Spontaneous calcification in F344/Slc and F344/JCL rats

F344/Slc and F344/JCL rats 2 years of age were histologically examined for the incidence and distribution of calcification. In the male rats of both strains, calcification was observed in the testis, lung, brain, kidney, heart, aorta, cornea, prostate and seminal vesicle respectively. In the female F344/JCL rats, calcification appeared in the kidney, lung, cornea, brain, stomach, ovary and heart. Among these of both sexes, the lung was one of the most affected organs for calcification. On the other hand, calcification in the kidney was more severe and frequent in the females than in the males, suggesting that the sex may be one of enhancing factors for calcification.     

Osteosclerosis in F344/DuCrj rats

Osteosclerosis was observed in the tibia and sternum in F344/DuCrj rats of both sexes at 6, 18 and 30 months of age. The lesion first seen was a proliferation of osteogenic tissues on the marrow surface of the cortical bone and bone trabeculae, resulting in replacement of the marrow cavity by lamellar bone. Most of the affected rats had associated degenerative osteoarthrosis and regressive changes of the growth plate. Osteosclerosis was considered to be an aging change, lesions were observed at 6 months and increased in frequency with age.     

Senescent terminal weight loss in the male F344 rat

Loss of weight, often of unknown cause and culminating in death, commonly occurs in humans at advanced ages. Rats that live to old ages, such as the Fischer 344 (F344) strain, also exhibit a terminal loss in body weight. A presently held hypothesis is that the terminal weight loss in the F344 rat model is due to reduced food intake because of an alteration in hypothalamic function resulting in early satiation. We report findings on terminal weight loss and food intake in male F344 rats fed ad libitum (AL group) or a life-prolonging dietary regimen in which caloric intake was restricted (DR group). Rats in both dietary groups that did not exhibit a terminal weight loss died at younger ages than those exhibiting the loss. Terminal weight loss in the AL group was not associated with decreased food intake; indeed, half of the rats in this group had an increased food intake during the period of terminal weight loss. This finding is not in accord with the presently held hypothesis. In the DR group, terminal weight loss was associated with reduced food intake. Pathology (renal disease and neoplasms) did not explain the presence or absence of the association between reduced food intake and weight loss in either dietary group. The duration of the period of terminal weight loss was similar for the AL and DR groups. Apparently, restricting calories delays the occurrence but does not affect the duration of senescent terminal weight loss.     

Pharmacokinetics of propetamphos following intravenous administration in the F344 rat

Propetamphos [(E)-l-methylethyl 3[[(ethylamino)methoxyphosphinothioyl]oxy]-2-bu-tenoate], the active ingredient in Safrotin,® is an organophosphate developed by Sandoz, Ltd.® (Switzerland) as an insecticide (1). Although metabolism of propetamphos has been previously investigated (2,3), there is no pharmacokinetic data available in the literature. The current studies were undertaken to investigate the pharmacokinetics of propetamphos following intravenous administration in male and female Fischer 344 (F344) rats. Rats were dosed via an indwelling jugular cannula at a dose of 12 mg/kg (one-tenth the oral LD-50). Blood samples were withdrawn via the cannula at predetermined timepoints to quantitate plasma concentrations of propetamphos over time. Propetamphos is highly bound to plasma proteins (free fraction = 0.06). Free propetamphos concentration in plasma vs. time data were analyzed by noncompartmental methods. The terminal elimination rate constant, λ, was significantly different for males versus females (0.015 min^?1 for males and 0.037 min^?1 for females, p = 0.001). Plasma was cleared of unbound propetamphos at rates of 0.559 ± 0.069 and 0.828 ± 0.181 L/min/kg for males and females (mean ± standard error). Mean residence times (MRTs) for propetamphos in the body for males and females were 28.3 ± 5.7 and 14.4 ± 3.5 min, and the volume of distribution at steady state (Vss) was 14.7 ± 2.6 and 12.3 ± 4.5 L/kg. The differences in these parameters, clearance (CI), MRT, and Vss, were not statistically significant at the p < 0.05 level for males versus females, but MRT was nearly significantly different (p = 0.08). Because of the rapid elimination of propetamphos from plasma following intravenous administration, it is unlikely that propetamphos would bioaccumulate in environmentally exposed animals. Although the pharmacokinetic parameters were not statistically different for males and females in these studies, there was a clear clinical difference in their susceptibility to propetamphos toxicity. Female rats presented with overt signs of organophosphate intoxication, whereas males were only slightly effected. The observed gender-related clinical difference in susceptibility to toxicity suggests that there may be a difference in the extent of elimination due to activation versus detoxication of propetamphos in males and females. Another possible explanation for the clinical difference in propetamphos toxicity is that inhibition of acetyl-cholinesterase by the activated, oxygenated form of propetamphos (propetamphos oxon) may be greater in females than in males.     

