Effects of maternal exposure to thiamazole on behavioral development in infant cynomolgus monkeys.
Thiamazole, an anti-hyperthyroidism agent, was administered orally to pregnant cynomolgus monkeys at doses of 2.0 and 3.5 mg/kg per day from GD 120 to GD 150 to investigate effects on behavioral development of their infants. Swelling of the throat region due to enlargement of the thyroid glands was observed at birth in thiamazole-treated infants, and it returned to normal around postnatal day (PND) 30. At necropsy of infants at 12 months of age, thyroidal weight in the thiamazole groups was increased. This finding suggested the likelihood that administration of thiamazole to maternal animals during the late gestational period induced thyroid goiter in fetal/infant monkeys through placental transfer of thiamazole. No clear changes were noted in thyroid histopathology or serum thyroid hormone levels in maternal animals or infants, but goiter formation might have been indicative of exposure to high thyroid stimulating hormone (TSH) and low T3 or T4 in utero from maternal treatment with thiamazole. Age-related changes were observed in the control in behavioral development tests, while infants at 3.5 mg/kg showed no age-related decrease in contact behavior and no increase in exploratory activity on PND 90 or PND 170. In addition, the number of eye contacts between PND 210 and PND 240 was less frequent. This indicated that maternal exposure to thiamazole induced mental retardation-like behaviors in infants. Thiamazole may directly inhibit thyroid hormone synthesis in the fetus by placental transfer. From these results, it was speculated that oral administration of thiamazole to maternal animals during the late gestational period induced retardation of behavioral development in their infants.
Drug Safety Research Laboratories, Shin Nippon Biomedical Laboratories (SNBL), Ltd, Kagoshima, Japan; Division of Biomodeling, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
Ayumi
A
Inoue
Akihiro
A
Arima
Hirohito
H
Kato
Nobuyoshi
N
Yamashita
Yoshiro
Y
Nishida
Yojiro
Y
Ooshima
Shizufumi
S
Ebihara
D000818:Animals; D000831:Animals, Newborn; D013956:Antithyroid Agents / Q000008:administration & dosage / Q000009:adverse effects; D001522:Behavior, Animal / Q000187:drug effects*; D005260:Female; D008252:Macaca fascicularis; D018811:Maternal Exposure / Q000009:adverse effects*; D008713:Methimazole / Q000008:administration & dosage / Q000009:adverse effects*; D009034:Mother-Child Relations; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013961:Thyroid Gland / Q000033:anatomy & histology; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
D013956:Antithyroid Agents; D014284:Triiodothyronine; D008713:Methimazole; D013972:Thyrotropin; D013974:Thyroxine
behavioral development; cynomolgus monkey; infant; thiamazole; thyroid hormone