Hewitt, Philip G. and Singh, Prafull Kumar and Kumar, Arun and Gnewuch, Carsten and Liebisch, Gerhard and Schmitz, Gerd and Borlak, Juergen (2014) A rat toxicogenomics study with the calcium sensitizer EMD82571 reveals a pleiotropic cause of teratogenicity. REPRODUCTIVE TOXICOLOGY, 47. pp. 89-101. ISSN 0890-6238,
Full text not available from this repository. (Request a copy)Abstract
The calcium sensitizer and PDEIII inhibitor EMD82571 caused exencephaly, micrognathia, agnathia and facial cleft in 58% of fetuses. In pursue of mechanisms and to define adverse outcome pathways pregnant Wistar rats were dosed daily with either EMD82571 (50 or 150 mg/kg/day) or retinoic acid (12 mg/kg/day) on gestational days 6-11 and 6-17, respectively. Hypothesis driven and whole genome microarray experiments were performed with whole embryo, maternal liver, embryonic liver and malformed bone at gestational days 12 and 20. This revealed regulation of genes critically involved in osteogenesis, odontogenesis, differentiation and development and extracellular matrix. Importantly, repression of osteocalcin and members of TGF-beta/BMP signaling hampered osteo- and odontogenesis. Furthermore, EMD82571 impaired neurulation by inhibiting mid hinge point formation to cause neural tube defects. Taken collectively, a molecular rationale for the observed teratogenicity induced by EMD82571 is presented that links molecular initiating events with AOPs. (C) 2014 Elsevier Inc. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NEURAL-TUBE DEFECTS; EXTRACELLULAR-MATRIX; RETINOIC ACID; CRANIOFACIAL DEVELOPMENT; BILE-ACIDS; BONE; EXPRESSION; CELLS; DIFFERENTIATION; ASSOCIATION; Calcium sensitizer; Osteocalcin; Teratogen; EMD82571; Exencephaly; Agnathia; Adverse outcome pathway (AOP) |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Sep 2019 13:44 |
| Last Modified: | 30 Sep 2019 13:44 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9833 |
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