Background Data for General Toxicology Parameters in RccHan:WIST Rats at 8, 10, 19 and 32 Weeks of Age

Recently, RccHan(TM):WIST (Wistar Hannover) rats were introduced to toxicity studies in Japan. The present study was performed to obtain control data for general toxicological parameters as an aid for interpretation of results in toxicity studies using this strain of rats. Four test groups comprising of 25 male and 25 female RccHan(TM):WIST rats were housed for 2, 4, 13 or 26 weeks from 6 weeks of age and observed and examined for clinical observation, body weight, food consumption, urinalysis, hematology, blood chemistry, organ weight, necropsy and/or histopathology. Ophthalmological examination was not conducted in this study, and the data in this report were obtained from an ongoing 104-week background study in RccHan(TM):WIST rats. These data were compared with the historical control data of CD(SD) (Sprague-Dawley) and/or F344 (Fischer) rats. The body weights of RccHan(TM):WIST rats were lower than those of CD(SD) rats and higher than those of F344 rats. The ophthalmological examination revealed a greater incidence of focal corneal opacity. Histopathology revealed focal mineralization of the cornea and Berlin blue-positive pigmentation in the epididymal interstitium as well as hepatocytes. Other than the above, some minor differences were found in urinalysis, hematology, blood chemistry and organ weights as compared with CD(SD) rats.     

Carcinogen-induced Thyroid Proliferative Lesions in Wistar Hannover GALAS Rats with Thyroid Dysplasia

Incidences and morphological features of thyroid proliferative lesions induced by carcinogens in Wistar Hannover GALAS rats (GALAS rats) showing normal growth with or without thyroid dysplasia were examined. All thyroid tissue samples were obtained from our recently conducted study using male GALAS rats treated with 5 carcinogens according to the medium-term multiorgan carcinogenicity bioassay protocol (called DMBDD treatment). In the DMBDD-treated rats, thyroid dysplasia was found in 9 out of 114 rats. Follicular cell adenomas were found in 5 out of 9 rats with thyroid dysplasia and in 7 out of 105 rats without thyroid dysplasia. The incidence of adenoma was significantly increased in rats with thyroid dysplasia (55.6%) compared with that in rats without thyroid dysplasia (6.7%). Adenomas in rats with thyroid dysplasia were observed as single or multiple nodules, well demarcated and composed of variously sized vacuolated cells or unvacuolated cells. These histopathological features and staining profiles of luminal colloid for PAS and thyroglobulin, together with PCNA-positive cells, were fundamentally similar to those of rats without thyroid dysplasia. On the other hand, the luminal colloid in adenomas of rats with thyroid dysplasia had a tendency to be poorly stained for T(4) compared with that of rats without thyroid dysplasia. From these findings, it appears that dysplastic thyroids of rats showing normal growth are more sensitive to carcinogens than normal thyroids. In addition, the morphological features of carcinogen-induced thyroid proliferative lesions in GALAS rats with thyroid dysplasia were fundamentally similar to those of rats without thyroid dysplasia, except for the vacuoles and T(4) staining profile.     

Spontaneous chondrosarcoma in Wistar rat: a case report

In rats, chondrosarcomas have been reported to occur both spontaneously and secondary to chemical induction. In a rare case, a spontaneous chondrosarcoma was identified in the deformed femur of a young male Wistar rat. After gross examination of the femur and knee joint, tissue was collected and preserved. The formalin-fixed tissue was decalcified, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Microscopic examinations revealed a large, highly proliferative, noncapsulated growth of chondrocytic or chondroblastic origin in the femoral bone, with proliferating chondrocytes invading the bone and surrounding tissues in an infiltrative growth pattern. Based on its histomorphological features, the lesion was diagnosed as a malignant cartilaginous neoplasm of spontaneous origin.     

Histological Characteristics of the Regression of Corpora Lutea in Wistar Hannover Rats: the Comparisons with Sprague-Dawley Rats

We examined the ovaries of 44 Wistar Hannover (RccHan^TM:WIST) (WH) and 30 Sprague-Dawley (SD) rats at 32-weeks of age to determine whether the ovarian structure and formation/regression of the corpora lutea (CLs) differ between the two strains. The average ovary weight was higher in WH rats. The average number of all CLs, including currently formed and previously formed CLs, was higher in WH rats in all cycles; however, no appreciable difference was detected in the number of newly or currently formed CLs between the two strains. CLs regression characterized by degeneration and necrosis of luteal cells began to appear in diestrus in both strains; however, the distribution of degenerated/necrotic cells in CLs differed. Necrotic cells were scattered in SD rats but were focally observed in the center of the CL in WH rats. The reduction in size of previously formed CLs accompanied by regression started about 2 or more stages later in WH rats than in those of SD rats. In conclusion, the higher number of CLs in WH rats is considered to be due to slow CL regression compared with in SD rats.     

