title: A rat toxicogenomics study with the calcium sensitizer EMD82571 reveals a pleiotropic cause of teratogenicity.
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 150mg/kg/day) or retinoic acid (12mg/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-β/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.
authors: Non-Clinical Safety, Merck Serono, 64283 Darmstadt, Germany. Electronic address: philip.hewitt@merckgroup.com.
authors: Philip G
authors: PG
authors: Hewitt
authors: Centre for Pharmacology and Toxicology, Hannover Medical School, 30625 Hannover, Germany. Electronic address: Singh.Prafull@mh-hannover.de.
authors: Prafull Kumar
authors: PK
authors: Singh
authors: Centre for Pharmacology and Toxicology, Hannover Medical School, 30625 Hannover, Germany. Electronic address: Kumar.Arun@mh-hannover.de.
authors: Arun
authors: A
authors: Kumar
authors: Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Medical Center, 93053 Regensburg, Germany. Electronic address: carsten.gnewuch@ukr.de.
authors: Carsten
authors: C
authors: Gnewuch
authors: Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Medical Center, 93053 Regensburg, Germany. Electronic address: gerhard.liebisch@ukr.de.
authors: Gerhard
authors: G
authors: Liebisch
authors: Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Medical Center, 93053 Regensburg, Germany. Electronic address: gerd.schmitz@ukr.de.
authors: Gerd
authors: G
authors: Schmitz
authors: Centre for Pharmacology and Toxicology, Hannover Medical School, 30625 Hannover, Germany. Electronic address: Borlak.Juergen@mh-hannover.de.
authors: Juergen
authors: J
authors: Borlak
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000139:chemically induced; D005260:Female; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects / Q000473:pathology; D009436:Neural Tube Defects / Q000139:chemically induced; D054261:Neurulation / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis; D058987:Phosphodiesterase 3 Inhibitors / Q000633:toxicity*; D011247:Pregnancy; D011804:Quinolines / Q000633:toxicity*; D017208:Rats, Wistar; D013723:Teratogens / Q000633:toxicity*; D013829:Thiadiazines / Q000633:toxicity*; D043922:Toxicogenetics
chemical_list: C000596530:5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; D001647:Bile Acids and Salts; D058987:Phosphodiesterase 3 Inhibitors; D011804:Quinolines; D013723:Teratogens; D013829:Thiadiazines; D002118:Calcium
keywords: Adverse outcome pathway (AOP); Agnathia; Calcium sensitizer; EMD82571; Exencephaly; Osteocalcin; Teratogen