-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.

The morphological effects of β-naphthoflavone (β-NF) on placental development in pregnant rats were examined. β-NF, administered to pregnant rats intraperitoneally at 15 mg/kg bw from gestation day (GD) 9 to GD 14, had no effect on maternal body weight gain, mortality, or clinical sign. In the β-NF-exposed rats, intrauterine growth retardation (IUGR) rates increased on GDs 17 and 21, although there was no effect on fetal mortality rate, fetal or placental weight, or external fetal abnormality. Histopathologically, β-NF induced apoptosis and inhibition of cell proliferation of the trophoblastic septa in the labyrinth zone, resulting in its poor development. In the basal zone, β-NF induced spongiotrophoblast apoptosis and delayed glycogen islet regression, resulting in their cystic degeneration. β-NF-induced CYP1A1 expression was detected in the endothelial cells of the fetal capillaries in the labyrinth zone and in the endothelial cells of the spiral arteries in the metrial gland, but not in any trophoblasts. This indicates that CYP1A1 is inducible in the endothelial cells of the fetal capillaries in the labyrinth zone, and that these cells have an important role in metabolizing CYP1A1 inducers crossing the placental barrier.

Chronic kidney disease leads to high morbidity rates among humans. Kidney transplantation is often necessary for severe symptoms; however, options for new curative treatments are desired because of donor shortage. For example, it has been established that the kidneys can efficiently generate urine after transplantation of the metanephros, ureter, and bladder as a group. After transplantation, the urine can indirectly flow into the recipient’s bladder using a stepwise peristaltic ureter system method where the anastomosis is created via the recipient’s ureter for urinary tract reconstruction. However, the growth of the regenerated metanephros varies significantly, whereas the time window for successful completion of the stepwise peristaltic ureter system that does not cause hydronephrosis of the metanephros with bladder (ureter) is quite narrow. Therefore, this study was conducted to periodically and noninvasively evaluate the growth of the transplanted metanephros, ureter, and bladder in rats through computed tomography and ultrasonography. The ultrasonographic findings highly correlated to the computed tomography findings and clearly showed the metanephros and bladder. We found that the degree of growth of the metanephros and the bladder after transplantation differed in each case. Most of the rats were ready for urinary tract reconstruction within 21 days after transplantation. Optimizing the urinary tract reconstruction using ultrasonography allowed for interventions to reduce long-term tubular dilation of the metanephros due to inhibited overdilation of the fetal bladder, thereby decreasing the fibrosis caused possibly by transforming growth factor-β1. These results may be significantly related to the long-term maturation of the fetal metanephros and can provide new insights into the physiology of transplant regeneration of the metanephros in higher animals. Thus, this study contributes to the evidence base for the possibility of kidney regeneration in human clinical trials.

It is extremely rare to have multiple spontaneous proliferative lesions in young adult rats. Here, we report the occurrence of different proliferative lesions in multiple tissues of a 7-week-old female rat in a 1-week repeated toxicity study. Grossly, multiple white patches and nodules in the bilateral kidneys, femoral, and subcutaneous masses, and a nodule in the liver were observed. Renal lesions were diagnosed as renal mesenchymal tumors. One of the femoral subcutaneous masses was diagnosed as an adenolipoma consisting of mammary epithelial cells and mature adipocytes. The other femoral and abdominal subcutaneous masses were diagnosed as lipomas consisting of mature adipocytes. The liver nodule was diagnosed as non-regenerative hepatocellular hyperplasia, which was characterized by the proliferation of slightly hypertrophic hepatocytes. In the cauda equina, the growth of enlarged Schwann cells around the axon was observed, and this lesion was diagnosed as a neuroma.

22Chronic kidney disease leads to high morbidity rates among humans. It is a 23 serious disease that requires curative treatments other than kidney transplantation. 24 Recently, we successfully established the iPS-derived generated kidney, which might 25 produce urine. The urine can be directed to the native bladder with a stepwise peristaltic 26 ureter system, followed by anastomosis with the recipient ureter for reconstruction of 27 the urinary tract. However, the growth of the regenerated kidney varies significantly, 28 whereas the time window of the anastomosis is quite narrow. Therefore, this study was 29 conducted to evaluate the growth of transplanted metanephros with bladder periodically 30 and noninvasively using computed tomography and ultrasonography. Ultrasonographic 31 findings showed high correlations with computed tomographic findings and clearly 32 evaluated metanephros with bladder. We found that the degree of growth of the 33 metanephros with bladder after the transplantation differed in each individual. However, 34 most of them reached the appropriate period for urinary tract reconstruction within 3 35 weeks after transplantation. Optimizing the stepwise peristaltic ureter system 36 anastomosis by ultrasonography reduced long-term tubular dilation of the metanephros, 37 thereby decreasing fibrosis caused by transforming growth factor-β. This may be 38 significantly related to long-term maturation of fetal grafts. These results provide new 4 39 insights into transplanting regenerated kidneys in higher animals. We are one step closer 40 to the first human trial of kidney generation. 41 42 6 74provide a route for excretion of the produced urine. Thus, metanephros can cause 75 hydronephrosis and renal insufficiency [11,12]. This may be solved using Stepwise 76 Peristaltic Ureter (SWPU), which (S1 Fig.) comprises anastomosis of the ureters of the 77 recipient rats to the bladder using a developed metanephros with bladder (MNB) [11]. 78 This new method made it possible to continuously excrete urine produced from the 79 MNB to the recipient bladder via the recipient ureter [11]. However, the timing of 80 anastomosis with the ureter of the recipient after transplantation is crucial and owing to 81 individual differences in the growth of MNB, hydronephrosis may occur at ambiguous 82 anastomosis times [11,13]. Postrenal nephropathy due to hydronephrosis imposes a 83 heavy burden on the kidneys, and the delayed release of obstruction has substantial 84 effects on the kidneys [14-16]. Ureteral primordia obstruction during the fetal stage has 85 been shown to cause dysplastic metanephros [17]. Therefore, we believe that early 86 released obstruction is significantly involved in subsequent renal functions, even with 87 fetal-derived grafts. In the case of xenotransplantation and MNB transplantation in large 88 experimental animals, the effects of individual differences are considered to be greater.89 Appropriate time must be allowed for urinary tract reconstruction using a minimally 90 invasive method ...