Evaluation of developmental toxicity of propylthiouracil and methimazole

Abstract

Background: Propylthiouracil (PTU) and methimazole (MMI) are antithyroid drugs used to treat hyperthyroidism. Despite the widespread use of PTU and MMI during pregnancy, modest clinical data and less 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 or 100 mg/kg), MMI (2 or 20 mg/kg), or vehicle from gestation day (GD) 6 to 16. GD 18 fetuses were evaluated for gross and histopathological abnormalities. Next, pregnant Sprague-Dawley rats were treated daily with PTU (50 or 100 mg/kg), MMI (10 or 20 mg/kg), or vehicle from GD 6 to 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 GD 18. In rats, no adverse effects on litter size, placental weights, or maternal body weights were observed with either PTU or MMI treatment. PTU treatment (50 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.

Keywords: antithyroid drugs; developmental toxicity; methimazole; propylthiouracil.

Figure 1

In utero PTU and MMI treatment had no effect on placental and fetal weights or on litter size and resorption rates in mice. Dams were treated with vehicle, PTU, or MMI from GD 6–16 and examined at GD18. No significant differences were detected among vehicle-, PTU- or MMI- treated mice in A) placental weight, B) litter size, C) fetal weight, or D) resorption rate per litter. Fetuses from dams exposed to vehicle (n = 6 litters), PTU 50 mg/kg (n = 8 litters), PTU 100 mg/kg (n = 8 litters), MMI 2 mg/kg (n = 10 litters), or MMI 20 mg/kg (n = 8 litters) were examined.

Figure 2

PTU and MMI reduced serum T4 levels in rat dams treated during pregnancy. T4 serum levels were examined in pregnant rat dams at GD 20 following treatment from GD 6–19. All anti-thyroid drug treatments significantly reduced serum T4 levels. Dams were treated with vehicle (n = 9), 50 mg/kg PTU (n = 11), 100 mg/kg PTU (n = 8), 10 mg/kg MMI (n = 10), and 20 mg/kg MMI (n = 10). *p ≤ 0.0001.

Figure 3

PTU treatment induced lower body weights at GD 20 in rat dams. Dam weights were measured at GD 0, 6, 9, 12, 15, 18, and 20 in dams treated from GD 6–19 with vehicle, PTU, or MMI. A) Dam body weights were measured during pregnancy and at GD 20 they were significantly lower in PTU treated dams compared to vehicle controls. B) Changes in dam body weight from GD 6 to GD 20 revealed that PTU treated dams gained less weight over the treatment period. C) Examining the adjusted body weights (total dam weight-gravid uterus weight) showed no difference in weight among all treatment groups. Pregnant rats were treated with vehicle (n = 9), 50 mg/kg PTU (n = 11), 100 mg/kg PTU (n = 8), 10 mg/kg MMI (n = 10), and 20 mg/kg MMI (n = 10). *p ≤ 0.0001.

Figure 4

No effects on litter size or resorption rates were observed with PTU or MMI treatment in rats. Litters of rat dams treated from GD 6–19 were examined on GD 20. A) Mean litter sizes and B) percent resorption rates per litter were measured and no significant differences were detected among the treatment groups. Rat dams were treated with vehicle (n = 9), 50 mg/kg PTU (n = 11), 100 mg/kg PTU (n = 8), 10 mg/kg MMI (n = 10), and 20 mg/kg MMI (n = 10).

Figure 5

In utero PTU treatment caused a slight decrease in crown-rump lengths in rat fetuses. Fetal tissues from rat dams treated with vehicle, PTU, or MMI from GD 6–19 were analyzed at GD 20. A) No effects on placenta weights were observed with PTU or MMI treatment. B) The higher dose of PTU (100 mg/kg) resulted in lower fetal weights. C) Both PTU (50 and 100 mg/kg) and the higher MMI (20 mg/kg) dose significantly reduced the mean crown-rump lengths of fetuses compared to vehicle controls. Rat dams were treated with vehicle (n = 9), 50 mg/kg PTU (n = 11), 100 mg/kg PTU (n = 8), 10 mg/kg MMI (n = 10), and 20 mg/kg MMI (n = 10). *p ≤ 0.005.