to determine the drug regulated genes. In the high dose treatment group, approximately 58% of the fetuses showed malformations i.e. exencephaly and agnathia, and toxicogenomics evidenced that the genes critically involved in osteogenesis, odontogenesis and extra cellular matrix components to be significantly regulated by MSC1096199, therefore providing a molecular rational for the observed teratogenic effects. Two-condition experiment, RA vs EMD 82571. Biological replicates:5 control, 5 treated. RNA from control and treatment groups were labeled with Cy3 and Cy5 fluorochromes, respectively. Cy3-channel pictures and correspondig raw data files are marked as 1b. Cy5-channel pictures and correspondig raw data files are marked as 2b.

ORGANISM(S): Rattus norvegicus

SUBMITTER: JM-CM-<rgen Borlak

PROVIDER: E-GEOD-54121 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A rat toxicogenomics study with Calcium Sensitizer EMD 82571 reveals a pleiotropic cause and adverse outcome pathway of teratogenicity

Project description:The aim of reprotoxicity testing is to reveal adverse effects of chemicals and drugs on reproduction and on pre and postnatal fetal development. There is very limited data available on gene expression profiling for elucidation of the teratogenic effects of nongenotoxic teratogens. Therefore, research was undertaken to obtain knowledge on the molecular effects of MSC1096199 (previously known as EMD 82571), a calcium sensitizer that was abandoned in the preclinical development phase due to its teratogenic effects in some foetuses. Pregnant wistar rats were dose daily with either MSC1096199 (50 or 150 mg/kg) or Retinoic acid (10 mg/kg) on gestational days 6-17. Microarray experiment were performed using four different tissues (maternal liver, embryo liver (GD20), embryo bone (GD20), and whole embryo (GD12)) under four different conditions (vehicle, low dose and high dose of MSC1096199 and Retinoic acid) to determine the drug regulated genes. In the high dose treatment group, approximately 58% of the fetuses showed malformations i.e. exencephaly and agnathia, and toxicogenomics evidenced that the genes critically involved in osteogenesis, odontogenesis and extra cellular matrix components to be significantly regulated by MSC1096199, therefore providing a molecular rational for the observed teratogenic effects. Pregnant wistar rats were treated daily with the dose of either MSC1096199 (50 or 150 mg/kg) or Retinoic acid (10 mg/kg) on gestational days 6-17. Microarray experiment were performed using four different tissues (maternal liver, embryo liver, embryo bone, and whole embryo) under four different conditions (vehicle, low dose and high dose of MSC1096199 and Retinoic acid) to determine the drug regulated genes.

2014-06-07 | E-GEOD-58225 | biostudies-arrayexpress

A rat toxicogenomics study with Calcium Sensitizer EMD 82571 reveals a pleiotropic cause and adverse outcome pathway of teratogenicity

Project description:The aim of reprotoxicity testing is to reveal adverse effects of chemicals and drugs on reproduction and on pre and postnatal fetal development. There is very limited data available on gene expression profiling for elucidation of the teratogenic effects of nongenotoxic teratogens. Therefore, research was undertaken to obtain knowledge on the molecular effects of MSC1096199 (previously known as EMD 82571), a calcium sensitizer that was abandoned in the preclinical development phase due to its teratogenic effects in some foetuses. Pregnant wistar rats were dose daily with either MSC1096199 (50 or 150 mg/kg) or Retinoic acid (12 mg/kg) on gestational days 6-17. Microarray experiment were performed using four different tissues (maternal liver, embryo liver (GD20), embryo bone (GD20), and whole embryo (GD12)) under four different conditions (vehicle, low dose and high dose of MSC1096199 and Retinoic acid) to determine the drug regulated genes. In the high dose treatment group, approximately 58% of the fetuses showed malformations i.e. exencephaly and agnathia, and toxicogenomics evidenced that the genes critically involved in osteogenesis, odontogenesis and extra cellular matrix components to be significantly regulated by MSC1096199, therefore providing a molecular rational for the observed teratogenic effects.

2014-06-07 | GSE58225 | GEO

A rat toxicogenomics study with Calcium Sensitizer EMD 82571 reveals a pleiotropic cause in teratogenicity

2014-01-16 | GSE54121 | GEO

Transcription profiling of human tongue carcinoma cells treated with emdogain and TGF beta1

Project description:Background: The composition of Emdogain® (EMD) is unclear, but it has been postulated to contain transforming growth factor-beta-1 (TGF-beta1) as the main functioning cytokine. The purpose of this study was to compare target genes of EMD and TGF-beta1 on invasive oral carcinoma HSC-3 cells. Particular focus was on matrix metalloproteinase (MMP) family genes. <br>Methodology/Principal Findings: Affymetrix microarrays were conducted to study differentially (P<0.05) expressed genes in HSC-3 cells after 6h and 24h of EMD (200 ?g/ml) or TGF-beta1 (10 ng/ml) incubations. Gene Ontology (GO) enrichment analyses from the regulated genes were also conducted. After 6h of EMD or TGF-?1 treatment, 48 and 393 genes, respectively, were regulated. After 24h incubations, only 12 genes by EMD but 346 genes by TGF-beta1 were regulated. Among the most regulated genes by both of the study reagents were several genes commonly regulated in carcinomas, including MMP-9 and -10. The expression of MMP-10 by EMD treated carcinoma cells was also verified in protein level. <br>Conclusions/Significance: Our results show that EMD and TGF-beta1 can regulate genes related to carcinogenesis, but TGF-beta1 regulates significantly greater number of genes. This suggests that TGF-beta1 cannot be present in EMD at the studied concentration, if present at all.<br>

2010-04-30 | E-MEXP-2645 | biostudies-arrayexpress

CSF2 x gender interactions on the transcriptome of Day 15 bovine extra-embryonic membrane

Project description:We aimed to study the effects of CSF2 treatment on the transcriptome of the Day 15 female and male embryo. Within the raw files, channel 1= Cy3 and channel 2= Cy5

2014-10-01 | GSE55364 | GEO

Toxicogenomic signatures associated with methylmercury induced developmental toxicity in the zebrafish embryos.