Natural killer activity in the rat. III. Characterization of transplantable large granular lymphocyte (LGL) leukemias in the F344 rat

Six transplantable large granular lymphocyte (LGL) tumor lines in F344 rats were examined for natural killer (NK) and antibody-dependent cell-mediated cytotoxicity. Tumor cells from all six lines were highly cytotoxic, even at low effector to target ratios, when tested against NK-susceptible targets, but were unreactive against an NK-resistant target (C58NT)D) and a macrophage-susceptible target (P815). Three lines showed significant levels of lysis against antibody-coated tumor cells. After in vivo transplantation, the levels of cytotoxicity steadily increased in three lines and decreased in one. The cytotoxic activity of one line (RNK-16) remained high through 12 transplant generations. Tumor cells injected i.p. spread via the lymphatics to regional lymph nodes, mediastinal nodes, blood, and eventually the bone marrow. Leukemia occurred concurrently with organ enlargement and increased levels of NK. Studies in (F344 X W/Fu)F1 rats clearly demonstrated that the cytotoxic cells from leukemic animals were the transplanted tumor cells themselves and not merely the activation of normal host LGL. These results demonstrate that naturally occurring, transplantable LGL leukemias are an easily obtainable and excellent source of materials for those studies requiring a large number of functionally active LGL.     

Age-related reduction in retinal deimination levels in the F344BN rat

Increased deimination and peptidyl arginine deiminase type 2 (PAD2) expression has been observed in age-related neurodegenerative diseases without discrimination between their aging and disease component. Here, we describe reduced levels of deimination commensurate with reduced protein, mRNA and activity of peptidylarginine deiminase type 2 in the retina, optic nerve and plasma of aged rats when compared to young rats. The decrease was significant in the ganglion cell layer, inner plexiform layer and inner nuclear layer. Because our observations suggest reduced deimination is a consequence of aging, we conclude that increased deimination must be a consequence of disease. Our findings are important to understand late-onset and progressive diseases such as glaucoma, pseudoexfoliation syndrome, age-related macular degeneration and Oguchi's disease.     

Morphometric comparison of the rat mandible in f344 substrains, f344/du and f344/n.

The shape of the mandible was compared by morphometric methods to ascertain the genetic differences between two substrains of F344 rats, F344/DuCrlCrlj and F344/NSlc. Since these two substrains are clearly different in survival and the incidence of age associated disorders; thus, some genetic differences are suggested to be present between them. Although previous microsatellite analysis did not detect any differences between the two F344 substrains, the present study clearly detected interesting differences in the mandible morphology. At 2 months of age, the F344/Du mandible was characterized by a larger size, especially in length, than the F344/N mandible. The shape of the mandible seemed to be more variable in F344/N. This clear substrain difference suggests the importance of the substrain recognition in F344 rats, especially in experimental usage.     

Comparison of rat mandible bone characteristics in f344 substrains, f344/du and f344/n.

The characteristics of the mandible bone were compared through DXA methods between two major substrains of F344 rats, F344/DuCrlCrlj and F344/NSlc at around 60 days of age. Since these two substrains are clearly different in survival and mandible morphology, some genetic differences are supposed to exist. In contrast to a previous microsatellite analysis, clear and significant differences were detected in the body and mandible weights, the mandible bone mineral contents (BMC), bone area (AREA), bone mineral density (BMD) and bone mineral ratio (BMR), between F344/DuCrlCrlj and F344/NSlc, with the mandible molar teeth intact in the bone. Thus, care is needed in the experimental use of these substrains, as results may differ between them. The newly proposed parameter, BMR, may especially contribute to the comparison of bone characteristics among species.     

Normal gene expression in male F344 rat nasal transitional and respiratory epithelium

The nasal epithelium is an important target site for chemically-induced toxicity and carcinogenicity in rodents. Gene expression profiles were determined in order to provide normal baseline data for nasal transitional/respiratory epithelium from healthy rats. Cells lining the rat nasal passages were collected and gene expression analysis was performed using Clontech cDNA Rat Atlas 1.2 arrays (1185 genes). The percentages of genes within specific average expression ranges were 4.2% at 45,000-1000, 14.8% at 1000-200, 25.0% at 200-68, and 56.0% below 68. Nine out of a subset of ten genes were confirmed for relative signal intensity using quantitative real-time RT-PCR. The most highly expressed genes included those involved in phase I (e.g. cytochrome P450s) and phase II (e.g. glutathione S-transferases) xenobiotic metabolism, bioenergetics (e.g. cytochrome oxidase), osmotic balance (e.g. Na(+)/K(+) ATPase) and epithelial ionic homeostasis (e.g. ion channels). Such baseline data will contribute to further understanding the normal physiology of these cells and facilitate the interpretation of responses by the nasal epithelial cells to xenobiotic treatment or disease.     

The LEXF: A new set of rat recombinant inbred strains between LE/Stm and F344

A new set of rat RI strains consisting of 11 independent strains and 13 of their substrains was established by inbreeding F₂ rats between F344/DuCrj and LE/Stm. The strain distribution pattern was examined for 66 microsatellite loci, 8 biochemical genetic markers, 2 histocompatibility loci, and 2 coat color genes. A rat salivary protein gene Spe1 was newly mapped on Chr 1. Received: 13 August 1996 / Accepted: 23 December 1996     

A congenic strain (F344.OLETF-Imfm) displays the existence of intramuscular fat accumulation QTL on rat chromosome 1.

