title: Dimethadione embryotoxicity in the rat is neither correlated with maternal systemic drug concentrations nor embryonic tissue levels.
abstract: Pregnant rats treated with dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant trimethadione, produce offspring having a 74% incidence of congenital heart defects (CHD); however, the incidence of CHD has high inter-litter variability (40-100%) that presents a challenge when studying the initiating events prior to the presentation of an abnormal phenotype. We hypothesized that the variability in CHD incidence was the result of differences in maternal systemic concentrations or embryonic tissue concentrations of DMO. To test this hypothesis, dams were administered 300 mg/kg DMO every 12h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses). Maternal serum levels of DMO were assessed on GD 11, 12, 13, 14, 15, 18 and 21. Embryonic tissue concentrations of DMO were assessed on GD 11, 12, 13 and 14. In a separate cohort of GD 12 embryos, DMO concentrations and parameters of growth and development were assessed to determine if tissue levels of DMO were correlated with these endpoints. Embryos were exposed directly to different concentrations of DMO with whole embryo culture (WEC) and their growth and development assessed. Key findings were that neither maternal systemic concentrations nor tissue concentrations of DMO identified embryos that were sensitive or resistant to DMO in vivo. Direct exposure of embryos to DMO via WEC also failed to show correlations between embryonic concentrations of DMO with developmental outcomes in vitro. We conclude that neither maternal serum nor embryonic tissue concentrations of DMO predict embryonic outcome.
authors.affiliation: Department of Biomedical and Molecular Sciences, Program in Pharmacology and Toxicology, Queen's University, Botterell Hall, Kingston, ON K7L 3N6, Canada. Electronic address: ozolinst@queensu.ca.
authors.forename: Terence R S
authors.initials: TR
authors.lastname: Ozolinš
authors.affiliation: Currently at Applied Biotechnology/Lead Discovery, Bristol-Myers Squibb, 5 Research Pkwy Wallingford, CT 06492-1996, USA.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Weston
authors.affiliation: Currently at Pfizer Research and Development, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Perretta
authors.affiliation: Currently at Yale Stem Cell Center, Yale School of Medicine, PO Box 208073, New Haven, CT 06520-8073, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Thomson
authors.affiliation: Division of Basic Medical Sciences, St. George's University of London, UK SW17 0RE.
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Brown
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity; D004114:Dimethadione / Q000097:blood / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects*; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D005865:Gestational Age; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014293:Trimethadione / Q000633:toxicity
chemical_list: D000927:Anticonvulsants; D004114:Dimethadione; D014293:Trimethadione
keywords: Cardiac defects; Dimethadione; Pharmacokinetics; Teratogens; Ventricular septation defect; Whole embryo culture