Clear evidence of the carcinogenic potential of anthracene: A 2-year feeding study in rats and mice.

Anthracene is an environmental pollutant and its adverse effects on human health have long been a concern due to its persistence and bioaccumulation properties. However, there is insufficient evidence for its chronic toxicity, especially carcinogenicity, in either humans or experimental animals. In this study, its carcinogenicity and chronic toxicity were investigated in compliance with the OECD test guideline 451 (OECD TG 451) and Good Laboratory Practice Standards. Fifty male and 50 female F344 rats and 50 female BDF1 mice were administrated 0, 8000, 20000, or 50000 ppm anthracene in the diet for 104 weeks, and 50 male BDF1 mice were fed diets containing anthracene at 0, 3200, 8000, or 20000 ppm. Anthracene treatment had no adverse effect on either the survival rate or general condition of the rats or mice during the study period. Body weights were lower or tended to be lower in the anthracene-treated groups than in the control groups. Increased incidence of hepatocellular carcinoma and hepatocellular adenoma was observed in male rats and female mice. Renal cell carcinoma and renal cell adenoma, fibroadenoma in the mammary gland, and uterine endometrial stromal sarcoma were increased in female rats. Transitional cell carcinoma and transitional cell papilloma in the urinary bladder were also increased in male and female rats. In addition, several different pre-neoplastic lesions were increased in the anthracene-treated male and female rats and female mice. These results provide clear evidence that oral administration of anthracene for 104 weeks has a carcinogenic effect in male and female rats and female mice.

Pulmonary dust foci as rat pneumoconiosis lesion induced by titanium dioxide nanoparticles in 13-week inhalation study.

BACKGROUND: Most toxicological studies on titanium dioxide (TiO2) particles to date have concentrated on carcinogenicity and acute toxicity, with few studies focusing of pneumoconiosis, which is a variety of airspace and interstitial lung diseases caused by particle-laden macrophages. The present study examined rat pulmonary lesions associated with pneumoconiosis after inhalation exposure to TiO2 nanoparticles (NPs). METHODS: Male and female F344 rats were exposed to 6.3, 12.5, 25, or 50 mg/m3 anatase type TiO2 NPs for 6 h/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. After the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. RESULTS: Numerous milky white spots were present in the lungs after exposure to 25 and 50 mg/m3 TiO2 NPs. Histopathological analysis revealed that the spots were alveolar lesions, characterized predominantly by the agglomeration of particle-laden macrophages and the presence of reactive alveolar epithelial type 2 cell (AEC2) hyperplasia. We defined this characteristic lesion as pulmonary dust foci (PDF). The PDF is an inflammatory niche, with decreased vascular endothelial cells in the interstitium, and proliferating AEC2 transformed into alveolar epithelial progenitor cells. In the present study, the AEC2 in the PDF had acquired DNA damage. Based on PDF induction, the lowest observed adverse effect concentration for pulmonary disorders in male and female rats was 12.5 mg/m3 and 6.3 mg/m3, respectively. The no observed adverse effect concentration for male rats was 6.3 mg/m3. There was a sex difference in lung lesion development, with females showing more pronounced lesion parameters than males. CONCLUSIONS: Inhalation exposure to TiO2 NPs caused PDF, an air-space lesion which is an alveolar inflammatory niche containing particle-laden macrophages and proliferating AEC2. These PDFs histopathologically resemble some pneumoconiosis lesions (pulmonary siderosis and hard metal pneumoconiosis) in workers and lung disease in smokers, suggesting that PDFs caused by exposure to TiO2 NPs in rats are an early pneumoconiosis lesion and may be a common alveolar reaction in mammals.

Spontaneous well-differentiated pancreatic islet cell carcinoma with vascular invasion in a male F344 rat.

This case report describes a case of spontaneous pancreatic islet cell carcinoma with vascular invasion in a 110-week-old male F344 rat. Histologically, a pancreatic nodule consisting of tumor cells and many blood-rich vessels, and covered with a fibrous capsule showed local invasion in the capsule and adjacent acinar tissues, encircling a large duct-like structure (DS). The tumor was composed of well-differentiated tumor cells resembling normal pancreatic islet cells, which had small round nuclei and eosinophilic cytoplasm. Mitotic figures were rare. Immunohistochemistry revealed that the tumor cells were positive for insulin. Although endothelial cells were not detected, the DS wall showed cells positive for α-smooth muscle actin and elastic fibers, suggesting that the DS is the pancreatic artery. This is a rare case of islet cell carcinoma consisting of well-differentiated tumor cells with invasion of the pancreatic artery in a rat.

