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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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE54121 | GEO | 2014/01/16

SECONDARY ACCESSION(S): PRJNA235212

REPOSITORIES: GEO

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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

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. 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.

2014-01-16 | E-GEOD-54121 | biostudies-arrayexpress

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 Keywords: ordered

2004-03-11 | GSE1072 | GEO

Comparison of Bzrp ligands

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

2CdA-induced microphthalmia

Project description:In this dose series pregnant CD-1 (outbred) dams were exposed to the 2-chloro analogue of 2'-deoxyadenosine (a metabolic toxin) on 8 d.p.c. Test doses were developed from a teratological series for 2CdA-induced microphthalmia using BMDS modeling software from the US EPA. Benchmark doses for microarray analysis were: 5.0 mg/kg (25% risk), 2.5 mg/kg (5% risk), 1.25 mg/kg (NOAEL), and 0.625 mg/kg (subNOAEL). All measurements were on RNA from the embryo proper at 3.0h post-treatment. Keywords = dose series Keywords = 2-chloro-2'deoxyadenosine Keywords = embryo Keywords = microphthalmia Keywords: dose response

2004-03-11 | GSE1068 | GEO

MeHg-induced encephalopathy

Project description:In this dose series pregnant CD-1 (outbred) dams were exposed to methylmercury (MeHg) as monomethylmercuric chloride injected intraperitoneally on 9 d.p.c. Test doses were 10.0 mg/kg and below. This regimen induces symptoms of Fetal Minimata Disease (FMD) in term fetuses. Risks with respect to FMD for the various test doses were 10.0 mg/kg (40% risk), 5.0 mg/kg (20% risk), 2.5 mg/kg (NOAEL), and 1.25 mg/kg (subNOAEL). All measurements were on RNA from the embryonic forebrain (prosencephalon and surrounding tissue) at 3.0h post-treatment. Keywords = dose series Keywords = mercury Keywords = embryo Keywords = Fetal Minamata Disease Keywords: dose response

2004-03-11 | GSE1075 | GEO

Transcriptomic profiling of S2/S3 proximal tubules in response to LPS treatment

Project description:To investigate the mechanisms of endotoxin-mediated kidney injury as well as renoprotective effects of endotoxin preconditioning, we performed manual microdissection of S2/S3 proximal tubules in mice as follows: 1) Non-preconditioned mice subjected to single-dose 5 mg/kg LPS (0111:B4) i.p. for 4 hrs. 2) Non-preconditioned mice subjected to single-dose 5 mg/kg LPS (0111:B4) for 24 hrs. 3) Preconditioned mice subjected to 0.25 mg/kg LPS followed 24 hour later by 5 mg/kg LPS for 4 hrs. 4) Preconditioned mice subjected to 0.25 mg/kg LPS followed 24 hour later by 5 mg/kg LPS for 24 hrs. 5) Control mice (untreated).

2018-10-06 | GSE120879 | GEO

Impacts of 2-amino-4,6-dinitrotoluene (2-ADNT) Exposure in Northern Bobwhite

Project description:Effects of 2A-DNT on global protein expression were investigated in liver tissue for both sexes and kidney in males, all at a 30 mg/kg-d dose using nLC-MS/MS.

2016-07-06 | PXD001206 | Pride

MeHg intervention with PK11195

Project description:In this time course pregnant CD-1 (outbred) dams were exposed to MeHg as monomethylmercuric chloride intraperitoneally on 9 d.p.c. The test dose of 5.0 mg/kg MeHg was selected as a dose with an estimated 20% increased risk for encephalopathy in term fetuses, with no evidence of maternal toxicosis. Exposed embryos were co-treated with PK11195, a nontoxic ligand of the mitochondrial peripheral-type benzodiazepine receptor (Bzrp) that effectively suppresses developmental toxicity induced with MeHg. The anticipated remediation with 5.0 mg/kg and 4.0 mg/kg PK11195 is <10% malformations. Sampling intervals ranged from 3.0h to 6.0h post-exposure. All measurements were on RNA from the embryonic forebrain (prosencephalon). Keywords = time series Keywords = mercury Keywords = PK11195 Keywords = embryo Keywords = Fetal Minamata Disease Keywords: time-course

2004-03-11 | GSE1077 | GEO

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