A rat toxicogenomics study with the calcium sensitizer EMD82571 reveals a pleiotropic cause of teratogenicity

• EMD82571 was developed for the treatment of coronary heart disease.
• Reprotox studies evidenced exencephaly, micrognathia, agnathia and facial cleft.
• Toxicogenomics applied to maternal, embryo and fetal tissue reveal an AOP concept.
• Improper Ca2+, TGF-β/BMP and osteocalcin signaling impairs osteo- and odentogenesis.
• EMD82571 impairs neurulation leading to cranial neural tube defects.

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-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.