Spontaneous adenolipoma of the mammary gland in the male F344 rat.

A 110-week-old male F344 rat from the high-dose group of a 104-week carcinogenicity study, exhibited a spontaneously occurring subcutaneous mass in the left axilla extending to the chest. Histologically, the mass was well-demarcated from the adjacent mammary tissue and slightly encapsulated without evidence of infiltration into the surrounding tissues. The mass contained both epithelial and adipose components. The epithelial component consisted of ductal structures of various sizes lined by a single layer of flattened to cuboidal epithelial cells with relatively clear or vacuolated cytoplasm. These ductal structures were well-intermingled with an adipose component that consisted of a uniform monomorphic cell population of mature adipocytes. Both cell types were well-differentiated and did not exhibit cellular atypia. Within the mass, fibrous connective tissue was found in the stroma with infiltration of numerous mast cells. Based on these findings, the mass was diagnosed as an adenolipoma of the mammary gland.

Background data of 2-year-old male and female F344 gpt delta rats.

Although gpt delta rats, as reporter gene-transgenic rats, were originally developed for in vivo mutation assays, they have also been used to evaluate chemical carcinogenesis and comprehensive toxicity. Therefore, it is necessary to accumulate background data on carcinogenicity and general toxicity in gpt delta rats. Here, we investigated the background data of 110-week-old male and female F344 gpt delta rats and wild-type rats. There was no effect of reporter gene transfection on animal survival rates and body weights during the experiment. The relative weight of male gpt delta rat adrenals was significantly higher than that of wild-type rats, possibly due to the higher incidence of pheochromocytoma. There were no intergenotype differences in the incidence of nonneoplastic lesions in both sexes, including chronic progressive nephropathy and focus of cellular alteration in the liver, which had a higher incidence in both genotypes. Additionally, the significantly higher incidence of adrenal pheochromocytoma in male gpt delta rats than that in wild-type rats was likely incidental because of the lack of differences in the incidences of preneoplastic (male and female) and neoplastic (female) adrenal lesions in both genotypes. Other neoplastic lesions in both sexes showed no intergenotype differences in incidence rates, although large granular lymphocytic leukemia in the spleen and Leydig cell tumors in the testes of males showed higher incidence rates. Overall, there were no effects of reporter gene transfection on the spectrum of spontaneous lesions in F344 gpt delta rats, thus supporting their applicability in evaluating chemical toxicity and carcinogenicity.

Effect of Kv3 channel modulators on auditory temporal resolution in aged Fischer 344 rats.

AUT00063 and AUT00202 are novel pharmaceutical modulators of the Kv3 subfamily of voltage-gated K+ channels. Kv3.1 channels, which control fast firing of many central auditory neurons, have been shown to decline with age and this may contribute to age-related deficits in central auditory processing. In the present study, the effects of the two novel compounds that specifically modulate Kv3 channels on auditory temporal processing were examined in aged (19-25-month-old) and young-adult (3-5 month-old) Fischer 344 rats (F344) using a behavioral gap-prepulse inhibition (gap-PPI) paradigm. The acoustic startle response (ASR) and its inhibition induced by a gap in noise were measured before and after drug administration. Hearing thresholds in tested rats were evaluated by the auditory brainstem response (ABR). Aged F344 rats had significantly higher ABR thresholds, lower amplitudes of ASR, and weaker gap-PPI compared with young-adult rats. No influence of AUT00063 and AUT00202 administration was observed on ABR hearing thresholds in rats of both age groups. AUT00063 and AUT00202 had suppressive effect on ASR of F344 rats that was more pronounced with AUT00063. The degree of suppression depended on the dose and age of the rats. Both compounds significantly improved the gap-PPI performance in gap detection tests in aged rats. These results indicate that AUT00063 and AUT00202 may influence intrinsic firing properties of neurons in the central auditory system of aged animals and have the potential to treat aged-related hearing disorders.

Anticancer effects and possible mechanisms of lycopene intervention on N-methylbenzylnitrosamine induced esophageal cancer in F344 rats based on PPARγ1.

