Preliminary evaluation of an in utero-lactation assay using 6-n-propyl-2-thiouracil

Abstract

In this preliminary study, the potential of an in utero-lactation assay to detect thyroid effectors was evaluated by treating three dams/group with 6-n-propyl-2-thiouracil (PTU), a known thyroid antagonist, by oral gavage at doses of 0, 0.0032, 0.016, 0.08 and 0.4 mg/kg/day during fetal organogenesis and lactation. Hearing disturbances and an elevated relative thyroid weight were observed in offspring of both sexes in the 0.4 mg/kg/day group. The Biel-type water T-maze test showed an increase in the number of errors made by females in the 0.4 mg/kg/day group. Histopathologically, flattening of follicular epithelium, a decrease in resorptive colloid droplets, degeneration of follicular epithelium, and hyperplasia of follicular epithelium were observed in males belonging to the 0.4 mg/kg/day group. Histopathological abnormalities were also observed in some offspring belonging to the 0.08 mg/kg/day group. In the dams, hypertrophy of the follicular epithelium of the thyroid was observed in the 0.4 mg/kg/day group. Although we could not explain the mechanism for the difference in the effects seen in the offspring and the dams, the effect of PTU in utero through lactational exposure is apparently different from that resulting from exposure in homeostatically mature rats. Most reports studying PTU have involved administration in water or in food, and reports on the oral gavage of PTU during the fetal organogenesis and lactation period are very rare. This assumes that dosages >0.4 mg/kg/day would also produce clear anti-thyroid effects by oral gavage and, possibly, emphasizes that dosages <0.4 mg/kg/day did not have a noticeable effect. Based on the present results, a study to determine the reproducibility of the data in a much larger number of dams will be performed to confirm the findings in the present study, and to evaluate other endpoints, such as hormonal evaluation of dams and their offspring, sexual developmental landmarks, and fertility of the offspring.