Maternal rat serum concentrations of dimethadione do not explain intra-litter differences in the incidence of dimethadione-induced birth defects, including novel findings in foetal lung

Toxicology. 2014 Dec 4;326:142-52. doi: 10.1016/j.tox.2014.10.014. Epub 2014 Nov 1.

Abstract

To investigate mechanisms of chemical-induced congenital heart defects (CHD) we have developed a rat model using dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant, trimethadione (TMD). Dosing pregnant rats with 300mg/kg DMO every 12h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses) produces a mean 74% incidence of CHD with inter litter variability ranging from 40 to 100%. The goal of this study was to determine if the variability in maternal serum concentrations of DMO on GD 14, a surrogate marker for total exposure, was related to the inter-litter differences in teratogenic outcomes. To test this hypothesis, pregnant rats were dosed as described above and serum levels of DMO assessed on GD 14. On GD 21, foetuses were collected by caesarean section, assessed for a number endpoints and the outcomes were correlated with the GD 14 serum concentrations of DMO. DMO exposure was associated with decreased foetal body weight, increased incidence of sternal defects and CHD, but these endpoints were not meaningfully correlated with maternal concentrations of DMO. Novel findings were decreased viability as measured one-hour following caesarean section, and delayed alveolar maturation. The major conclusions from these studies were first, that serum DMO concentrations on GD 14 did not predict teratogenicity, and second, delayed lung development may contribute to the decreased survival of foetuses at the time of caesarean section.

Keywords: Alveolar development; Anticonvulsant; Congenital heart defect; Dimethadione; Lung.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Drug-Induced / blood
  • Abnormalities, Drug-Induced / etiology*
  • Animals
  • Anticonvulsants / blood
  • Anticonvulsants / toxicity*
  • Biomarkers / blood
  • Dimethadione / blood
  • Dimethadione / toxicity*
  • Female
  • Fetal Weight / drug effects
  • Gestational Age
  • Heart Defects, Congenital / blood
  • Heart Defects, Congenital / chemically induced*
  • Maternal Exposure / adverse effects*
  • Pregnancy
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / embryology
  • Pulmonary Alveoli / physiopathology
  • Rats, Sprague-Dawley
  • Sternum / abnormalities
  • Sternum / drug effects

Substances

  • Anticonvulsants
  • Biomarkers
  • Dimethadione