Lycopene, a natural carotenoid, has potential chemopreventive effects in many cancers. This study aimed to examine the effects of lycopene on regulating the inflammation and apoptosis of N-nitrosomethylbenzylamine(NMBzA) induced esophageal cancer in F344 rats. After the rats were fed normal diets containing different concentrations of lycopene for 25 weeks (10, 25, 50 mg/kg·d of lycopene, respectively), the incidence of tumors in the rats treated with lycopene was significantly lower than that in the simple exposed group (P < 0.05). The antioxidant activity of lycopene was exerted by measuring the levels of GSH-PX, SOD and MDA activity by oxidative stress kits. Furthermore, through western blotting analysis lycopene intervention was found to have significantly improved apoptosis cytokines by increasing the protein expression levels of PPARγ and caspase-3, and also significantly reduced inflammatory cytokines by decreasing the protein expression of NF-κB and COX-2 in the esophagus tissue, especially in the 25 mg/kg of lycopene intervention group (all P < 0.05). These results demonstrated that appropriate dose of lycopene intervention could inhibit the carcinogenesis of esophageal in F344 rats through the possible mechanisms of anti-inflammatory and pro-apoptosis.

Immunohistochemical Review of Leydig Cell Lesions in Ochratoxin A-Treated Fischer Rats and Controls.

Ochratoxin A is best known as a potent renal carcinogen in male rats and mice after necessarily protracted ingestion, although valid extrapolation to any human disease has not been verified. The hypothesis that the toxin is a cause of human testicular cancer was proposed a decade ago and has proliferated since, partly through incomplete study of the scientific literature. Archived tumorous rat testes were available from Fischer F344 rats exposed to continuous dietary exposure for half of or the whole life in London in the 2000s. Renal cancer occurred in some of these cases and testicular tumours were observed frequently, as expected, in both treated and untreated animals. Application of clinical immunohistochemistry has for the first time consistently diagnosed the testicular hypertrophy in toxin-treated rats as Leydig cell tumours. Comparison is made with similar analysis of tumorous testes from control (untreated) rats from U.S. National Toxicology Program studies, both of ochratoxin A (1989) and the more recent one on Ginkgo biloba. All have been found to have identical pathology as being of sex cord-stromal origin. Such are rare in humans, most being of germinal cell origin. The absence of experimental evidence of any specific rat testicular cellular pathology attributable to long-term dietary ochratoxin A exposure discredits any experimental animal evidence of testicular tumorigenicity. Thus, no epidemiological connection between ochratoxin A and the incidence of human testicular cancer can be justified scientifically.

The localization and distribution of cells labeled by a somatic stem cell-recognizing antibody (A3) in rat colon development; possible presence of a new cell type forming the intestinal stem cell niche.

A3, generated as a monoclonal antibody against rat malignant fibrous histiocytoma (MFH)-derived cloned cells, recognizes somatic stem cells (bone-marrow/hair follicle stem cells). We investigated the distribution of cells immunoreactive to A3 in the developing rat intestine (particularly, the colon), focusing on the ontogenic kinetics of A3-positive cells. In the rat intestine, A3 labeled spindle-shaped stromal cells localized in the submucosa and labeled endothelial cells of capillaries in the lamina propria forming villi in the early development stage. With development progression, A3-positive cells were exclusively localized around the crypts of the colon. Double immunofluorescence revealed that A3-positive cells around the crypts reacted to vimentin (for mesenchymal cells) and Thy-1 (for mesenchymal stromal cells) but not to α-SMA (for mesenchymal myofibroblastic cells) or CD34 (for hematopoietic stem cells), indicating that A3-positive cells around the crypts may have characteristics of immature mesenchymal cells. In addition, A3 labeled a few epithelial cells at the base of colon crypts. Furthermore, immunoelectron microscopy revealed that A3-positive cells lay inside myofibroblasts adjacent to the epithelium of the crypts. A3-positive cells were regarded as a new type of immature mesenchymal cells around the crypts. Collectively, A3-positive cells might take part in the stem cell niche in the colon, which is formed through epithelial-mesenchymal interaction.

Early Alterations in Operant Performance and Prominent Huntingtin Aggregation in a Congenic F344 Rat Line of the Classical CAGn51trunc Model of Huntington Disease.

