Jurgen Borlak
Hannover Medical School, Germany
Title: A rat toxicogenomics study with the calcium sensitizer EMD82571 reveals a pleiotropic cause of teratogenicity
Biography
Biography: Jurgen Borlak
Abstract
Calcium sensitizers are used as an inotropic agent for the treatment of decompensated heart failure. In a preclinical safety study, the calcium sensitizer and PDEIII inhibitor EMD 82571 caused developmental defects in some fetuses. To explore mechanisms of toxicity, pregnant Wistar rats were dosed daily with either EMD 82571 (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. In the high dose EMD 82571 treatment group (150 mg/kg/day), approximately 58% of the fetuses presented cranial malformations, i.e. exencephaly and agnathia. Toxicogenomics revealed regulation of genes critically involved in osteogenesis, odontogenesis, differentiation & development and extracellular matrix and included bone y-carboxyglutamate (Bglap) which codes for osteocalcin. This protein functions as a hormone and plays a crucial role in fetal brain development as observed in osteocalcin knock out mice. 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.