In utero and postnatal deficits in rat cardiac function following gestational exposure to dimethadione, the N-demethylated metabolite of the anticonvulsant trimethadione
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BACKGROUND: The ventricular septal defect (VSD), a hole between the ventricles of the heart, is the most common birth defect. Despite its commonality, little is known about related in utero functional deficits. Furthermore, although about 80% of clinical VSD resolve within a year, the long-term effects after their resolution are unknown due to lack of clinical follow-up. Chemical treatment was used to induce VSD in the rat and to investigate their functional consequences both in utero and postnatally. METHODS: Pregnant Sprague-Dawley rats were administered six 300mg/kg doses of dimethadione (DMO) by oral gavage every 12 hours beginning at 19h00 on gestational day (GD) 8 (Weston et al., 2011). DMO is the N-demethylated metabolite of the anticonvulsant trimethadione, a potent inducer of VSDs clinically and in laboratory animals. Fetal heart structure and function were examined with high-resolution ultrasound on GD 14, 15, 16, 17, and 21. A separate cohort of rats was dosed using the described paradigm, but offspring were allowed to reach parturition and mature naturally. Postnatal heart structure and function were assessed using telemetry (70 days postnatally), high-resolution ultrasound, and electrocardiography (ECG) (one year postnatally). RESULTS: Relative to controls, DMO-treated fetal rats had structural defects including VSD, an increased incidence of bradycardia (23 vs. 45%) and dysrhythmia (1.2 vs. 11%), and a reduction in cardiac output, stroke volume, and mean heart rate. Adult rats exposed to DMO in utero were more physically active, had elevated blood pressure, and had a higher incidence of dysrhythmia associated with ECG disturbances compared to controls. Both in utero and postnatal functional deficits occurred independent of septum patency. CONCLUSIONS: Gestational exposure to DMO disrupted cardiac function both in utero and postnatally, even in the absence of gross structural defects, indicating chemical exposures in utero may have permanent pathophysiological consequences on the heart.