The transgenic rat model of Huntington disease expressing a fragment of mutant HTT (tgHD rat) has been thoroughly characterized and reproduces hallmark symptoms of human adult-onset HD. Pursuing the optimization of this model for evaluation of translational therapeutic approaches, the F344 inbred rat strain was considered as advantageous genetic background for the expression of the HD transgenic construct. In the present study, a novel congenic line of the SPRDtgHD transgenic model of HD, carrying 51 CAG repeats, was generated on the F344 rat genetic background. To assess the behavioral phenotype, classical assays investigating motor function, emotion, and sensorimotor gating were applied, along with automated screening of metabolic and activity parameters as well as operant conditioning tasks. The neuropathological phenotype was analyzed by immunohistochemistry and ex vivo magnetic resonance imaging. F344tgHD rats displayed markedly reduced anxiety-like behavior in the social interaction test and elevated impulsivity traits already at 3 months of age. Neuropathologically, reduced striatal volume and pronounced aggregation of mutant huntingtin in several brain regions were detected at later disease stage. In conclusion, the congenic F344tgHD model reproduces key aspects of the human HD phenotype, substantiating its value for translational therapeutic approaches.

Spontaneous nephroblastoma with striated muscle differentiation in an F344 rat.

An eleven-month old male F344/DuCrj (F344) rat was found dead and had right kidney mass at necropsy. Histopathologically, the mass was composed of nests of neoplastic stellate cells. At the center of the nests, neoplastic epithelial cells formed a tubular structure. In the fibrous connective tissue surrounding the nests, neoplastic cells with striations demonstrable by phosphotungstic acid hematoxylin were observed. Immunohistochemically, neoplastic stellate cells were partially positive for Wilms Tumor 1 and vimentin, and neoplastic cells with striations were partially positive for desmin. We diagnosed this tumor as a nephroblastoma with striated muscle differentiation. To our knowledge, this is the first case of nephroblastoma with apparent striated muscle differentiation in an F344 rat.

Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34).

Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 µg/kg or 30 µg/kg hPTH(1-34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1-34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1-34) treated rats. Comparing the effects of abaloparatide and hPTH(1-34) at the 25 and 30 µg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1-34) at similar exposure.

Gene expression kinetics of renal transporters induced by ochratoxin A in male and female F344 rats.

Ochratoxin A (OTA) is a mycotoxin that contaminates foodstuffs. The most relevant concern is its high kidney carcinogenicity in male rats and its unclear mechanism of action. It has been hypothesized that variations in transport mechanisms in kidney cells may be the reason of different sex-dependent sensitivities towards OTA. The aim of this study was to analyze, by RT- qPCR, renal transporters expression in 15-week-old male (M) and female (F) F344 rats at basal level and after single oral OTA administration (0.50 mg/kg bw). Temporal profiles (24h, 48h, 72h, 96h, 1 and 2 months) were studied per sex and transporter. The reference gene for all comparisons was Ppia. At basal level, sex differences were confirmed for Oatp1, Bcrp (M>F) and Oat2 (F>M). OTA tended to inhibit the expression of almost all transporters in both sexes, but clearly induced the expression of Oat2 in males. Regarding time profiles, the highest sex differences involved Oat (Slc22) transporters: Oat2, Oat3 and Oat5 expression showed a significant increase in males (24h) while Oat1, Oat2 and Oat5 level decreased in females (48h). Overall, basal sex differences in F344 rats and the specific sex-dependent response to OTA of Oat2 might contribute to high kidney damage in male rats.

α-Tocopherol Attenuates the Triglyceride- and Cholesterol-Lowering Effects of Rice Bran Tocotrienol in Rats Fed a Western Diet.

Previous studies demonstrated the ability of tocotrienol (T3) to lower levels of lipids, including cholesterol (Cho) and triglycerides (TG). Although α-tocopherol (α-Toc) reportedly inhibits the hypocholesterolemic effect of T3, there is no information about whether α-Toc influences the TG-lowering effect of T3 in vivo. In this study, we investigated the influence of α-Toc on the antihyperlipidemic effects (Cho- and TG-lowering) of rice bran tocotrienols (RBT3) in F344 rats fed a western diet. α-Toc attenuated both the Cho- and TG-lowering effects of RBT3 in vivo, whereas α-Toc alone exhibited no hypolipidemic effects. RBT3-induced Cpt-1a and Cyp7a1 gene expression was reduced by α-Toc. Furthermore, coadministration of α-Toc decreased liver and adipose tissue concentrations of tocotrienols in F344 rats. These results indicate that α-Toc has almost no antihyperlipidemic effect in vivo, but abrogates the antihyperlipidemic effect of RBT3 by reducing tissue concentrations of tocotrienols and regulating expression of genes involved in lipid metabolism. Understanding the underlying mechanism of the beneficial effects of T3 on lipid metabolism and the interaction with α-Toc will be important for developing T3-based therapeutics.

