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Inbred Strains of Rats: F344

F344

Inbr.F155.

Colour: Albino.

Genet. c.

Origin: Curtiss and Dunning 1920 at Columbia University Institute for Cancer Research,To Heston 1949 (Billingham and Silvers 1959). To National Institutes of Health in 1951 (Hansen et al 1982). Subsequent sublines from Dunning or NIH. This is easily the most widely used general-purpose inbred rat strain, being particularly favoured for cancer research and toxicology. There is now considerable background information on strain characteristics, including life-span, spontaneous diseases and response to chemicals.


Characteristics


Anatomy

Unlike seven other strains it does not develop brownish skin scales on the dorsum of the body, the perineum and the tail (Tayama and Shisa 1994). Low relative heart weight in 10-week old males (2/23) (Tanase et al 1982).


Behaviour

Low open field defaecation (10/12) in males (Harrington 1972). Low wheel activity (11/12 females, 8/12 females) (Harringtom 1971b). Moderately easy to handle. Good breeding performance (1/12) and large litter size (1/12) (Hansen et al 1973). Low response to operant morphine-reinforced behaviour (4/4) (Ambrosio et al 1995). Low preference for ethanol and low capability to develop acute tolerance to ethanol hypnosis, like BN (York et al, 1994). Behavioural performance declined more rapidly with aging than in strain BN (Spangler et al, 1994). Develops smaller acoustic and tactile startle response than strain LEW, which may be associated with strain differences in hypothalmic-pituitary-adrenal activation (Glowa et al,1992). Unusual in its lack of preference for any concentration of salt. However, there is a dramatic change from aversion to preference following transection of the chorda tympani nerve, which in other strains causes little change in salt preference (Sollars and Bernstein, 1994). A preference can be induced by depletion of sodium chloride (Breslin et al, 1995).


Life-span and spontaneous disease

Life-span and tumour incidence depend both on strain characteristics and the environment. The following has been reported: Median lifespan about 31 months in males and 29 months in females with about 87% survival to 24 months in both sexes. (Sass et al 1975). Cameron et al (1985) found a 75% survival at 26 months of age, and Cameron et al (1982) reported a median life-span of 31.5 months in males. Mean lifespan 24 months in both sexes in presence of severe pulmonary infection (Davey and Moloney 1970). Median life-span 23-31 months in barrier-reared males and 26-29 months in barrier-reared females (Sass et al 1975, Coleman et al 1977, Jacobs and Huseby 1967, Hoffman 1979, Yu et al 1982). Food restriction to 60% of ad-libitum prolongs median life-span to more than 34 months in males (Yu et al 1982), but food restriction limited to early life and protein restriction caused only a small increase in longevity (Yu et al 1985). Other studies of life-span and neoplasia include Soleveld et al (1984) and Maekawa et al (1983). Most animals older than 2 years exhibit small local areas of nephritis; less than 25% show severe nephritis (Snell 1967).

Tumours: Mammary tumours 41% in females and 23% in males, pituitary adenomas 36% in females and 24% in males, testicular interstitial cell tumours 85% in males. Other tumour types less common (Sass et al 1975). Thyroid carcinoma 22% (Lindsey et al 1968). Interstitial cell testicular tumours 65%, mononuclear cell leukaemia 24%, subcutaneous fibroadenoma 9% in females. Both sexes have a 5% incidence of nodular hyperplasia of the liver. (Davey and Moloney 1970). In various studies incidence of leukaemias 23-26% and of testicular intersticial tumours 65-90% (Jacobs and Huseby 1967, Davey and Moloney 1970, Moloney et al 1970, Sass et al 1975, Cockrell and Garer 1976). Uterine polyploid tumours of endometrial origin 21% (Jacobs and Huseby 1967). In germ-free conditions leukaemia 26% in males, 36% in females, mammary tumours 12% in males 20% in females, all other tumours 9% in males, 5% in females (Sacksteder 1976).

Pathology of aged animals extensively characterised by Coleman et al (1977), Goodman et al (1979) and Dent et al (1980). Aged rats exhibit peripheral retinal degeneration which is exacerbated by fluorescent light of moderate intensity (32 foot-candles). They also develop cardiomyopathy with myocardial degeneration, fibrosis and chronic intersticial myocarditis (males 33%, females 18%) and nephropathy (67% in males, 39% in females) (Lai et al 1979). Retinas of both sexes show a steady decline with age in the thickness of the outer nuclear layer and photoreceptor layer, with a drastically accelerated rate of peripheral retinal degeneration seen only in males after 12 months of age (Diloreto et al, 1994, see also Faktorovich et al, 1992).


