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

Reprod Toxicol. 2014 Aug;47:89-101. doi: 10.1016/j.reprotox.2014.06.006. Epub 2014 Jun 28.

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.

Keywords: Adverse outcome pathway (AOP); Agnathia; Calcium sensitizer; EMD82571; Exencephaly; Osteocalcin; Teratogen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism
  • Bone and Bones / metabolism
  • Calcium / metabolism
  • Craniofacial Abnormalities / chemically induced
  • Female
  • Gene Expression Profiling
  • Liver / drug effects
  • Liver / pathology
  • Neural Tube Defects / chemically induced
  • Neurulation / drug effects
  • Oligonucleotide Array Sequence Analysis
  • Organ Size / drug effects
  • Osteogenesis
  • Phosphodiesterase 3 Inhibitors / toxicity*
  • Pregnancy
  • Quinolines / toxicity*
  • Rats, Wistar
  • Teratogens / toxicity*
  • Thiadiazines / toxicity*
  • Toxicogenetics

Substances

  • 5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one
  • Bile Acids and Salts
  • Phosphodiesterase 3 Inhibitors
  • Quinolines
  • Teratogens
  • Thiadiazines
  • Calcium