Models of androgen insensitivity in the study of androgen action.
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Androgen-Insensitivity Syndrome↗
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Inhibition of rhodamine 123 secretion by cyclosporin A as a model of P-glycoprotein mediated transport in liver.
The interaction between P-glycoprotein modulators and P-glycoprotein mediated transport was investigated using rhodamine 123 in the isolated perfused rat liver of a mutant (TR-) rat strain. TR- rats, deficient in the canalicular multispecific anion transport system, are unable to extrude organic anions (glucuronides) and therefore excrete solely unconjugated rhodamine 123 via P-glycoprotein. Cyclosporin A, a modulator of multidrug resistance in tumor cells, inhibited the biliary secretion of rhodamine 123 dose dependently in a non-competitive manner. Both cyclosporin A and rhodamine inhibited photoaffinity labeling of immunoprecipitated P-glycoprotein with azidopine, indicating binding to hepatic P-glycoprotein. Our results indicate that monitoring the biliary rhodamine 123 secretion in the isolated perfused liver of TR- rats offers a new system for testing modulators of P-glycoprotein like cyclosporin A.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Shaking rat Kawasaki (SRK): a new neurological mutant rat in the Wistar strain.
Shaking rat Kawasaki (SRK), a newly discovered neurological mutant rat in the Wistar strain, is described. The abnormalities of SRK rats are transmitted as an autosomal recessive trait. The neurological signs are shaking of the body and an ataxic-paretic gait from day 10 postnatal. The affected rats survive for about 1 month. Macroscopically, the cerebellum is small and frequently the vermis and paraflocculus lacking. The most conspicuous histological finding in the central nervous system is malposition of the neurons in the cerebral cortex, hippocampus and cerebellum. Myelination and synapse formation are intact. Abnormal myelinated fibers are present in the molecular layer of the cerebral cortex and in the central gray matter of the spinal cord. These morphological abnormalities resemble those reported in the reeler mutant mouse. SRK rats are another good animal model of human congenital malformations with neuronal migration disorders.
Animals↗
Suppression of antibody responses in vitro by bone marrow cells in rats with hereditary liver injury.
The primary antibody responses of spleen cell cultures were investigated for LEC rats, a mutant strain of LEA rats, which are known to develop spontaneous hepatic injuries. Compared to LEA rats, LEC rats were significantly low in responding not only to a T-dependent antigen, SRBC, but also to a B-cell stimulant, LPS. The antibody responses of LEC rats having fed a diet deprived of Cu metal (LEC/Cu-) showed values intermediate between LEA and LEC rats, thus suggesting a recovery from an immuno-deficient state as well as liver damage in LEC/Cu- rats. The addition of LEA bone marrow cells prior to culture to LEA or LEC spleen cells, strikingly enhanced the antibody response, whereas LEC bone marrow cells were totally ineffective, or sometimes depressed the response. These results have suggested a newer concept for a possible correlation between liver-dysfunction and bone marrow cell-functions in LEC rats, both encoded by autosomal genes.
Animals↗
Stereotypy, locomotor and cataleptic effects produced by drugs influencing dopaminergic systems in a mutant strain of Wistar rats: a genuine model of basal ganglia dysfunction?
The mutant strain of Wistar rats carrying an autosomal recessive gene defect is characterized by a sequence of progressively developing behavioural alterations including hyperexcitability, tremor, olfactory and gustatory automatisms, bradykinesia, ataxia, rigidity, paresis and cachexia. The stereotypy and locomotor responses to increasing doses of apomorphine hydrochloride and D-amphetamine sulphate, and the catalepsy response to increasing doses of haloperidol were studied in mutant rats at the age of 6-7 weeks. In the mutants, both the stereotypy and locomotor responses to amphetamine were enhanced, while stereotypy and locomotor effects induced by apomorphine were unaltered. The cataleptic response to haloperidol was significantly diminished compared to controls. These findings indicate a derangement in the function of basal ganglia in the mutants.
Animals↗
Altered cellular distribution of iron in the central nervous system of myelin deficient rats.