Hepatic Lesions Caused by Large Granular Lymphocyte Leukemia in Fischer 344 Rats: Similar Morphologic Features and Morphogenesis to Those of Nodular Regenerative Hyperplasia (NRH) in the Human Liver.

To characterize the hepatic lesions in Fischer 344 (F344) rats afflicted with large granular lymphocyte (LGL) leukemia, the livers of rats with LGL leukemia at various stages were examined histopathologically and immunohistochemically. The morphologic features in the livers of rats afflicted with LGL leukemia were diffuse, uniform-sized, granular, or micronodular lesions consisting of hepatocytes showing centrilobular atrophy and perilobular hypertrophy (CAPH) without fibrosis. With progression in the stage of the LGL leukemia, the severity of the CAPH of hepatocytes increased resulting in fatty change and/or single-cell necrosis, along with compensatory hyperplasia of the hepatocytes, finally resulting in lesions similar to those seen in nodular regenerative hyperplasia (NRH) in the human liver. The CAPH of hepatocytes was a nonspecific tissue adaptation against ischemia or hypoxemia and/or imbalance in blood supply due to disturbance in the portal circulation and hemolytic anemia induced by the leukemia cells. In addition, direct and/or indirect hepatocellular injuries by leukemia cells were considered to be necessary for the formation of human NRH-like lesions. Morphogenetic investigation of the livers of rats afflicted with LGL leukemia may be helpful to clarify the pathogenesis of NRH in the human liver.

Photoperiodic effects on seasonal physiology, reproductive status and hypothalamic gene expression in young male F344 rats.

Seasonal or photoperiodically sensitive animals respond to altered day length with changes in physiology (growth, food intake and reproductive status) and behaviour to adapt to predictable yearly changes in the climate. Typically, different species of hamsters, voles and sheep are the most studied animal models of photoperiodism. Although laboratory rats are generally considered nonphotoperiodic, one rat strain, the inbred Fischer 344 (F344) rat, has been shown to be sensitive to the length of daylight exposure by changing its physiological phenotype and reproductive status according to the season. The present study aimed to better understand the nature of the photoperiodic response in the F344 rat. We examined the effects of five different photoperiods on the physiological and neuroendocrine responses. Young male F344 rats were held under light schedules ranging from 8 h of light/day to 16 h of light/day, and then body weight, including fat and lean mass, food intake, testes weights and hypothalamic gene expression were compared. We found that rats held under photoperiods of ≥ 12 h of light/day showed increased growth and food intake relative to rats held under photoperiods of ≤ 10 h of light/day. Magnetic resonance imaging analysis confirmed that these changes were mainly the result of a change in lean body mass. The same pattern was evident for reproductive status, with higher paired testes weight in photoperiods of ≥ 12 h of light/day. Accompanying the changes in physiological status were major changes in hypothalamic thyroid hormone (Dio2 and Dio3), retinoic acid (Crabp1 and Stra6) and Wnt/ß-Catenin signalling genes (sFrp2 and Mfrp). Our data demonstrate that a photoperiod schedule of 12 h of light/day is interpreted as a stimulatory photoperiod by the neuroendocrine system of young male F344 rats.

The influence of chronic L-carnitine supplementation on the formation of preneoplastic and atherosclerotic lesions in the colon and aorta of male F344 rats.

L-Carnitine, a key component of fatty acid oxidation, is nowadays being extensively used as a nutritional supplement with allegedly "fat burning" and performance-enhancing properties, although to date there are no conclusive data supporting these claims. Furthermore, there is an inverse relationship between exogenous supplementation and bioavailability, i.e., fairly high oral doses are not fully absorbed and thus a significant amount of carnitine remains in the gut. Human and rat enterobacteria can degrade unabsorbed L-carnitine to trimethylamine or trimethylamine-N-oxide, which, under certain conditions, may be transformed to the known carcinogen N-nitrosodimethylamine. Recent findings indicate that trimethylamine-N-oxide might also be involved in the development of atherosclerotic lesions. We therefore investigated whether a 1-year administration of different L-carnitine concentrations (0, 1, 2 and 5 g/l) via drinking water leads to an increased incidence of preneoplastic lesions (so-called aberrant crypt foci) in the colon of Fischer 344 rats as well as to the appearance of atherosclerotic lesions in the aorta of these animals. No significant difference between the test groups regarding the formation of lesions in the colon and aorta of the rats was observed, suggesting that, under the given experimental conditions, L-carnitine up to a concentration of 5 g/l in the drinking water does not have adverse effects on the gastrointestinal and vascular system of Fischer 344 rats.