Drugs and chemicals

The F344 strain has been used in nearly 400 2-year National Cancer Institute/National Toxicology Program (NCI/NTP) toxicity/carcinogenicity studies which are individually reported in the NCI/NTP Technical Report series. The resulting material, involving data on over 100,000 rats is preserved at the NTP Archives. These include over eight million histological slides, and a corresponding number of paraffin blocks and residual formalin-fixed tissue. The archive is computerised so that individual lesions can be located for retrospective study. A detailed account of the pathology of F344 rats, which is based largely on this material is given by Boorman et al (1990).

Neurological toxicity of polybrominated biphynals and acrylamide described by Tilson et al (1978) and Tilson and Cabe (1979a,b). Low biliary excretion of copper after intravenous injection of CuSO4 (4/4) (Nederbragt and Lagerwerf 1986). Susceptible to the induction of tumours of the tongue by 4-nitroquinoline-1-oxide (Tanaka et al 1993). Susceptible to the development of anaplastic astrocytomas and glioblastomas following treatment with N-methyl-N-nitrosourea in the drinking water (Shibutani et al 1993). Isolated tracheal rings hyperresponsive to carbachol compared with LEW and F344 (Jia et al 1995). Realtively insensitive to the induction of tumours by N-methyl-N-nitrosourea (MNU) following treatment with cyproterone acetate which caused a high incidence of tumours in the outbred Cpb:WU strain (Bosland et al, 1992a). However, treatment with cyproproterone acetate for 21 days, testosterone proprionate for three days and a single i.p. injection of MNU results in atypical hyperplasia of the ventral prostate (Bosland et al, 1992b).

Severity of spontaneous nephropathy in aged rats reduced by treatment with arylsulfonylurea (Milman et al 1979). Exposure of weanling rats to terephthalic acid or dimethyl terephthalate in the diet induced urolithiasis (Wolkowski et al 1982). Phenylketonurea can be induced by p-Chloro-DL-phenylalanine with L-phenylalanine (Andersen and Guroff 1974, Anderson 1982). Bleomycin induces pulmonary fibrosis, which can be reduced by treatment with indomethacin (Thrall et al 1979) . Treatment with 3,2'-dimethyl-4-aminobiphenyl (DMAB) provides the best model for prostatic cancer of five tested (Shirai et al 1990). Slow metaboliser of MPPB (LEW is fast) (Takahara et al 1993). Morphene does not increase nose-poking behaviour, and phenobarbital does not decreases it, in contrast with strain NBR (Witkin and Goldberg, 1992). Compared with LEW rats, F344 show a much lower preference for several classes of drugs of abuse. This may be associated with levels of neurofilament proteins in the ventral tegmental area of the brain (Guitart et al, 1992). Duration of morphine-induced EEG slow-wave bursts and associated behavioural stupor was less in F344 than in LEW (Myomichelson and Young, 1993). F344 rats self-administer less morphine than LEW rats (Gosnell and Krahn, 1993). Duration of EEG slow-wave bursts and behavioural stupor also shorter in F344 than in LEW following administration of ethylketocyclazocine, suggesting differences in opioid-related receptor populations between these strains (Mayomichelson and Young, 1993). Resistant (1/4) to the organophosphate diisopropyl fluorophosphate (DFP) in terms of hypothermic response and recovery of day-night difference in core temperature (Gordon and Watkinson, 1995).

Resistant (compared with Sprague-Dawley rats) to the ventricular hypertrophy and pressure changes induced by monocrotaline. This is associated with pulmonary vascular response rather than hepatic metabolism (Pan et al, 1993).

Oral administration of hydroquinone for two years resulted in dose-related nephropathy and renal tubule adenomas in males but not females, whereas Sprague-Dawley rats were resistant (English et al, 1994). Sensitive to the convulsive effects of kainic acid (2/4) (Golden et al, 1995). Relatively resistant (1/3) to carcinogenic effects of tamoxifen, possibly associated with reduced cell proliferation in the liver (Carthew et al, 1995).


Immunology

Resistant to spontaneous autoimmune thyroiditis (Hajdu and Rona 1969), but susceptible to experimental allergic encephalomyelitis (Gasser et al 1975), experimental allergic neuritis (Levine and Wenk 1968), and autologous immune complex nephritis (Watson and Dixon 1966). Relatively insensitive to the induction of experimental autoimmune glomerulonephritis (4/4, cf WKY)(Sado et al 1986). Susceptible to the development of experimental autoimmune myasthenia gravis (8/9) (Biesecker and Koffler 1988). Resistant to the induction of thyroiditis by 3-methylcholanthrene (Glover et al 1969). Resistant to group A Streptococcus pyogenes and Lactobacillus casei-induced chronic polyarthritis (Lehman et al 1984). Epitope specificities of collagen-induced arthritis studied by Cremer et al (1992). Normally resistant to the development of adjuvent arthritis, but germ-free F344 rats are susceptible, and the use of paraffin oil rather than mineral oil also induces susceptibility (Vandelangerijt et al, 1993).