Under normal conditions, iron is found predominantly in oligodendrocytes, the myelin producing cell, in the rat brain. A genetic mutant strain of rats known as myelin deficient rats is examined in the present study because their number of oligodendrocytes is decreased and those oligodendrocytes present are structurally abnormal. The levels of iron in the liver (major site of iron storage) and in the pons-cerebellum did not differ statistically between the myelin deficient rats and the littermate control rats, whereas only half of the iron normally found in the cerebrum-midbrain was present in the myelin deficient rat. Histologically, iron was found predominantly in oligodendrocytes in the littermate control rats, as expected. In the myelin deficient rat, iron staining was confirmed to astrocytes and microglia. The results of this study strongly suggest that iron uptake into the brain continues in the absence of normal oligodendrocytes and myelin. Furthermore, these data suggest that iron metabolism can be substantially altered, as indicated by the accumulation of iron in astrocytes and microglia, when normal or near normal levels of iron are quantitatively demonstrated. The response of astrocytes and microglia to sequester the iron (presumably through phagocytosis) in the absence of invasive damage represents, to our knowledge, a new functional observation for these cells. Based on these observations it is clear that iron histochemistry in combination with quantitative analysis is necessary to interpret data regarding iron physiology, at least in neurobiology, and iron accumulation by astrocytes and microglia may provide clues of altered iron metabolism despite normal iron levels.
Animals↗
A set of highly informative rat simple sequence length polymorphism (SSLP) markers and genetically defined rat strains.
BACKGROUND: The National Bio Resource Project for the Rat in Japan (NBRP-Rat) is focusing on collecting, preserving and distributing various rat strains, including spontaneous mutant, transgenic, congenic, and recombinant inbred (RI) strains. To evaluate their value as models of human diseases, we are characterizing them using 109 phenotypic parameters, such as clinical measurements, internal anatomy, metabolic parameters, and behavioral tests, as part of the Rat Phenome Project. Here, we report on a set of 357 simple sequence length polymorphism (SSLP) markers and 122 rat strains, which were genotyped by the marker set. RESULTS: The SSLP markers were selected according to their distribution patterns throughout the whole rat genome with an average spacing of 7.59 Mb. The average number of informative markers between all possible pairs of strains was 259 (72.5% of 357 markers), showing their high degree of polymorphism. From the genetic profile of these rat inbred strains, we constructed a rat family tree to clarify their genetic background. CONCLUSION: These highly informative SSLP markers as well as genetically and phenotypically defined rat strains are useful for designing experiments for quantitative trait loci (QTL) analysis and to choose strategies for developing new genetic resources. The data and resources are freely available at the NBRP-Rat web site 1.
Animals↗
A new rat mutant with chronic conjugated hyperbilirubinemia and renal glomerular lesions.
A new mutant strain of inbred Sprague Dawley rats with autosomal recessive hyperbilirubinuria, were studied by biochemical, histologic, and ultrastructural methods. The plasma bilirubin concentration in the homozygote was significantly higher than that of the heterozygote, and about 80% of the bilirubin was conjugated. Plasma BSP and ICG clearance were both severely delayed in the homozygote. Plasma BSP elimination kinetics suggested that the pathophysiologic defect was not hepatic uptake or storage but rather in secretion into bile. Histopathology of the liver demonstrated brown pigment in the hepatocytes that appeared to be lipofuscin. The electron microscopic features of the hepatic pigment resembled those of the Dubin-Johnson syndrome. Homozygote histopathology also revealed glomerular lesions with mesangial expansion and proliferation in the kidneys. Immunohistologic studies disclosed mesangial granular deposition of IgG, IgA, and to a lesser degree, IgM and C3. These renal changes resembled those of IgA nephropathy. The spontaneous hyperbilirubinuric rat (EHBR) may be a useful animal model for studying constitutive conjugated hyperbilirubinemia, bilirubin metabolism, cholestasis, and glomerulonephropathy subsequent to hepatic dysfunction.
Animals↗
Elevated level of 8-hydroxydeoxyguanosine in DNA of liver, kidneys, and brain of Long-Evans Cinnamon rats.
Long-Evans Cinnamon (LEC) rats, a mutant strain originating from Long-Evans rats, spontaneously develop hereditary hepatitis followed by hepatocellular carcinoma. The hepatic disorder in LEC rats is associated with their abnormal copper metabolism; metal-catalyzed reactions often give rise to oxygen radicals, which may be related to the carcinogenesis. By means of high-pressure liquid chromatography with electrochemical detection, cellular DNA damage caused by oxygen radicals can be assessed in terms of the amount of 8-hydroxydeoxyguanosine (oh8dG). We assayed the amount of oh8dG in DNA of liver, kidneys, and brain of LEC and Long-Evans Agouti (LEA) control rats in seven groups (n = 3 to 6) aged from 5 weeks to 24 months. Control rats, a healthy sibling line, were age-matched. The amount of oh8dG was correlated with the severity of the age-related clinical symptoms in LEC rats. The amount was higher in LEC rats than in the controls, especially in the liver at the acute stage of hepatitis. These findings suggest that oxygen radicals may be important in the carcinogenesis that occurs in LEC rats.
8-Hydroxy-2'-Deoxyguanosine↗
Isolation of multiple normal and functionally defective forms of uridine diphosphate-glucuronosyltransferase from inbred Gunn rats.
