BackgroundHyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed.MethodsWe examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis.ResultsWhen dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss of malformed embryos. These data show that PTU exposure during embryogenesis is associated with delayed neural tube closure and cardiac abnormalities. In contrast, we did not observe structural or cardiac defects associated with MMI exposure except at the higher dose. We find that PTU exposure during embryogenesis is associated with fetal loss. These observations suggest that PTU has teratogenic potential.
Background Propylthiouracil (PTU) and methimazole (MMI) are anti-thyroid drugs used to treat hyperthyroidism. Despite the widespread use of PTU and MMI during pregnancy, modest clinical data and little animal data are available on the teratogenic potential of these drugs. Methods We evaluated the teratogenicity of in utero exposure to PTU or MMI in mice and rats. First, pregnant C57Bl/6 mice were treated daily with PTU (10 mg/kg or 100 mg/kg), MMI (2 mg/kg or 20 mg/kg), or vehicle from gestation day (GD) 6–16. GD 18 fetuses were evaluated for gross and histopathological abnormalities. Next, pregnant Sprague-Dawley rats were treated daily with PTU (50 mg/kg or 100 mg/kg), MMI (10 mg/kg or 20 mg/kg) or vehicle from GD 6–19, followed by evaluation for gross and histopathological abnormalities at GD 20. Results In mice treated with PTU or MMI, no significant histopathological abnormalities or external gross malformations, and no adverse effects on placental weight, litter size, resorption rates, or fetal weight were observed at GD18. In rats, no adverse effects on litter size, placental weights, or maternal body weights were observed with either PTU- or MMI- treatment. PTU (50 mg/kg and 100 mg/kg), and MMI (10 mg/kg) treatment resulted in a decrease in crown-rump length in rat fetuses but no external gross malformations or histopathological abnormalities were observed. Conclusion We did not observe either gross external malformations or histopathological malformations in mice or rats treated long-term with high doses of PTU or MMI during pregnancy.
Previous work in our laboratory showed reduced myocardium and dilated ventricular chambers in gestation day (GD) 17 hearts that were collected from hyperglycemic CD1 mouse dams. Prebreeding maternal immune stimulation, using Freund's complete adjuvant (FCA), diminished the severity of these fetal heart lesions. The following experiments were performed to detect possible changes in fetal heart apoptotic cell death, under hyperglycemic conditions and with or without maternal immune stimulation. Female CD1 mice were injected with 200 mg/kg of streptozocin (STZ) to induce insulin-dependent diabetes mellitus. Half of these mice received prior FCA injection. Fetal hearts were collected on GD 17 and myocardial apoptotic cells were quantified using flow cytometry. A panel of apoptosis regulatory genes (Bcl2, p53, Casp3, Casp9, PkCe) was then examined in the fetal myocardium using RT-PCR. Early apoptotic cells and late apoptotic/ necrotic cells were significantly increased in fetal hearts from STZ or STZ + FCA dams. Paradoxically in the face of such increased cell death, the expression of pro-apoptotic genes Casp3 and Casp9 was decreased by diabetes, while the anti-apoptotic gene Bcl2 was increased.
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