三聚氰胺对雌性Wistar大鼠的慢性毒性研究

三聚氰胺（melamine,MA）对小鼠的经口LD50为4550mg/（kg.bw）,急性毒性属于低毒物质。为证实和客观评价其慢性毒性,以每千克饲料500、1000和2000mgMA/kg饲料的剂量对6周龄雌性Wistar大鼠进行了6个月慢性毒性试验。结果表明,各剂量组雌性Wistar大鼠肾、肝和膀胱均有不同程度地功能异常和器质性病变;血液ALT、AST、CRE和UA等生化指标均有不同程度地升高,肾、肝和膀胱黏膜均有不同程度地病理变化或损伤;每千克饲料2000mgMA/kg饲料的剂量能够抑制大鼠生长和采食,肾病理变化显著,出现结石;染毒组大鼠脾脏、骨髓等未见病变;MA对大鼠的最大无作用剂量应小于（35.7±15.4）mg/（kg.bw.d）。     

封闭群 Wistar大鼠的微卫星 DNA遗传监测分析

随机选取9只SPF级Wistar大鼠,其中4只雌性和5只雄性.在大鼠染色体上筛选了30个基因座位点,利用PCR扩增技术对封闭群Wistar大鼠群体进行了微卫星DNA多态性分析.结果有30对引物经扩增后均有图带产生,没有无效基因存在,图带均为双带.不同个体间的相似系数主要分布在0.3～0.8之间,在0.5～0.8之间占总数的94.4%,最高值为0.733.9号个体与其余个体间相似系数相对低于其他个体间的相似系数.筛选出了19个微卫星位点具有显著多态性,为建立一种对Wistar大鼠进行准确可靠、快速简便的遗传监测方法提供了依据.     

Hematological Characteristics of the BB Wistar Rat

Complete blood counts, differential white blood cell and platelet counts were performed on male and female BB Wistar diabetic rats (BBWd), their nondiabetic siblings (BBWnd) and outbred Wistar rats of the line from which the BB Wistar rats were derived. Most of the observed changes were strain-related (those present in both BBWd and BBWnd but not in control rats) rather than diabetes-related (those in BBWd but neither BBWnd nor control rats) and therefore probably due to the inbreeding process. The BBW strain had significantly lower numbers of white cells and platelets, as well as markedly changed differential white cell counts. Differential counts showed a pattern of lymphopenia, neutrophilia, monocytosis and eosinophilia. It is possible that these white blood cell changes contribute to the increased susceptibility to infection reported for the BBW strain. No significant difference in serum immunoglobulin concentrations was found in any of these three groups of rats. There- fore, hypogammaglobutinemia cannot account for the increased susceptibility to infections, but it is not possible to rule out an abnormality in the distribution of immunoglobulin fractions as an etiological factor.     

The interaction between plant lectins and the small intestinal epithelium: A primary cause of intestinal disturbance

Summary

The literature concerning the effects of plant lectins on the small intestinal epithelium is reviewed. It appears that after oral intake, intact plant lectins can reach the small intestinal lumen. Their binding to the mucosal surface evokes an increased synthesis of glycoproteins and a degeneration of the intestinal epithelium. The epithelial alterations may result in hyperregenerative villus atrophy and endogenous nitrogen loss. These changes ultimately can lead to less efficient feed conversion, diminished growth, scouring, wasting and death. The possible significance of plant lectins in digestive disturbances in farm animals is suggested.     

饲粮添加精氨酸对娩后Wistar大鼠乳腺组织发育及酪蛋白合成的影响

本试验旨在研究饲粮添加精氨酸(Arg)对娩后Wistar大鼠乳腺组织发育及其酪蛋白合成的影响。采用同窝对照的方法,选择同窝12只已受孕的Wistar大鼠,随机平均分为2组。Arg组在基础饲粮中添加与其等量的Arg(饲粮Arg含量1.280%),对照组饲粮用谷氨酸替代Arg组中的Arg以平衡饲粮氮水平。预试期4 d(分娩前4天)和正试期17 d(分娩后17天),结束后采集泌乳大鼠的乳腺组织,制作组织切片并测定其酪蛋白含量。结果表明:Arg能促进乳腺组织的发育,且乳腺腺泡切面面积的极显著增大(P0.01)。另外,Arg对乳腺β-酪蛋白的含量有显著的提高作用(P0.05),同时娩后大鼠体重也有增加的趋势(P0.05)。结果提示,饲粮添加Arg对Wistar大鼠乳腺组织发育及β-酪蛋白的合成有显著的促进作用。     

