BN

Inbr. F71 (Pit).

Colour: Brown.

Genet. a, b, hⁱ.

Origin: Billingham and Silvers 1958, from a brown mutation maintained by DH King and P Aptekman in a pen-bred colony (Billingham and Silvers 1959). A plasma kininogen-deficient mutant strain (BN/Ka) has been described in which release of heat-induced substance P is defective (Tang et al, 1994) and response to the hypertensive effects of deoxycorticosterone acetate salt is much faster than in normal BN rats (Majima et al, 1995a,b).

---

Characteristics

---

Behaviour

Can not be triggered into paradoxical sleep by dark pulse stimulation (ie. turning off the lights), in contrast with LEW (Leung et al, 1992). Higher precentage of paradoxical sleep than LEW (Rosenberg et al 1987). Low preference for ethanol and low capability to develop acute tolerance to ethanol hypnosis (York et al, 1994). Behavioural performance declined less rapidly with aging than in strain F344 (Spangler et al, 1994).

Pathology and spontaneous disease

Endocardial disease 7% at an average age of 31 months (Boorman et al 1973). Tumours of epithelium 28% in males, 2% in females. Ureter tumours 20% in females, 6% in males. Estimated median life-span more than 24 months in males and more than 25 months in females (Boorman and Hollander 1974).

Median lifespan 29 months in males (n=74) and 31 months in females (n=236). Most common neoplastic lesions in males were urinary bladder carcinoma 35%, pancreas islet adenoma 15%, pituitary adenoma 14%, lymphoreticular sarcoma 14%, adrenal cortex adeneoma 12%, medullary thyroid carcinoma 9%, adrenal pheochromocytoma 8%. Four other types of tumours were observed. In females: pituitary adenoma 26%, ureter carcinoma 22%, adrenal cortical adenoma 19%, cervix sarcoma 15%, mammary gland fibroadenoma 11%, islet adenoma 11%. Twelve other tumour types were observed (Burek and Hollander 1975a).

The chance of death from metastases increased with age in females, but reaches a peak at 25-30 months in males (Burek and Hollander 1975b). The cervical and vaginal tumours have been studied in more detail by Burek et al (1975a), and further details of an aging colony are given by Hollander (1976) and Burek and Hollander (1977). Vaginal and cervical tumours, mostly sarcomas but also seven squamous-cell carcinomas and four leiomyomas, were seen in 20% of animals that died naturally (Burek et al 1976). High incidence (31%) of hydronephrosis reported in 2-month-old BN/Bi (Cohen et al 1970), but little seen by Gray et al (1982) before 30 months, after which the disease progressed slowly. A high incidence was observed at all ages by Spangler et al (1994).

Drugs and chemicals

Dimethylbenzanthracene induced a transplantable myeloid leukaemia (Colly and Hagenbeek 1977). Intermediate susceptibility to pentobarbital sodium (3/7) with LD₅₀ of 90mg/kg (Shearer et al 1973).

---

Immunology

Resistant to induction of experimental allergic encephalomyelitis (1/7) (Gasser et al 1975, McFarlin et al 1975a,b). However, resistance can be modulated by endogenous corticosteroids (Peers et al, 1995). Resistant to induction of autologous immune compex glomerulonephritis (Strenglein et al 1975). Like strain MAXX, but in contrast to 17 other strains BN is susceptible to the development of mercury-induced autoimmunity to renal basement membranes with the development of membraneous glomerulonephritis (Henry et al 1988). Susceptible to the autoimmune effects of mercury showing a decrease of peripheral RT6.2(+) T lymphocytes compared with strain LEW (Kosuda et al 1994), but no release of hydrogen peroxide in peritoneal polymorphonuclear leukocytes and macrophages in contrast with LEW (Contrino et al, 1992). Susceptible to the development of autoimmunity to skin-injected HgCl₂ , in contrast to LEW (Warfvinge and Larsson, 1994). Develop a T-helper 2 cell-mediated autoimmune syndrome following treatment with mercuric chloride, gold or D-penicillamine which amy be associated with the response of mast cells (Oliveira et al, 1995)

Moderately sensitive to the development of experimental glomerulonephritis following injection of nephritogenic antigen from bovine renal basement membrane (Naito et al, 1991)

Develops severe experimental allergic encephalomyelitis when immunised with rat spinal cord and carbonyl iron adjuvent (Levine and Sowinski 1975). Linington et al (1986) induced experimental allergic neuritis using T-cells and bovine P2 (a peripheral nerve myelin protein). Resistant to the induction of Haymann nephritis (Badalamenti et al 1987). High IgE response to Japanese Cedar pollen antigen (1/7): may be a useful model for studying physiological and pathological changes in the nose after pollen challenge (Imaoka et al, 1993). Resident macrophages (ramified microglea) of the central nervous system are constitutively major histocompatibility complex class-II positive, in contrast with LEW (Sedgwick et al, 1993). Following lethal irradiation and re-constitution with syngeneic bone marrow and given cyclosporin A for several weeks LEW rats will develop cyclosporin-induced autoimmunity after withdrawal of the cyclosporin. The condition resembles graft-versus host disease in terms of acute dermatitis and chronic scleroderma. However, BN rats do not develop this disease (Wodzig et al, 1993). Resistant to the induction of experimental autoimmune uveoretinitis and endotoxin-induced uveitis which appears to be associated with the production of tumour necrosis factor (TNF) by retinal Muller glia and retinal pigmented epithelium. Strain LEW is susceptible (Dekozak et al, 1994). Susceptible to the induction of proteinuria following treatment with the monoclonal antibody 5-6-1, like LEW and outbred Wistar, but unlike resistant outbred Sprague-Dawley rats which were also resistant to glomerular damage (Gollner et al, 1995).

