title: In utero dimethadione exposure causes postnatal disruption in cardiac structure and function in the rat.
abstract: In utero exposure of rat embryos to dimethadione (DMO), the N-demethylated teratogenic metabolite of the anticonvulsant trimethadione, induces a high incidence of cardiac heart defects including ventricular septal defects (VSDs). The same exposure regimen also leads to in utero cardiac functional deficits, including bradycardia, dysrhythmia, and a reduction in cardiac output (CO) and ejection fraction that persist until parturition (10 days after the final dose). Despite a high rate of spontaneous postnatal VSD closure, we hypothesize that functional sequelae will persist into adulthood. Pregnant Sprague Dawley rats were administered six 300 mg/kg doses of DMO, one every 12 h in mid-pregnancy beginning on the evening of gestation day 8. Postnatal cardiac function was assessed in control (CTL) and DMO-exposed offspring using radiotelemetry and ultrasound at 3 and 11 months of age, respectively. Adult rats exposed to DMO in utero had an increased incidence of arrhythmia, elevated blood pressure and CO, greater left ventricular volume and elevated locomotor activity versus CTL. The mean arterial pressure of DMO-exposed rats was more sensitive to changes in dietary salt load compared with CTL. Importantly, most treated rats had functional deficits in the absence of a persistent structural defect. It was concluded that in utero DMO exposure causes cardiovascular deficits that persist into postnatal life in the rat, despite absence of visible structural anomalies. We speculate this is not unique to DMO, suggesting possible health implications for infants with unrecognized gestational chemical exposures.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Kristiina L
authors.initials: KL
authors.lastname: Aasa
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Purssell
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Adams
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6 ozolinst@queensu.ca.
authors.forename: Terence R S
authors.initials: TR
authors.lastname: Ozolinš
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D004114:Dimethadione / Q000633:toxicity*; D004452:Echocardiography; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005318:Fetal Heart / Q000187:drug effects*; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000196:embryology / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D038081:Organogenesis / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D013686:Telemetry
chemical_list: D000927:Anticonvulsants; D004114:Dimethadione
keywords: cardiovascular function; congenital heart defect; dimethadione; fetal programming; ventricular septal defects