不同周龄SPF级SD大鼠胰腺自发性病变的组织学观察

研究不同周龄SPF级SD大鼠胰腺自发性病变的种类及其病变发生率,为药物安全性评价提供背景资料。收集3年安评试验中11、19、31周龄试验对照组大鼠胰腺制作病理切片,光学显微镜下观察SD大鼠胰腺病变的种类及组织形态学特点,并统计其病变发生率。结果显示,大鼠胰腺主要出现了以下病变:①单核细胞浸润:11周龄大鼠该病变的总体发生率为0.6%,其中雌性为0,雄性为1.25%;19周龄大鼠该病变的总体发生率为1.0%,其中雌性为1.0%,雄性为1.0%;31周龄大鼠该病变的总体发生率为1.0%,其中雌性为0,雄性为1.96%。②腺泡细胞空泡变性:11周龄大鼠未观察到该病变的发生;19周龄大鼠该病变的总体发生率为1.0%,其中雌性为0,雄性为2.0%;31周龄大鼠该病变的总体发生率为3%,其中雌性为2.1%,雄性为3.9%。③腺泡细胞萎缩、腺管增生:11周龄大鼠未观察到该病变的发生;19周龄大鼠该病变的总体发生率为0.5%,其中雌性为0,雄性为1.0%;31周龄大鼠该病变的总体发生率为3.0%,其中雌性为1.0%,雄性为4.9%。结果表明,SPF级大鼠胰腺可发生单核细胞浸润、腺泡细胞空泡变性、腺泡细胞萎缩及腺管增生等自发性病变,且病变发生率可随着年龄的增加而增加。     

不同比例虫草培养基混合料对SPF级Wistar大鼠血液生化指标的影响

为了探讨不同比例的虫草培养基混合料对SPF级Wistar大鼠血液生化指标的影响， 收集3组共60只Wistar大鼠的18项血液生化指标进行统计分析。结果发现，试验组Wistar大鼠的血红蛋白、嗜酸性细胞的水平均显著低于对照组；试验组雄性Wistar大鼠的胆固醇、甘油三酯水平均显著低于对照组，尿素氮和血糖显著高于对照组；试验组雌性Wistar大鼠的谷丙转氨酶和谷草转氨酶水平均显著高于对照组，而胆固醇和甘油三酯水平均显著低于对照组；其他指标各组间和不同性别间均无显著差异。研究结果表明，饲喂不同比例的虫草培养基混合料，可使SPF级Wistar大鼠的部分血液生化指标发生明显改变。      

Promotion of liver and kidney carcinogenesis by ethyl tertiary-butyl ether (ETBE) in male Wistar rats

Tumor-promoting effects of ethyl tertiary-butyl ether (ETBE) were investigated in a 2-stage carcinogenesis bioassay with regard to hepatic and renal carcinogenesis in rats. Male 6-week-old Wistar rats were given drinking water containing N-ethyl-N-(2-hydroxyethyl)nitrosamine (EHEN), as an initiator, at a dose of 500 ppm for 2 weeks. Starting one week thereafter, the animals were administered ETBE at dose levels of 0 (control), 100, 300, 500 or 1,000 mg/kg/day by gavage for 19 weeks from week 4 to 22. Necropsy of all rats was performed at week 23, and livers and kidneys were examined histopathologically. Incidences of hepatocellular adenomas, and those of combined hepatocellular adenomas and carcinomas were significantly elevated in rats given 1,000 mg/kg/day ETBE, but not 100‒500 mg/kg/day ETBE, and there was a significant increase in the average numbers of lesions. No significant differences in incidences and average numbers of renal tubule neoplasms were found in rats administered 100‒1,000 mg/kg/day ETBE. However, the average numbers of atypical tubule hyperplasias, considered to be preneoplastic lesions, were significantly increased in rats given ETBE at 1,000 mg/kg/day, but not in rats given 500 mg/kg/day or lower doses. Thus, these results imply that ETBE has hepatic and renal tumor-promoting activities that affect EHEN-induced carcinogenesis in male rats, and the no-observed-effect level is 500 mg/kg/day under the present experimental conditions.     