Low antibody response to streptococcal group A carbohydrate, not linked to the MHC (Stankus and Leslie 1976). Neonatal pancreatic islets derived by non-enzymic (in vitro) isolation procedures can be transplanted across MHC barriers without any immune suppression, in contrast with other strains such as ACI (Ketchum et al, 1992). Tachykinins cause bronchoconstriction in susceptible F344 mainly by an indirect mechanism that involves stimulation of NK1 receptors and mast cell activation, in contrast with the less sensitive strain BDE where they cause bronchoconstriction by a direct effect on the airway smooth muscle via activation of NK2 receptors (Joos et al, 1994).

Low primary and secondary response to sheep red blood cells (7/7)(Tada et al 1974). Poor producers of reaginic antibody in response to ovalbumin in aluminium hydroxide (Murphy et al 1974). Bouleter and Sell (1985) have described the alphafetoprotein and albumin genes and compared these with ACI andf BUF. Haematology; high RBC (7/7), Hb (6/7), PCV (6/7), and monocytes (6/7), but low MCV (1/7), MCH (1/7), MCHC (2/7) (Lovell et al 1981). See also Festing et al (1984).

Biochemistry and physiology

Growth described by Cameron et al (1985). Resistant to the development of salt-induced hypertension (Hall et al 1976). High specific activity but low inducibility of NADP cytochrome C reductase compared with outbred Sprague-Dawley rats (Gold and Widnell 1975). Hepatic microsomal activity before and after induction by phenobarbitone well characterised (Page and Vesell 1969, Gold and Widnell 1975, Dent et al 1980). Large pituitaries, susceptible to Cysticercus in infection and rapid absorption of diethylstilboestrol leading to death (Dunning et al 1947). Low LD50 of pentobarbital sodium (5/7=70mg/kg) (Shearer et al 1975). Have substantially higher levels of diurnal and stress related corticosterone levels with higher levels of corticosteroid-binding globulin in plasma, spleen and thymus than LEW or Sprague-Dawley rats (Dhabhar et al, 1993). Higher concentrations of cortical and hippocampal 5-HT1A receptors compared with LEW rats (Burnet et al, 1994). Hippocampal neurones are more vulnerable to ishemic insult than those of other strains (1/3) (Iwasaki et al, 1995).


Infection

Infection with Hymenolepsis diminuata cysticercoids results in no worm loss and no mastocytosis in contrast with DA where there was significant mastocytosis six weeks post infection and low persistance of worms (Ishih, 1992, 1994).


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Cremer M. A., Terato K., Watson W. C., Griffiths M. M., Townes A. S., and Kang A. H. (1992) Collagen-induced arthritis in rats - examination of the epitope specificities of circulating and cartilage-bound antibodies produced by outbred and inbred rats using cyanogen bromide-derived peptides purified from heterologous and homologous type-II collagens. J. Immunol. 149, 1045-1053. \par

Davey F. R. and Moloney W. C. (1970) Postmortem observations of Fischer rats with leukemia and other disorders. Lab. Invest. 23, 327-334. \par

Dent J. G., Graichen M. E., Schnell S., and Lasker J. (1980) Constitutive and induced hepatic microsomal cytochrome P-450 monooxygenase activities in male Fischer-344 rats and CD rats. A comparative study. Toxicol. Appl. Pharmacol. 52, 45-53. \par

Dhabhar F. S., McEwen B. S., and Spencer R. L. (1993) Stress-response, adrenal-steroid receptor levels and corticosteroid- binding globulin levels - a comparison between Sprague-Dawley, Fischer-344 and Lewis rats. Brain Res. 616, 89-98. \par

Diloreto D., Cox C., Grover D. A., Lazar E., Delcerro C., and Delcerro M. (1994) The influences of age, retinal topography, and gender on retinal degeneration in the Fischer-344 rat. Brain Res. 647, 181-191. \par

Dunning W. F., Curtis M. R., and Segaloff A. (1947) Strain differences in response to diethylstilbestrol and the induction of mammary gland and bladder cancer in the rat. Cancer Res. 7, 511-521. \par

English J. C., Perry L. G., Vlaovic M., Moyer C., and Odonoghue J. L. (1994) Measurement of cell-proliferation in the kidneys of Fischer-344 and Sprague-Dawley rats after gavage administration of hydroquinone. Fundam. Appl. Toxicol. 23, 397-406. \par

Faktorovich E. G., Steinberg R. H., Yasumura D., Matthes M. T., and Lavail M. M. (1992) Basic fibroblast growth-factor and local injury protect photoreceptors from light damage in the rat. Journal of Neuroscience 12, 3554-3567. \par