Gunn rats are a mutant strain of Wistar rats that have unconjugated hyperbilirubinemia due to absence of hepatic uridine diphosphate-glucuronosyltransferase (UDPGT; EC. 2.4.1.17) activity toward bilirubin. We isolated five UDPGT isoforms from solubilized microsomal fractions from liver of inbred Wistar (RHA) rats and congeneic Gunn rats. UDPGT isoform V (elution pH 7.5) from Wistar (RHA) rats is active toward bilirubin and 4'-hydroxydimethylaminoazobenzene. The corresponding isoform from Gunn rat liver was enzymically inactive but exhibited normal elution pH and mobility on NaDodSO4/polyacrylamide gel electrophoresis (Mr 53,000), and was recognized by a UDPGT-specific antiserum. UDPGT isoform I (elution pH 8.7) from Wistar (RHA) and Gunn rats was active toward 4-nitrophenol. The isoform from Gunn rat liver had only 10% of normal UDPGT activity, however UDPGT activity increased to normal upon addition of 15 mM diethylnitrosamine in vitro. Isoforms II (elution pH 8.4), III (elution pH 8.0), and IV (elution pH 7.8) from Gunn rats had normal UDPGT activities, except that Isoform IV was inactive toward bilirubin.
Animals↗
Reproductive activity of analbuminemic rats.
Long-term feeding and breeding in a conventional environment have been investigated in analbuminemic rats, a mutant strain established from Sprague-Dawley rats. Analbuminemic rats kept alive for over two years and maintained normal reproductive performance for over one year. The rotational system of one male and four females was better reproductive efficiency than the continuous pairing system of one male and one female. The litter size and weaning rate in analbuminemic rats were similar to those in Sprague-Dawley rats. Although we tried to establish a caesarean delivered SPF colony of analbuminemic rats, no changes in reproductive performance were recognized.
Animals↗
Effects of restricted food access on diurnal fluctuation of behaviors and biochemical functions in hereditary microphthalmic rats.
The characteristics in circadian rhythms of spontaneous locomotor activity, and some metabolic properties were examined in microphthalmic mutant rats of the Donryu strain under ad lib or restricted food access conditions. The growth of microphthalmic rats was retarded compared to that of normal-sighted rats from the same strain. Under a 12:12-h light:dark (LD) cycle with free access to food, normal-sighted rats showed basically nocturnal patterns of the locomotor activity rhythms, but most of microphthalmic rats manifested free-running rhythms and a few of them showed arrhythmic. When food access was restricted only for 6 h in the light period of the LD cycle, the normal and hereditary blind rats generated gradually new patterns of the locomotor activities in which the animals showed to be more active in the light period. Plasma glucose concentration in normal rats showed a peak after food consumption, but microphthalmic mutants exhibited no periodic changes of the glucose levels. Responses of the biochemical parameters of protein and mineral metabolism to restricted food access in the mutants did not differ from those in normal rats. These results suggest that microphthalmic mutant rats show the free-running circadian rhythm of locomotor activity due to a complete lack of their optic nerve and visual input to the circadian clock, but the mutants maintained the ability to shift their circadian phase induced by restricted food access similar to that in control rats, and also that the mutants have almost normal properties of biochemical and physiological functions except for glucose metabolism.
Analysis of Variance↗
Point mutation of aldehyde dehydrogenase-2 gene in mutant strains of Long-Evans rats.
Long-Evans Cinnamon (LEC) and Long-Evans Agouti (LEA) rats are mutant strains established from Long-Evans rats. LEC rats display hereditary hepatitis and spontaneous hepatocellular carcinoma, but LEA rats do not develop liver diseases. We previously demonstrated that LEC rats had an impairment of liver aldehyde dehydrogenase (ALDH) activities, and all LEC rats which were fed with a liquid diet containing 5% ethanol died within 2 weeks. In the present study, we also found that LEA rats could not metabolize ethanol and died after being fed the same diet. Remarkably, in the liver of LEA rats, low Km ALDH activities were suppressed as much as in LEC rats. These results suggested that both LEC and LEA rats have hereditary deficiencies in ALDH. Nucleotide sequence analysis of ALDH2 genes in both LEC and LEA rats demonstrated that the point mutation of the codon for residue 67 encoding Gln to Asp was observed; this was not so in either Long-Evans rats or Wistar rats. This mutation in ALDH2 genes may cause inactivation of ALDR activity in LEC and LEA rats.
Aldehyde Dehydrogenase↗
Bone marrow-derived progenitor T cells convey the origin of maturational arrest from CD4+CD8+ to CD4-CD8+ thymocytes in LEC mutant rats.