(+)-Usnic acid-induced myocardial toxicity in rats.

(+)-Usnic acid (UA) has been known to be a strong uncoupler, and mitochondrial and endoplasmic reticulum (ER)-related stresses are suggested to be involved in the mechanism of hepatotoxicity. However, it has not been clarified whether UA causes toxicity in other mitochondria-rich organs such as the heart. We elucidated whether UA induces cardiotoxicity and its mechanism. UA was orally administered to rats for 14 days, and laboratory and histopathological examinations were performed in conjunction with toxicogenomic analysis. As a result, there was no alteration in blood chemistry, whereas cytoplasmic rarefaction of myocardium was observed microscopically. This finding corresponded to the swollen mitochondria observed ultrastructurally. Immunohistochemically, expression of prohibitin, indicating mitochondrial imbalance, increased in the sarcoplasmic area. Toxicogenomic analysis highlighted the upregulation of gene groups consisting of oxidative stress, ER stress, and amino acid limitation. Interestingly, the number of upregulated genes was larger in the amino acid limitation-related gene group than that in other groups, implying that amino acid limitation might be one of the sources of oxidative stress, not only mitochondria and ER-originated stresses. In conclusion, the heart was manifested to be one of the target organs of UA. Mitochondrial imbalance with complex stresses may be involved in the toxic mechanism.

Occurrence of Spontaneous Tumors in the Central Nervous System (CNS) of F344 and SD Rats.

In order to accurately assess the carcinogenicity of chemicals with regard to rare tumors such as rat CNS tumors, sufficient information about spontaneous tumors are very important. This paper presents the data on the type, incidence and detected age of CNS tumors in F344/DuCrlCrlj (a total of 1363 males and 1363 females) and Crl:CD(SD) rats (a total of 1650 males and 1705 females) collected from in-house background data-collection studies and control groups of carcinogenicity studies at our laboratory, together with those previously reported in F344 and SD rats. The present data on F344/DuCrlCrlj rats (F344 rats) and Crl:CD(SD) rats (SD rats) clarified the following. (1) The incidences of all CNS tumors observed in F344 rats were less than 1%. (2) The incidences of malignant astrocytoma and granular cell tumor were higher in male SD rats than in female SD rats. (3) The incidences of astrocytoma and granular cell tumor were higher in SD rats than in F344 rats. (4) Among astrocytoma, oligodendroglioma and granular cell tumor, oligodendroglioma was detected at the youngest age, followed by astrocytoma, and ultimately, granular cell tumor developed in both strains. The incidences observed in our study were almost consistent with those previously reported in F344 and SD rats.

Neuromedin U partly mimics thyroid-stimulating hormone and triggers Wnt/ß-catenin signalling in the photoperiodic response of F344 rats.

In seasonal animals, photoperiod exerts profound effects on physiology, such as growth, energy balance and reproduction, via changes in the neuroendocrine axes. A key element of the photoperiodic response is the thyroid hormone level in the hypothalamus, which is controlled via retrograde transport of thyroid-stimulating hormone (TSH) from the pars tuberalis of the pituitary. TSH regulates type II deiodinase (Dio2) expression, which transforms inactive thyroid hormone to its active form, via TSH receptors expressed in the ependymal cells of the hypothalamus. In the present study, we hypothesised that a second peptide hormone, neuromedin U (NMU), may play a role in the photoperiodic response alongside TSH because the gene for NMU is also expressed in a strongly photoperiod-dependent manner in the pars tuberalis and its receptor NMU2 is expressed in the ependymal layer of the third ventricle in photoperiod-sensitive F344 rats. Consistent with other studies conducted in nonseasonal mammals, we found that acute i.c.v. injections of NMU into the hypothalamus negatively regulated food intake and body weight and increased core body temperature in F344 rats. At the same time, NMU increased Dio2 mRNA expression in the ependymal region of the hypothalamus similar to the effects of TSH. These data suggest that NMU may affect acute and photoperiodically controlled energy balance through distinct pathways. We also showed that TSH inhibits the expression of type III deiodinase (Dio3) in F344 rats, a response not mimicked by NMU. Furthermore, NMU also increased the expression of genes from the Wnt/ß-catenin pathway within the ependymal layer of the third ventricle. This effect was not influenced by TSH. These data indicate that, although NMU acts with some similarities to TSH, it also has completely distinct signalling functions that do not overlap. In summary, the present study of NMU signalling reveals the potential for a new player in the control of seasonal biology.