Project description:Methylmercury (MeHg) is a teratogen with adverse effects on embryogenesis from fish to man. The adverse developmental outcomes of MeHg are well understood, but molecular understanding of teratogenic effects is rather limited. We performed here a genome - wide transcriptional analyses of 6, 30 and 50 μg/L MeHg treated zebrafish embryos from 4 to 72 h post-fertilization (hpf) using RNA-sequencing and self-printed microarray, and conducted a systematical comparison of MeHg - induced transcriptomic responses observed in this and our previous studies. We found that genes linked to gene ontology in terms of oxidative stress, visual, photoreception and cilium, and GABAergic synapse were enriched in embryo exposed from 4 to 72 hpf. The significantly altered genes involved in MAP kinase, TGF beta signaling pathway, oxidative phosphorylation, and glutathione metabolism were enriched across different exposure scenarios. We obtain 22 genes significantly regulated by MeHg, particularly the significant changes were determined in embryos exposed to 6 μg/L MeHg, which did not cause obviously teratogenic effects. Our findings show that the genes whose expression is altered by MeHg in embryonic stages may play important roles in adverse developmental endpoints and might be served as signatures for teratogenic effects.

2022-12-21 | GSE206531 | GEO

miRNA Expression in Early Porcine Pregnancy

Project description:This study examined the expression of pig-specific microRNAs (miRNAs) at gestation day 20 (gd20) of pregnancy in Yorkshire sows. Tissue differences in miRNA expression, and miRNA differences between healthy and arresting embryo attachment sites (i.e., healthy endometrium vs. arresting endometrium; healthy trophoblast vs. arresting trophoblast), were of prime interest. For more information, please refer to the primary research paper.

2013-08-01 | GSE45761 | GEO

Comparison of Bzrp ligands

Project description:This series compares the effects that two pharmacologically distinct ligands at the mitochondrial peripheral-type benzodiazepine receptor (Bzrp). PK11195 (4.0 mg/kg, a presumed antagonist) has no observable adverse effects in pregnant mice on either 8 days post-coitus (d.p.c.) or 9 d.p.c. Furthermore, PK11195 is shown to rescue mouse fetuses from microphthalmia or microphthalmia-microcephaly induced with 2CdA or MeHg, respectively; effects of PK11195 on EtOH-induced craniofacial malformations are not yet unkown. Ro5-4864 (4.0 mg/kg, a presumed agonist) is weakly teratogenic on 8 d.p.c. (effects on 9 d.p.c. unknown) and this Bzrp ligand does not rescue fetuses from malformations induced with either 2CdA or MeHg; effects of Ro5-4864 on EtOH-induced craniofacial malformations is unknown for either sensitive (C57BL/6J) or insensitive (C57BL/6N) strains. The 4.0 mg/kg dose of Bzrp ligands is consistent with pharmacological activity in several studies. Pregnant mice were exposed to these agents on 8 d.p.c. (2CdA, EtOH) or 9 d.p.c. (MeHg). The test dose of 2.5 mg/kg 2CdA was modeled for a 5% increased risk of microphthalmia in term fetuses. Full remediation with PK11195 anticipated. The test dose of 5.0 mg/kg MeHg gives an estimated 20% increased risk of microphthalmia-microcephaly (encephalopathy) in term fetuses. Partial remediation with PK11195 is anticipated to <10% malformations. Again the effects of PK11195 on EtOH teratogenicity is not yet known. The sampling time was chosen as the time of p53 protein induction (3.0h to 4.5h post-treatment). Whereas co-treatment with PK11195 suppresses embryonic p53 protein induction Ro5-4864 does not block this reaction. All measurements were on RNA from the embryonic headfold (8 d.p.c.) or prosencephalon (9 d.p.c.). Keywords = peripheral benzodiazepine receptor Keywords = Bzrp ligands Keywords = PK11195 Keywords = Ro5-4864 Keywords = embryo Keywords = p53 protein induction

2010-06-09 | E-GEOD-1072 | biostudies-arrayexpress

Evaluating the relative potency and mechanism of action of azoles in the rat Whole Embryo Culture

Project description:We evaluated the effect of azoles on embryonic development in the rat whole embryo culture (WEC). Using the total morphological scoring system (TMS), we calculated the effective dose for 10% decrease in TMS. We collected transcriptomics data for rat WEC exposed to azoles at their ID10 for 4 hours. Results revealed shared expressions responses in genes involved in the retinoic acid (RA) and sterol biosynthesis pathways, which are respectively representatives of developmental toxicity and desired fungicidal action of the azoles. Azoles with more pronounced effects on the regulation of RA-associated genes were generally characterized as more potent embryotoxicants.

2017-10-04 | GSE102082 | GEO