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The Journal of Toxicological Sciences (J The Journal of Toxicological Sciences (J. Toxicol. Sci.) 689 Vol.42, No.6, 689-705, 2017 Original Article Background data on NOD/Shi-scid IL-2Rγnull mice (NOG mice) Kenichiro Kasahara1, Yachiyo Fukunaga1, Saori Igura1, Rie Andoh2, Tsubasa Saito2, Isamu Suzuki2, Hiroyuki Kanemitsu1, Daisuke Suzuki1, Ken Goto2, Daichi Nakamura1, Masahiro Mochizuki2, Masahiko Yasuda3, Ryo Inoue3, Kazutoshi Tamura2 and Mariko Nagatani2 1BoZo Research Center Inc., Tsukuba Research Institute, 8 Okubo, Tsukuba, Ibaraki, 300-2611, Japan 2BoZo Research Center Inc., Gotemba Research Institute, 1284 Kamado, Gotemba, Shizuoka, 412-0039, Japan 3Central Institute for Experimental Animals, 3-25-12, Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-0821, Japan (Received June 5, 2017; Accepted August 29, 2017) ABSTRACT — To obtain background data of NOD/Shi-scid IL-2Rγnull (NOG) mice, severely immune- deficient mice, a total of 120 animals were examined at 7, 26 and 52 weeks-old (20 mice/sex/group). The survival rate at 52 weeks-old was 95% (19/20) in both sexes. Clinically, circling behavior in one direction along the cage wall was observed in males after 8 weeks and females after 47 weeks-old, and hunchback position was found in males after 32 weeks-old. Hematologically, lymphocyte count marked- ly decreased at all ages, while white blood cell count increased in several mice at 52 weeks-old. Blood chemistry results revealed high values of aspartate aminotransferase, lactate dehydrogenase and creatine phosphokinase in some females at 26 weeks-old, without any related histological change. Histologically, lymphoid hypoplasia characterized by severe lymphocyte depletion with poorly developed tissue architec- tures was observed. In addition, spongiotic change in the nerve tissue was observed in both sexes at 7 and 26 weeks-old, and intracytoplasmic materials known as tubular aggregates in the skeletal muscles were found in males terminated at 26 and 52 weeks-old and in females at 52 weeks-old. Malignant lympho- ma was found in one female euthanized at 20 weeks-old. Further, small intestinal adenoma, hepatocellu- lar adenoma, leukemia, cerebral lipomatous hamartoma, Harderian gland adenoma and uterine polyp were also observed, and their incidences were low except for that of uterine polyp. This study provided detailed background data on NOG mice up to 52 weeks-old and provided information on appropriate use of NOG mice in the various research fields. Key words: NOG mice, Background data, Immuno-deficient, Lymphoid hypoplasia, Spongiotic changes, Tubular aggregate INTRODUCTION larly to the NSG (NOD/SCID/IL2rgKO) mice and SCID/ Beige and DKO (Rag2-γC double-knockout) mice, which NOD/Shi-scid IL-2Rγnull (NOG) mice, formally are characterized by loss of T and B lymphocytes and referred to as NOD.Cg-Prkdcscid I12rgtm1Sug/ShiJic mice, NK cells, NOG mice are able to integrate human cells are severely immuno-deficient animals established at the and tissues into them more efficiently in comparison with Central Laboratories for Experimental Animals by knock- the pre-existing immuno-deficient animals such as nude out introduction of IL-2 receptor γ-chain (IL2Rγc) into mice (Ito et al., 2012; Shibata et al., 1997; Mazurier et the NOD-scid strain (Ito et al., 2002). al., 1999). NOG mice are characterized by the absence of T and Through making good use of their severely immuno- B lymphocytes originated in the scid mutation, decreased deficient properties, NOG mice are attracting great atten- activity of the complements and insufficient function of tion as a possible candidate to re-establish human cells/ macrophages originated in the NOD strain, and absence tissues within them. They are estimated to be a useful of NK cells and malfunction of dendritic cells originat- evaluation system for pharmacological effects of antican- ed in the IL2Rγc knock-out mice (Ito et al., 2002). Simi- cer agents on tumor cells which have been transplanted / Correspondence: Kenichiro Kasahara (E-mail: [email protected]) Vol. 42 No. 6 690 K. Kasahara et al. live planted into them and for toxicological and oncologi- Ophthalmologic examinations cal properties of the products for tissue-engineered medi- All survivors were subjected to ophthalmologic exami- cal products. As an important precondition to utilize NOG nations before necropsy. The anterior portion and interme- mice in the above-mentioned evaluation system, it is nec- diate optic media were examined by a slit lamp (SL-15: essary to obtain clinical and especially histological back- Kowa Co., Ltd., Aichi, Japan), and the fundus oculi after ground data on them. Up to the present, there are, how- dilation of the pupil by mydriatic agent (Mydrin P: Santen ever, no reports of the long-term histological background Pharmaceutical Co., Ltd., Osaka, Japan) were exam- data on severely immuno-deficient animals. This study ined by a binocular indirect ophthalmoscope (Omega was carried out to clarify the clinical and histological 500: HEINE Optotechnik GmbH & Co. KG., Bayern, background data on NOG mice up to 52 weeks of age. Germany). MATERIALS AND METHODS Hematology