Low antibody response to phytohaemagglutinin, concanavalin A and streptococcal group A carbohydrate (Koch 1976, Stankus and Leslie 1976, Williams et al 1973). Good (1/5) antibody response to a synthetic 20 amino acid peptide derived from the alpha helical region of the RT1-D-u beta chain (Murphy et al, 1994).

---

Infection

Resistant to the induction of encephalitis by coronavirus, with a much shorter delay in lymphocyte proliferation following infection than in the susceptible LEW strain (Imrich et al, 1994).

Low plasma ceruloplasmin levels (Stolc 1984) Low fertility. Somewhat vicious. Poor performance in an active avoidance learning task (4/4), but good reference memory (Van Luijtelaar et al 1988).

---

Badalamenti J., Shea M., Cybulsky A. V., Quigg R. J., and Salant D. J. (1987) Heymann nephritis (HN) antigen in Lewis (LEW) and Brown Norway (BN) rats. Fed. Proc. 46, 1327.

Billingham R. E. and Silvers W. K. (1959) Inbred animals and tissue transplantation immunity. Transplant. Bull. 6, 399-406.

Boorman G. A. and Hollander C. F. (1973) Spontaneous lesions in the female WAG/Rij (Wistar) rat. J. Gerontol. 28, 152-159.

Boorman G. A. and Hollander C. F. (1974) High incidence of spontaneous urinary bladder and ureter tumors in the brown Norway rat. J. Natl. Cancer Inst. 52, 1005-1008.

Burek J. D. and Hollander C. F. (1975a) Studies of spontaneous lesions in aging BN/Bi rats. I. Neoplastic and non-neoplastic lesions, in Annual Report, Organization for Health Research, pp. 235-237. TNO, Rijswijk.

Burek J. D. and Hollander C. F. (1975b) Studies of spontaneous lesions in aging BN/Bi rats. II. Age associated incidence of tumors and tumor metastases, in Annual Report, Organization for Health Research, pp. 238-241. TNO, Rijswijk.

Burek J. D., Zurcher C., and Hollander C. F. (1976) High incidence of spontaneous cervical and vaginal tumors in an inbred strain of Brown Norway rats (BN/Bi). J. Natl. Cancer Inst. 57, 549-554.

Burek J. D. and Hollander C. F. (1977) Incidence patterns of spontaneous tumors in BN/Bi rats. J. Natl. Cancer Inst. 58, 99-105.

Cohen B. J., De Bruin R. W., and Kort W. J. (1970) Heritable hydronephrosis in a mutant strain of brown Norway rats. Lab. Anim. Care 20, 489-493.

Colly L. P. and Hagenbeek T. (1977) Experimental chemotherapy: A rat model for human acute myeloid leukemia, in Experimental hematology today (Baum S. J. and Ledney D. G., eds), pp. 211-219. Springer Verlag, New York.

Dekozak Y., Naud M. C., Bellot J., Faure J. P., and Hicks D. (1994) Differential tumor-necrosis-factor expression by resident retinal cells from experimental uveitis-susceptible and uveitis-resistant rat strains. J. Neuroimmunol. 55, 1-9.

Gasser D. L., Palm J., and Gonatas N. K. (1975) Genetic control of susceptibility to experimental allergic encephalomyelitis and the Ag-B locus of rats. J. Immunol. 115, 431-433.

Gollner D., Kawachi H., Oite T., Oka M., Nagase M., and Shimizu F. (1995) Strain variation in susceptibility to the development of monoclonal- antibody 5-1-6-induced proteinuria in rats. Clin. Exp. Immunol. 101, 341-345.

Gray J. E., van Zwieten M. J., and Hollander C. F. (1982) Early light microscopic changes of chronic progressive nephrosis in several strains of aging laboratory rats. J. Gerontol. 37, 142-150.

Henry G. A., Jarnot B. M., Steinhoff M. M., and Bigazzi P. E. (1988) Mercury-induced renal autoimmunity in the MAXX rat. Clin. Immunol. Immunopathol. 49, 187-203.

Hollander C. F. (1976) Current experience using the laboratory rat in aging studies. Lab. Animal Sci. 26, 320-328.

Imaoka K., Sakaguchi M., and Inouye S. (1993) Antibody-responses against Japanese cedar pollen allergen (Cry-j-I) in different strains of rats. Exp. Anim. 42, 61-65.