不同比例虫草培养基混合料对SPF级Wistar大鼠主要脏器重量及其系数的影响

为探讨不同比例的虫草培养基混合料对SPF级Wistar大鼠主要脏器重量及脏器系数的影响，用电子天平测定3组动物的体重、心、肝、脾、肺、肾、肾上腺、睾丸、卵巢和胃的重量，并计算其脏器系数。结果表明，不同比例组的同性别Wistar大鼠，其体重之间不存在显著差异；低比例组雄性Wistar大鼠心脏、肺脏和睾丸，雌性Wistar大鼠肺脏的重量显著或极显著高〖JP2〗于对照组、高比例组；低比例组雄性Wistar大鼠心脏、肺脏、肾脏和睾丸，雌性Wistar大鼠心脏、肝脏、肺脏、肾脏和胃的脏器系数显著或极显著高于对照组、高比例组；低、高比例组Wistar雄鼠和高比例组Wistar雌鼠的肾上腺重量及其系数均显著低于对照组。可见，适当比例的虫草培养基可以作为啮齿类试验动物的添加料，但是否适用于饲喂其它动物还有待于进一步的试验研究。     

Maintenance of mouse trophoblast stem cells in KSR-based medium allows conventional 3D culture

Mouse trophoblast stem cells (TSCs) can differentiate into trophoblast cells, which constitute the placenta. Under conventional culture conditions, in a medium supplemented with 20% fetal bovine serum (FBS), fibroblast growth factor 4 (FGF4), and heparin and in the presence of mouse embryonic fibroblast cells (MEFs) as feeder cells, TSCs maintain their undifferentiated, proliferative status. MEFs can be replaced by a 70% MEF-conditioned medium (MEF-CM) or by TGF-ß/activin A. To find out if KnockOut^TM Serum Replacement (KSR) can replace FBS for TSC maintenance, we cultured mouse TSCs in KSR-based, FBS-free medium and investigated their proliferation capacity, stemness, and differentiation potential. The results indicated that fibronectin, vitronectin, or laminin coating was necessary for adhesion of TSCs under KSR-based conditions but not for their survival or proliferation. While the presence of FGF4, heparin, and activin A was not sufficient to support the proliferation of TSCs, the addition of a pan-retinoic acid receptor inverse agonist and a ROCK-inhibitor yielded a proliferation rate comparable to that obtained under the conventional FBS-based conditions. TSCs cultured under the KSR-based conditions had a gene expression and DNA methylation profile characteristic of TSCs and exhibited a differentiation potential. Moreover, under KSR-based conditions, we could obtain a suspension culture of TSCs using extracellular matrix (ECM) coating-free dishes. Thus, we have established here, KSR-based culture conditions for the maintenance of TSCs, which should be useful for future studies.     

Background Data on Developmental Parameters During the Gestation Period in Rats

Abstract: Background data during the gestation period were obtained from 128 Wistar Hannover GALAS rats and 26 Crl:CD(SD) pregnant rats in the control groups of our previous toxicity studies. The body weights of dams in the Wistar Hannover GALAS rats were significantly lower throughout the gestation period than those in the Crl:CD(SD) rats. In contrast, the time-dependent change in the body weight gain (%) of dams showed very similar trends in both strains. The mean number of live embryos/fetuses in the Wistar Hannover GALAS rats was 12.0, and was lower than that (14.5) in the Crl:CD(SD) rats. The placental weights gradually increased with pregnancy progression and reached a plateau on gestation day (GD) 19, although the embryo/fetal weights rapidly increased from GD 17 to GD 21. The embryo/fetal weights in the Wistar Hannover GALAS rats were significantly lower on only GD 21 than those in the Crl:CD(SD) rats. It is considered that this fetal weight difference between the strains develops during the fetal period, but not during the organogenesis period. In contrast, there were no differences in the placental weights between the two strains. Microscopically, the thickness of the labyrinth zone in the Wistar Hannover GALAS rats was thicker throughout the gestation period than that in the Crl:CD(SD) rats.     

Pathological Lesions in Swine at Slaughter: V. Pathological Lesions in Relation to Some Environmental Factors in the Herds

The influence of environment on animal health was studied in 40 bacon herds. These herds delivered approx. 11,000 baconers annually to the slaughter-house. The data from the meat inspection was studied in connection with the environmental recordings, and the relationship between 18 lesions and 20 environmental factors were estimated by statistical methods. The data was collected in the period 1975–1977.The influence of environmental factors upon the prevalence of different lesions showed considerable variation. Ten environmental factors were significantly associated with pleurisy and tail lesions (cannibalism). On the other hand none of the environmental factors bore any significant relation to atrophic rhinitis, pericarditis, peritonitis, perihepatitis, polyarthritis, arthritis and claw lesions. Eight environmental factors influenced the proportion of healthy animals.The recorded environmental factors influenced the overall health situation to a varying degree. For example, design of pen walls, insulation of pen floors, occasional use of supplementary feed and free access to drinking water were related to 5–7 lesions, while the nature of the concentrate (meal/pellets) had no significant influence.The study indicated that many details in environment and management could be of importance to the health of bacon pigs. However, statistical analysis also showed that production systems had a considerably stronger influence upon the health situation than any of the “pure” environmental factors – even when these factors were added.     