At necropsy, carried out as scheduled, blood samples Animals were collected via the vena cava inferior into blood col- Sixty male and 60 female NOG mice, a specific path- lection tubes (MicrotainerTM, Nippon Becton Dicking- ogen free, were obtained from the Central Institute for son Co., Ltd., Tokyo, Japan) containing EDTA-2Na using Experimental Animals (Kanagawa, Japan) at 5 weeks of a syringe treated with heparin sodium, and then were age, and they were equally divided into 3 groups. The examined for red blood cell count (RBC), hemoglob- animals were kept untreated until euthanasia under isoflu- in (HGB), hematocrit (HCT), mean corpuscular volume rane anesthesia at 7, 26 or 52 weeks of age. All animals (MCV), mean corpuscular hemoglobin (MCH), mean cor- were housed in polycarbonate flat-bottomed cages (W160 puscular hemoglobin concentration (MCHC), reticulocyte x D370 x H130 mm, Tecniplast Japan Co., Ltd., Tokyo, ratio, platelet count, white blood cell count (WBC) and Japan) installed in a positive pressure rack individual- leukocyte differentiation using ADVIA® 2120i Hematol- ly for males and five animals per cage (W230 x D335 x ogy System (Siemens Healthcare Diagnostics Inc., New H140 mm, Clea Japan Inc., Tokyo, Japan) for females in York, NY, USA). a clean animal room controlled to maintain the tempera- ture at 23 ± 3°C, the relative humidity at 50 ± 20%, the Blood chemistry air ventilation at 10 to 20 times per hour and illumination At the same time as hematological examination, plas- for 12 hr a day, and were allowed free access to pelleted ma samples were obtained by centrifugation of the diet, CE-2 (irradiation sterilized, Clea Japan Inc.) and tap blood collected in tubes containing heparin lithium water. The equipment was disinfected by hypochlorous (Capiject Heparin Lithium: Terumo Co., Ltd., Tokyo, acid or autoclave. Moreover, traffic lines of human and Japan) and then were examined for aspartate aminotrans- equipment for access to animal room were strictly con- ferase (AST), alanine aminotransferase (ALT), lactate trolled. dehydrogenase (LDH), creatine phosphokinase (CPK), To compare with NOG mice, some parameters on alkaline phosphatase (ALP), γ-glutamyl transpeptidase hematology, blood chemistry and organ weights from (γ-GTP), total cholesterol (T-CHO), triglyceride (TG), both sexes of ICR mice that were housed in our facility phospholipid (PL), total bilirubin (T-BIL), glucose (GLU), and sacrificed at same time points as above were used. blood urea nitrogen (BUN), creatinine (CRNN), sodium This experiment was conducted after obtaining (Na), potassium (K), chloride (Cl), calcium (Ca), inor- approval of the Animal Experiment Committee of BoZo ganic phosphorus (P), total protein (TP), albumin (ALB) Research Center Inc. in 2015. It was conducted in accord- using Clinical Laboratory System TBA-120FR (Toshiba ance with the guidelines for the control and welfare of Medical Systems Corporation, Tokyo, Ja pan), and glob- experimental animals specified by the test facility (Rule ulin, A/G ratio and protein fraction using QuickScan of the Animal Experiment Committee, BoZo Research Densitometer (Helena Laboratories, Inc., Saitama, Japan). Center Inc.). Histology Clinical sings and measurement of body weights All mice were subjected to complete necropsy and Clinical signs were observed once every day and body the brain (cerebrum and cerebellum), spleen, heart, weights were measured once a week until 16 weeks of lungs, liver (including gallbladder), kidneys and testes age and twice a week thereafter. were weighed. Cerebrum, cerebellum, medulla oblon- gata, spinal cord (cervical, thoracic and lumbar), sciat- Vol. 42 No. 6 691 Background data on NOG mice ic nerves, Harderian glands, pituitary, thyroids, parath- age was 95% in both sexes. yroids, adrenals, thymus, spleen, submandibular lymph node, mesenteric lymph node, heart, thoracic aorta, tra- Clinical signs chea, lung (including the bronchus), tongue, esopha- Circling behavior in one direction along the cage wall gus, stomach, duodenum, jejunum, ileum (including the and hunchback position were observed. The former was Peyer’s patch), cecum, colon, rectum, submandibular found in males and females after 8 weeks and 28 weeks glands, sublingual glands, liver, gall bladder, pancreas, of age, respectively. Although such clinical signs were kidneys, urinary bladder, epididymides, prostate, seminal transient in some cases, hunchback position detected in vesicles, ovary, uterus, vagina, mammary glands (inguinal 8 males at 32 weeks of age continued until and including region, females only), sternum (including the bone mar- 52 weeks of age. row), femurs (including the knee joint and bone marrow), femoral skeletal muscles, skin (inguinal region), nasal Body weights cavity, and any gross lesions were fixed in 10% phos- Except for 3 mice which died or were euthanized, phate-buffered formalin. The eyeballs and optic nerves the body weight was relatively rapidly increased from were fi xed in mixture of 3% glutaraldehyde and 2.5% for- 5 weeks of age (male: 19.7 g, female: 16.4 g) to 30 weeks malin, and the testes were fi xed with Bouin’s fl uid.
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