The placenta grows rapidly for a short period with high blood flow during pregnancy and has multifaceted functions, such as its barrier function, nutritional transport, drug metabolizing activity and endocrine action. Consequently, the placenta is a highly susceptible target organ for drug- or chemical-induced adverse effects, and many placenta-toxic agents have been reported. However, histopathological examination of the placenta is not generally performed, and the placental toxicity index is only the placental weight change in rat reproductive toxicity studies. The placental cells originate from the trophectoderm of the embryo and the endometrium of the dam, proliferate and differentiate into a variety of tissues with interaction each other according to the development sequence, resulting in formation of a placenta. Therefore, drug- or chemical-induced placental lesions show various histopathological features depending on the toxicants and the exposure period, and the pathogenesis of placental toxicity is complicated. Placental weight assessment appears not to be enough to evaluate placental toxicity, and reproductive toxicity studies should pay more attention to histopathological evaluation of placental tissue. The detailed histopathological approaches to investigation of the pathogenesis of placental toxicity are considered to provide an important tool for understanding the mechanism of teratogenicity and developmental toxicity with embryo lethality, and could benefit reproductive toxicity studies.
Indole-3-acetic acid (IAA), known as natural auxin, induces cleft palate in rodents. However, there has been no report about the neurodevelopmental toxicity of IAA in rats. In the present study, we found microencephaly in the fetuses from the rats exposed to IAA. The purpose of this work was to examine the effects of IAA administration in pregnant rats on neuroepithelial cells in the embryos/fetuses. IAA was administered at 500 and 1,000 mg/kg on gestation days (days) 12, 13, and 14, and then embryos/fetuses were harvested on days 14.5, 15, 16, and 21. Cleft palate was induced at 1,000 mg/kg. The brain in treated groups exhibited reduction in the size and weight on day 21 in a dose-dependent manner. Histopathologically, apoptotic cells were observed mainly in the medial and dorsal layer of the neuroepithelium at 500 and 1,000 mg/kg on day 14.5. On day 15, they were observed in the medial and dorsal layer of the neuroepithelium, and preplate at 1,000 mg/kg. On day 16, they existed in the dorsal layer of the neuroepithelium and intermediate zone in the embryos from 1 dam at 1,000 mg/kg. On day 21, an increase in cell proliferative activity was observed in the neuroepithelium at 500 and 1,000 mg/kg. The reduction of the cortical plate, the enlargement of the neuroepithelium and a slight increase in neuron density in the intermediate zone were observed at 1,000 mg/kg. These findings indicated IAA might induce the neuronal apoptosis in the S phase and lead to microencephaly.
ABSTRACT. In order to investigate the toxic effects of 6-mercaptopurine (6-MP) on placental development, we examined sequential morphology in the placentas from rats exposed to 6-MP. 6-MP was intraperitoneally administered at 60 mg/kg during gestation days (GDs) 11 to 12, and the placentas were sampled on GD 13, 15 or 21. In the 6-MP-treated group, maternal body weight suppression, increased death embryo/fetus ratio and some malformations were observed. The placenta weights were decreased on GDs 15 and 21. Macroscopically, placentas on GD 21 were small, brittle and thin with a white peripheral rim. Histopathologically, in the labyrinth zone, 6-MP treatment mainly evoked decreased mitosis on GDs 13 and 15, increased apoptotic cell on GDs 13, 15 and 21 and thinning on GDs 15 and 21. In the basal zone, 6-MP evoked decreased mitosis on GDs 13, and PAS-positive material in the spongiotrophoblasts was still detected on GD 15. Thickening of the basal zone was observed with cytolysis of glycogen cells, apoptosis and an increased number of composed cells on GD 21. In conclusion, 6-MP administration in pregnant rats induced growth arrest of the labyrinth zone and developmental delay in the basal zone, leading to small placentas. The fetotoxicity of 6-MP may be responsible for its direct anti-proliferative effects and resulting placental dysfunction.
ABSTRACT. In order to investigate the morphological effects of ketoconazole on hypertrophied placentas, we examined the sequential histopathological changes in the placenta from rats exposed to ketoconazole. Ketoconazole was administered orally at 0 and 25 mg/kg/day during gestation days (GDs) 12 to 14, and the placentas were sampled on GDs 15, 17 and 21. All dams showed neither effect on body weight nor any abnormal clinical signs during the experimental period. In the treated group, the placentas appeared more hypertrophic with increases in the weight, diameter and thickness on GD 21. Histopathologically, increased thickness was noted in the labyrinth zone and basal zone on GDs 17 and 21, while on GD 15 the change had been already evident in the former zone. In the labyrinth zone, the mitotic figures of the trophoblasts were significantly elevated on GD 15. A multiple cystic dilatation of maternal sinusoids was observed in some placentas on GDs 15, 17 and 21. In the basal zone, an increase in spongiotrophoblasts and clusters of glycogen cells were detected on GDs 17 and 21. In the decidua basalis, there were no significant changes in either histology or thickness between the control and treated group during GDs 15 to 21. In conclusion, ketoconazole increased the population of composed cells in the labyrinth and basal zone, leading to placental hypertrophy in pregnant rats.
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