Festing M. F. W. and Bender K. (1984) Genetic relationships between inbred strains of rats. An analysis based on genetic markers at 28 biochemical loci. Genet. Res. 44, 271-281. \par

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Glowa J. R., Geyer M. A., Gold P. W., and Sternberg E. M. (1992) Differential startle amplitude and corticosterone response in rats. Neuroendocrinology 56, 719-723. \par

Gold G. and Widnell C. C. (1975) Response of NADPH cytochrome c reductase and cytochrome P-450 in hepatic microsomes to treatment with phenobarbital--Differences in rat strains. Biochem. Pharmacol. 24, 2106. \par

Golden G. T., Smith G. G., Ferraro T. N., and Reyes P. F. (1995) Rat strain and age-differences in kainic acid-induced seizures. Epilepsy Res. 20, 151-159. \par

Goodman D. C., Ward J. M., Squire R. A., Chu K. C., and Linhart M. S. (1979) Neoplastic and nonneoplastic lesions in aging F344 rats. Toxicol. Appl. Pharmacol. 48, 237-248. \par

Gordon C. J. and Watkinson W. P. (1995) Strain differences in the laboratory rat - impact on the autonomic, behavioral, and biochemical response to cholinesterase inhibition. J. Toxicol. Environ. Health 45, 59-73. \par

Gosnell B. A. and Krahn D. D. (1993) Morphine-induced feeding - a comparison of the Lewis and Fischer 344 inbred rat strains. Pharmacol. Biochem. Behav. 44, 919-924. \par

Guitart X., Beitnerjohnson D., Marby D. W., Kosten T. A., and Nestler E. J. (1992) Fischer and Lewis rat strains differ in basal levels of neurofilament proteins and their regulation by chronic morphine in the mesolimbic dopamine system. Synapse 12, 242-253. \par

Hajdu A. and Rona G. (1969) Spontaneous thyroiditis in laboratory rats. Experientia 25, 1325-1327. \par

Hall C. E., Ayachi S., and Hall O. (1976) Immunity of Fischer 344 rats to salt hypertension. Life Sci. 18, 1001-1007. \par

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Harrington G. M. (1972) Strain differences in open-field behavior of the rat. Psychon. Sci. 27, 51-53. \par

Hoffman H. J. (1979) Survival distributions for selected laboratory rat strains and stocks, in Development of the rodent as a model system for aging, Book II ed. (Gibson D. C., Adelman R. C., and Finch C., eds), pp. 19-34. DREW Pub. No. (NIH) 79-161, Washington, DC. (Department of Health, Education, and Welfare; Washington, D.C.: U.S.) \par

Ishih A. (1992) Mucosal mast-cell response to hymenolepis-diminuta infection in different rat strains. International Journal for Parasitology 22, 1033-1035. \par

Iwasaki H., Ohmachi Y., Kume E., and Krieglstein J. (1995) Strain differences in vulnerability of hippocampal-neurons to transient cerebral-ischemia in the rat. International Journal of Experimental Pathology 76, 171-178. \par

Jacobs B. B. and Huseby R. A. (1967) Neoplasms occurring in aged Fischer rats, with special reference to testicular, uterine, and thyroid tumours. J. Natl. Cancer Inst. 39, 303-307. \par

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Levine S. and Wenk E. J. (1968) The production and transfer of allergic adrenalitis. Am. J. Pathol. 52, 41-53. \par

Lindsey S., Nichols C. W. Jr., and Chaikoff I. L. (1968) Naturally occurring thyroid carcinoma in the rat. Similarities to human medullary carcinoma. Arch. Pathol. 86, 353-364. \par

Lovell D. P., Archer R. K., Riley J., and Morgan R. K. (1981) Variation in haematological parameters among inbred strains. Lab. Anim. 15, 243-249. \par

Maekawa A., Kurokawa Y., Takahashi M., Kokubo T., Ogiu T., Odonera H., Tanigawa H., Ohono Y., Furikawa F., and Hayashi Y. (1983) Spontaneous tumors in F344/DuCr rats. Gann 74, 365-372. \par

Milman H. A., Peckham J. C., Ward J. M., and Tyranny R. E. (1979) Reduction of the severity of nephropathy in aging Fischer 344 rats treated with analogs of arylsulfonylurea. Toxicol. Appl. Pharmacol. 49, 425-430. \par

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Murphy S. M., Brown S., Miklos H., and Fireman P. (1974) Reagin synthesis in inbred strains of rats. Immunol. 27, 245-253. \par

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Yu B. P., Masoro E. J., Murata I., Bertrand H. A., and Lynd F. T. (1982) Life span study of SPF Fischer 344 male rats fed ad libitum or restricted diets: Longevity, growth, lean body mass and disease. J. Gerontol. 37, 130-141. \par

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

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