Synergetic effects of oral administration of levamisole and Echinacea purpurea on immune response in Wistar rat

This research investigated the effects of levamisole and Echinacea purpurea (EP), separately and together on the immune response of the rat as a laboratory model. In this experiment, 40 male Wistar rats were obtained and divided into four groups (n = 10). These groups received normal saline (10 mg/kg), EP (500 mg/kg), levamisole (2 mg/kg) and EP (500 mg/kg) with levamisole (2 mg/kg) as oral gavages every day for a period of 4 weeks, respectively. After obtaining blood samples (at the end of each week), haematocrit (HCT), differential and total white blood cell (WBC) counts, phagocyte activity (number), total protein, albumin and globulins levels of samples were obtained. The results of the study showed that the gamma globulin level, WBC, neutrophil and monocyte counts and phagocyte activity increased significantly in comparison with normal saline group during the study. According to the results, each of the mentioned agents had a stimulant effect on the immune system separately and together on rats. In the group that received EP and levamisole simultaneously, these effects were synergistically increased. These compounds, by increasing the mentioned factors, will probably affect the immune system.     

Inhibitory effects of SKF96365 on the activities of K+ channels in mouse small intestinal smooth muscle cells

In order to investigate the effects of {"type":"entrez-protein","attrs":{"text":"SKF96365","term_id":"1156357400","term_text":"SKF96365"}}SKF96365 (SKF), which is a non-selective cationic channel blocker, on K⁺ channel currents, we recorded currents through ATP sensitive K⁺ (I_KATP), voltage-gated K⁺ (I_Kv) and Ca²⁺ activated K⁺ channels (I_BK) in the absence and presence of SKF in single small intestinal myocytes of mice with patch-clamp techniques. SKF (10 µM) reversibly abolished I_KATP that was induced by cromakalim (10 µM), which is a selective ATP sensitive K⁺ channel opener. These inhibitory effects were induced in a concentration-dependent and voltage-independent manner. The 50% inhibitory concentration (IC₅₀) was 0.85 µM, which was obviously lower than that reported for the muscarinic cationic current. In addition, SKF (1 µM ≈ the IC₅₀ value in I_KATP suppression) reversibly inhibited the I_Kv that was induced by repetitive depolarizing pulses from −80 to 20 mV. However, the extent of the inhibitory effects was only ~30%. In contrast, SKF (1 µM) had no significant effects on spontaneous transient I_BK and caffeine-induced I_BK. These results indicated that SKF inhibited ATP sensitive K⁺ channels and voltage-gated K⁺ channels, with the ATP sensitive K⁺ channels being more sensitive than the voltage-gated K⁺ channels. These inhibitory effects on K⁺ channels should be considered when SKF is used as a cationic channel blocker.     

Involvement of the Ca2+ signaling pathway in osteoprotegerin inhibition of osteoclast differentiation and maturation

The purpose of this study was to determine whether the Ca²⁺ signaling pathway is involved in the ability of osteoprotegerin (OPG) to inhibit osteoclast differentiation and maturation. RAW264.7 cells were incubated with macrophage colony-stimulating factor (M-CSF) + receptor activator of nuclear factor-κB ligand (RANKL) to stimulate osteoclastogenesis and then treated with different concentrations of OPG, an inhibitor of osteoclast differentiation. The intracellular Ca²⁺ concentration [Ca²⁺]_i and phosphorylation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) in the different treatment groups were measured by flow cytometry and Western blotting, respectively. The results confirmed that M-CSF + RANKL significantly increased [Ca²⁺]_i and CaMKII phosphorylation in osteoclasts (p < 0.01), and that these effects were subsequently decreased by OPG treatment. Exposure to specific inhibitors of the Ca²⁺ signaling pathway revealed that these changes varied between the different OPG treatment groups. Findings from the present study indicated that the Ca²⁺ signaling pathway is involved in both the regulation of osteoclastogenesis as well as inhibition of osteoclast differentiation and activation by OPG.