The placenta plays a pivotal role in fetal growth, and placental dysfunction and injury are associated with embryo/fetal toxicity. Histological examination of the rat placenta for safety evaluation provides valuable clues to the mechanisms of this toxicity. However, the placenta has specific and complex biological features unlike those of other organs, and placental structure dramatically changes depending on the time during the gestation period. Thus, time-dependent histopathological examination of the rat placenta should be performed based on the understanding of normal developmental changes in morphology and function. The placentas of rats and humans are both anatomically classified as discoid and hemochorial types. However, there are differences between rats and humans in terms of placental histological structure, the fetal-maternal interface, and the function of the yolk sac. Therefore, extrapolation of placental toxicity from rats to humans should be done cautiously in the evaluation of risk factors. This review describes the development, morphology, physiology, and toxicological features of the rat placenta and the differences between the rat and human placenta to enable accurate evaluation of reproductive and developmental toxicity in studies.

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The juvenile visceral steatosis (JVS) mouse is a mutant strain with an inherited systemic carnitine deficiency. Mice of this strain show clinical signs attributable to impaired heat production and disturbed energy production. Brown adipose tissue (BAT) is the primary site of non-shivering thermogenesis in the presence of uncoupling protein-1 (UCP-1) in rodents and humans, especially in infants. To investigate the possible cause of impaired heat production in BAT, we studied the morphological features, carnitine concentration, and UCP-1 production of BAT in JVS mice. The effect of carnitine administration on these parameters was also examined. JVS mice aged 5 or 10 days (60 each) and age-matched control mice were used in this study, along with 10-day-old JVS mice treated subcutaneously with L-carnitine once a day between postpartum days 5 and 10. JVS mice showed lower body temperatures and lower concentrations of carnitine in BAT. Morphologically, BAT cells in JVS mice contained large lipid vacuoles and small mitochondria, similar to those present in white adipose tissue cells. In addition, UCP-1 mRNA and protein expression levels were significantly reduced in JVS as compared with control mice. Carnitine treatment resulted in significant increases in body temperature and carnitine concentrations in BAT, together with the recovery of normal morphological features. UCP-1 mRNA and protein expression levels were also significantly increased. These findings strongly suggest that carnitine is essential for maintaining the function and morphology of BAT.

-In order to elucidate the effect of chorioallantoic and yolk sac placenta on the embryonic/fetal toxicity in dibutyltin dichloride (DBTCl)-exposed rats, we examined the histopathological changes and the tissue distribution of dibutyltin in the placentas and embryos. DBTCl was orally administered to the groups at doses of 0 mg/kg during gestation days (GD)s 7-9 (control group) and 20 mg/kg during GDs 7-9 (GD7-9 treated group), and GDs 10-12 (GD10-12 treated group). The total fetal mortality was increased, and malformations characterized by craniofacial dysmorphism were detected in the GD7-9 treated group. The embryonic/fetal weight and placental weight showed a decrease in both DBTCl-treated groups. Histologically, some embryos on GD 9.5 in the GD7-9 treated group underwent apoptosis without any changes of yolk sac. In the laser ablation-inductively coupled plasma-mass spectrometry analysis (LA-ICP-MS), tin was detected in the embryo, allantois, yolk sac, ectoplacental cone and decidual mass surrounding the conceptus on GD 9.5 in the GD7-9 treated group. Thus, it is considered that the embryo in this period is specifically sensitive to DBTCl-induced apoptosis, compared with other parts. The chorioallantoic placentas in both DBTCl-treated groups showed the developmental delay and hypoplasia in the fetal parts of placenta, resulting from apoptosis and mitotic inhibition. Thus, it was speculated that the DBTCl-induced malformations and fetal resorption resulted from the apoptosis in the embryo caused by the direct effect of DBTCl. The DBTCl-induced lesions in the chorioallantoic placenta were a non-specific transient developmental retardation in the fetal parts of placenta, leading to intrauterine growth retardation.

Retinopathy and choroidal angiopathy were both detected in aged male rats of the WBN/Kob strain with sustained diabetes. Hyperglycemia and glucosuria were found starting from 12 months of age and lasted through 24 months of age. Macroscopically, the vitreous body was partially or entirely replaced by white mass in 3 of 9 diabetic males. Histopathologically, the intravitreal white mass consisted of collagen fibers accompanied by numbers of newly formed vessels. Intraretinal angiopathy was accompanied with newly formed vessels, which were observed within the retina in 5 of 9 diabetic males, and marked hyalinization of intraretinal vessels was detected in 6 of 9 males irrespective of the presence of intravitreal neovascularization. Furthermore, hyperglycemia-related choroidal angiopathy was also seen with newly formed blood vessels originating from the choroid penetrating the retinal pigment epithelial layer and invading the retina in 8 of 9 diabetic males. Focal proliferation or degeneration of the pigment epithelial cells was associated in the region with choroidal angiopathy. In females, choroidal vessels slightly raised the pigment epithelial layer; however, they were localized in the choroid. The present study indicates that the WBN/Kob strain of rats is a useful model for both diabetic retinopathy and diabetic choroidal angiopathy.

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Intramacrophage MMPs may be responsible for basement membrane degradation at the optic fissure margins during normal eye development in mice.

Background Acrylamide (AA) is a rodent carcinogen and classified by the IARC into Group 2A (probable human carcinogen). AA has been reported to induce mutations in transgenic rodent gene mutation assays (TGR assays), the extent of which is presumed to depend on exposure length and the duration of expression after exposure. In particular, it is not clear in germ cells. To investigate mutagenicity with AA in somatic and germ cells at different sampling times, we conducted TGR assays using gpt delta transgenic mice. Results The male gpt delta mice at 8 weeks of age were treated with AA at 7.5, 15 and 30 mg/kg/day by gavage for 28 days. Peripheral blood was sampled on the last day of the treatment for micronucleus tests and tissues were sampled for gene mutation assays at day 31 and day 77, those being 3 and 49 days after the final treatment (28 + 3d and 28 + 49d), respectively. Another group of mice was treated with N-Ethyl-N-nitrosourea (ENU) at 50 mg/kg/day by intraperitoneal administration for 5 consecutive days and tissues were sampled at the day 31 and day 77 (5 + 26d and 5 + 72d). Frequencies of micronucleated erythrocytes in the peripheral blood significantly increased at AA doses of 15 and 30 mg/kg/day. Two- to three-fold increases in gpt mutation frequencies (MFs) compared to vehicle control were observed in the testes and lung treated with 30 mg/kg/day of AA at both sampling time. In the sperm, the gpt MFs and G:C to T:A transversions were significantly increased at 28 + 3d, but not at 28 + 49d. ENU induced gpt mutations in these tissues were examined at both 5 + 26d and 5 + 72d. A higher mutant frequency in the ENU-treated sperm was observed at 5 + 72d than that at 5 + 26d. Conclusions The gpt MFs in the testes, sperm and lung of the AA-treated mice were determined and compared between different sampling times (3 days or 49 days following 28 day-treatment). These results suggest that spermatogonial stem cells are less sensitive to AA mutagenicity under the experimental condition. Prolonged expression time after exposure to AA to detect mutagenicity may be effective in somatic cells but not in germ cells.