Imrich H., Schwender S., Hein A., and Dorries R. (1994) Cervical lymphoid-tissue but not the central-nervous-system supports proliferation of virus-specific T-lymphocytes during coronavirus- induced encephalitis in rats. J. Neuroimmunol. 53, 73-81.

Koch C. (1976) Genetic control of antibody responses to PHA in inbred rats. Scand.J. Immunol. 5, 1149-1153.

Kosuda L. L., Hosseinzadeh H., Greiner D. L., and Bigazzi P. E. (1994) Role of RT6(+) T-lymphocytes in mercury-induced renal autoimmunity -experimental manipulations of susceptible and resistant rats. J. Toxicol. Environ. Health 42, 303-321.

Leung C., Bergmann B. M., Rechtschaffen A., and Benca R. M. (1992) Heritability of dark pulse triggering of paradoxical sleep in rats. Physiol. Behav. 52, 127-131.

Levine S. and Sowinski R. (1975) Allergic encephalomyelitis in the reputedly resistant Brown Norway strain of rats. J. Immunol. 114, 597-601.

Linington C., Mann A., Izumo S., Uyemura K., Suzuki M., Meyermann R., and Wekerle H. (1986) Induction of experimental allergic neuritis in the BN rat: P2 protein-specific T cells overcome resistance to actively induced disease. J. Immunol. 137, 3826-3831.

Majima M., Adachi K., Kuribayashi Y., Mizogami S., and Katori M. (1995a) Increase in vascular sensitivity to angiotensin-II and norepinephrine after 4-day infusion of 0.3 m sodium-chloride in conscious kininogen- deficient Brown-Norway Katholiek rats. Jpn. J. Pharmacol. 69, 149-158.

McFarlin D. E., Hsu S. C.-L., Slemenda S. B., Chou S. C.-H., and Kibler and R. F. (1975a) The immune response against an encephalitogenic fragment of guinea pig basic protein in the Lewis and Brown Norway strains of rat. J. Immunol. 115, 1456-1458.

Murphy G., Dalchau R., Parker K. E., Sawyer G. J., Carter C. A., and Fabre J. W. (1994) T-cell recognition of an allogeneic RT1-db^u class-II MHC peptide. Immunology Letters 41, 195-199.

Naito I., Kagawa M., Sado Y., and Okigaki T. (1991) Strain specific responses of inbred rats on the severity of experimental autoimmune glomerulonephritis - presence of a broad- spectrum of the susceptibility. International Journal of Immunopathology and Pharmacology 4, 145-154.

Peers S. H., Duncan G. S., Flower R. J., and Bolton C. (1995) Endogenous corticosteroids modulate lymphoproliferation and susceptibility to experimental allergic encephalomyelitis in the Brown-Norway rat. International Archives of Allergy and Immunology 106, 20-24.

Rosenberg R. S., Bergman B. M., Son H. J., Arnason B. G. W., and Rechtschaffen A. (1987) Strain differences in the sleep of rats. Sleep 10, 537-541.

Sedgwick J. D., Schwender S., Gregersen R., Dorries R., and Termeulen V. (1993) Resident macrophages (ramified microglia) of the adult Brown Norway rat central-nervous-system are constitutively major histocompatibility complex class-II positive. J. Exp. Med. 177, 1145-1152.

Shearer D., Creel D., and Wilson C. E. (1973) Strain differences in the response of rats to repeated injections of pentobarbital sodium. Lab. Animal Sci. 23, 662-664.

Stankus R. P. and Leslie G. A. (1976) Rat interstrain antibody response and crossidiotypic specificity. Immunogenet. 3, 65-73.

Stolc V. (1984) Genetic polymorphism of ceruloplasmin levels in the rat. J. Hered. 70, 145-146.

Tang F. D., Yonehara N., Imai Y., Takiuchi S., Inoki R., and Bian R. L. (1994) Releases of bradykinin and substance-P by heating hind paw of rat. Acta Pharmacologica Sinica 15, 232-234.

Van Luijtelaar E. L. J. M. and Coenen A. M. L. (1988) Circadian rhythmicity in absence epilepsy in rats. Epilepsy Res. 2, 331-336.

Williams R. M., Moore M. J., and Benacerraf B. (1973) Genetic control of thymus-derived cell function. III. DNA synthetic responses of rat lymph node cells stimulated in culture with concanavalin A and phytohemagglutinin. J. Immunol. 111, 1571-1578.

Wodzig K. W. H., Majoor G. D., and Vriesman P. J. C. V. (1993) Susceptibility and resistance to cyclosporine-A-induced autoimmunity in rats. Autoimmunity 16, 29-37.

York J. L. and Chan A. W. K. (1994) Absence of acute tolerance to ethanol hypnosis in F344 and BN/BiRij rats. Alcohol 11, 31-34.

---

INBRED STRAINS OF RATS
Updated 9 Apr. 1998
Michael FW Festing
MRC Toxicology Unit, Hodgkin Building,
University of Leicester, UK