A mutant strain of rats, LEC, shows a novel arrest of T cell maturation from CD4+CD8+ to CD4+CD8- but not to CD4-CD8+ cells in the thymus. Transplantation of LEC rat fetal thymuses into the subcapsule of the kidney of athymic nude rats resulted in a normal maturation of thymocytes in the thymus graft. Furthermore, both single-positive thymocytes and peripheral lymph node T cells expressed T cell receptor alpha/beta antigen, and lymph node T cells acquired the ability to produce interleukin 2 upon mitogen stimulation. Transplantation of fetal thymuses from LEA rats, which express the same major histocompatibility complex haplotype as LEC rats, into LEC rat kidney subcapsule resulted in the maturational arrest from CD4+CD8+ to CD4+CD8- cells in the thymus graft. These data strongly suggest that bone marrow-derived progenitor T cells carry the cause of maturational arrest and that the thymic stroma of LEC rats has a normal potential to nurse thymocytes.
Animals↗
A mutant strain (LEC) of rat with low degree of zinc-induced hepatic metallothionein gene expression.
A mutant strain (LEC) of rats was found to possess the feature of low degree of the zinc-induced hepatic metallothionein (MT) gene expression due to an alteration of the transcription factor concerned in the gene expression. Northern blot analyses showed that the amount of MT-1 mRNA induced by intraperitoneal zinc injection is smaller in LEC mutant rat liver than in normal rat liver, while the amount of MT-1 mRNA induced by copper injection is indistinguishable between LEC and normal rat livers. Gel retardation assays showed that LEC and normal rat livers are different in the nuclear protein which binds to the metal-responsive element (MRE) of the MT gene in a zinc-dependent manner, and that the efficiency of the zinc-dependent binding of the nuclear protein to the MRE is lower in LEC rat liver than in normal rat liver. LEC rat should provide a useful model to understand the transcription factor concerned in the MT gene expression by zinc.
Animals↗
Dissociation of interleukin-2 production from the cell activation in response to the mitogenic lectin in peripheral CD4+ T cells of LEC mutant rats.
A mutant strain of rat, LEC, exhibits a novel maturational arrest of T cells in the thymus, that is, an arrest of the differentiation from CD4+ CD8+ to CD4+ CD8- cells. However, CD4+ T cells were found to arise in lymph nodes (LN) of LEC rats. These CD4+ T cells were T-cell receptor (TcR)/CD3+ and the cross-linking of either TcR alone or both TcR and CD4 molecules induced [3H]thymidine deoxyribose (TdR) incorporation, similar to functional CD4+ T cells. Stimulation with a T-cell mitogen, concanavalin A (Con A), also induced the [3H]TdR incorporation and interleukin-2 receptor (IL-2R) expression in LEC rat CD4+ T cells. Nevertheless, Con A stimulation did not induce IL-2 production by these cells. However, when the stimulation signals were bypassed by ionomycin and phorbol 12-myristate 13-acetate (PMA), IL-2 was normally produced, suggesting that the IL-2 gene and nuclear factors for the IL-2 gene transcription are normal in LEC rats. These results suggest that signals induced by Con A are separated into the one for IL-2 secretion and the other for cell activation including DNA synthesis and IL-2R expression, and that the former signal transduction is blocked in LEC rat CD4+ T cells. Thus, CD4+ T cells in LEC rat LN might provide a good tool for investigating the regulatory mechanisms of IL-2 production.
Animals↗
Evolution of the activity of UGT1A1 throughout the development and adult life in a rat.
Biliary excretion is the main route of disposal of bilirubin and impaired excretion results in jaundice, a well recognisable symptom of liver disease. Conjugation of bilirubin in the liver is essential for its clearance. The glucuronidation of bilirubin is catalysed by the microsomal UDP-glucuronosyltransferase UGT1A1. Patients with Crigler-Najjar syndrome type 1 and Gunn rats, mutant strain of the Wistar rats, bear an autosomal recessive disorder resulting in hyperbilirubinemia. The aim of this work is to add new data about activity of UGT1A1 during the perinatal period and adult life. The results showed that activity of UGT1A1 is detectable from day 22 of the gestation. After birth, activity of UGT1A1 gradually increases and reaches the levels of adult life. Furthermore, bilirubin azopigments have been separated and characterized by thin layer chromatography. We have found that concentration of samples by evaporation and ulterior storing at -20 degrees C seemed to be suitable for the maintenance of samples.
Aging↗
Hereditary renal disease in a mutant strain of rats.
Disease of the kidney developed in breeding stock of Gunn rats. The renal lesion is the result of a new mutation. The genetic defect is inherited as an autosomal dominant trait and is apparently lethal in the homozygous condition. The abnormality manifests itself as a congenital hydronephrosis with related cystic changes in the kidney.
Animals↗