Fetal and Neonatal Goiter in Cynomolgus Monkeys Following Administration of the Antithyroid Drug Thiamazole at High Doses to Dams During Pregnancy

Abstract

To evaluate morphologic alterations in the thyroid gland in the second generation in cynomolgus monkeys, pregnant dams were exposed to high doses of thiamazole. In Experiment A, dams received thiamazole intragastrically via a nasogastric catheter from gestation day (GD) 50 to GD 150 or on the day before delivery. Initially, the dose level was 20 mg/kg/day (10 mg/kg twice daily); however, the dose level was subsequently decreased to 5 mg/kg/day (2.5 mg/kg twice daily), since deteriorated general conditions were observed in two dams. Six out of seven neonates died on the day of birth. The cause of neonatal death was tracheal compression and suffocation from goiter. The transplacental exposure to thiamazole affected the fetal thyroid glands and induced goiter in all neonates. The surviving neonate was necropsied 767 days after discontinuation of thiamazole exposure and showed reversibility of the induced changes. In Experiment B, dams were intragastrically administered thiamazole at 5 mg/kg/day (2.5 mg/kg twice daily) for treatment periods from GDs 51 to 70, 71 to 90, 91 to 110, 111 to 130 and 131 to 150. All fetuses showed enlarged thyroid glands but were viable. Histopathologically, hypertrophy and/or hyperplastic appearance of the follicular epithelium of the thyroid gland was observed at the end of each treatment period. The most active appearance of the follicular epithelium, consisting of crowded pedunculated structure, was demonstrated at end of the treatment period from GD 131 to 150. This is the first report on the morphology of fetal and neonatal goiter in the cynomolgus monkey.

Effects of maternal exposure to thiamazole on behavioral development in infant cynomolgus monkeys

“…In all surviving infants, the weights of thyroids in the treated groups were three-to four-fold heavier than those in the control group; yet no histopathological abnormalities were seen in these organs at necropsy. It has been reported that oral treatment of maternal monkeys with thiamazole during GD 50 to 150 at an initial dose of 20 mg/kg per day induced newborn deaths due to tracheal compression and suffocation from extreme enlargement of the thyroids at birth, although the dose level was later reduced to 5 mg/kg per day (Yoshikawa et al 2011). The thyroids of fetuses receiving 5 mg/kg per day during the middle or late gestational period also showed histopathologic abnormalities such as hyperplasia and hypertrophy of the follicular epithelium consisting of crowded pedunculated structure (Yoshikawa et al 2011).…”

“…It has been reported that oral treatment of maternal monkeys with thiamazole during GD 50 to 150 at an initial dose of 20 mg/kg per day induced newborn deaths due to tracheal compression and suffocation from extreme enlargement of the thyroids at birth, although the dose level was later reduced to 5 mg/kg per day (Yoshikawa et al 2011). The thyroids of fetuses receiving 5 mg/kg per day during the middle or late gestational period also showed histopathologic abnormalities such as hyperplasia and hypertrophy of the follicular epithelium consisting of crowded pedunculated structure (Yoshikawa et al 2011). These Yoshikawa's observations suggest that fetal thyroids in the treated groups had ever been hyperplastic and possessed microscopic abnormalities in the present study.…”

“…The thyroids of fetuses receiving 5 mg/kg per day during the middle or late gestational period also showed histopathologic abnormalities such as hyperplasia and hypertrophy of the follicular epithelium consisting of crowded pedunculated structure (Yoshikawa et al. ). These Yoshikawa's observations suggest that fetal thyroids in the treated groups had ever been hyperplastic and possessed microscopic abnormalities in the present study.…”