A genomic region between D1Wox8 and D1Rat90 on rat chromosome 1 was previously shown to be linked to intramuscular fat accumulation by quantitative trait locus (QTL) analysis using a F2 population derived from the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, which exhibits an increase in the levels of intramuscular fat content in Musculus longissimus, and the F344 rat. There exist two regions showing major and minor lod peaks for linkage to intramuscular fat accumulation, in the chromosomal region. We constructed a congenic strain introgressing the OLETF allele on the minor but not the major lod peak region in the F344 rat strain. The congenic strain had higher levels of intramuscular fat content in Musculus longissimus than the inbred partner F344 rat, thereby proving the existence of a QTL, designated Imfm (for Intramuscular fat-minor), responsible for the intramuscular fat accumulation in the congenic region of the minor lod peak region of about 10 cM. The F344.OLETF-Imfm congenic strain might provide a refined tool for the analysis of the gene causing intramuscular fat accumulation.     

F344／N－Smu－D大鼠生长发育若干生物学特性的检测

Ｆｉｓｃｈｅｒ３４４大鼠在国外广泛应用于肿瘤研究与慢性毒性试验,八十年代中期引入我国。我们对Ｆ３４４／Ｎ－Ｓｍｕ－Ｄ大鼠的生长发育的若干生物学特性进行了检测。结果表明,该品系大鼠体型较ＳＤ大鼠与Ｗｉｓｔａｒ大鼠小,除睾丸、垂体、肾上腺、乳腺外的大部分器官与组织的自发性肿瘤的发生率相对较低,将Ｆ３４４／Ｎ－Ｓｍｕ－Ｄ大鼠种群与Ｆ３４４／ＤｕＣｒｊ种群比较,在体重、耗食量,血液学与生化学等方面的若干特性差异较大,肿瘤发生率与死亡差别不大。     

Populations of follicles in F344/N rats during aging

Follicular populations were investigated in female F344/N rats to better understand the aging process of the rat ovary. Ovaries dissected at various ages (spanning 1–36 months old) were submitted for histological examination. The total number of primordial, growing (primary and secondary), tertiary, and atretic follicles as well as corpora lutea (CL) were counted in hematoxylin–eosin- and azocarmine–aniline-blue-stained ovarian sections. The number of healthy follicles including primordial, growing and tertiary follicles decreased rapidly between the first and third months and gradually thereafter. CL were found in 3-month-old rats, and their number remained unchanged until 18 months of age, at which point it decreased. The number of atretic follicles started to increase in rats older than 18 months, which corresponded to the cessation of estrous cyclicity. Several healthy follicles and CL were observed even in 36-month-old rats.     

Methionine restriction effects on 11 -HSD1 activity and lipogenic/lipolytic balance in F344 rat adipose tissue

Methionine restriction (MR) limits age-related adiposity in Fischer 344 (F344) rats. To assess the mechanism of adiposity resistance, the effect of MR on adipose tissue (AT) 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) was examined. MR induced 11beta-HSD1 activity in all ATs, correlating with increased tissue corticosterone. However, an inverse relationship between 11beta-HSD1 activity and adipocyte size was observed. Because dietary restriction controls lipogenic and lipolytic rates, MR's effects on lipogenic and lipolytic enzymes were evaluated. MR increased adipose triglyceride lipase and acetyl-coenzyme A carboxylase (ACC) protein levels but induced ACC phosphorylation at serine residues that render the enzyme inactive, suggesting alterations of basal lipolysis and lipogenesis. In contrast, no changes in basal or phosphorylated hormone-sensitive lipase levels were observed. ACC-phosphorylated sites were specific for AMP-activated protein kinase (AMPK); therefore, AMPK activation was evaluated. Significant differences in AMPKalpha protein, phosphorylation, and activity levels were observed only in retroperitoneal fat from MR rats. No differences in protein kinase A phosphorylation and intracellular cAMP levels were detected. In vitro studies revealed increased lipid degradation and a trend toward increased lipid synthesis, suggesting the presence of a futile cycle. In conclusion, MR disrupts the lipogenic/lipolytic balance, contributing importantly to adiposity resistance in F344 rats.     

Modulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in F344 rats by di(2-ethylhexyl)phthalate

The effects of cotreatment with a hyperlipidemic chemical, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and a hypolipidemic agent, di(2-ethylhexyl)-phthalate (DEHP), on lipid metabolism and toxicologic responses were studied in F344 rats. Treatment with TCDD alone (160 micrograms/kg) caused an increase in serum triglycerides and cholesterol while treatment with DEHP alone (2 g/kg/day) caused a decrease in triglycerides and cholesterol versus untreated controls. When administered before or after TCDD, DEHP caused a decrease in TCDD-induced hyperlipidemia. This change was attributed to enhanced hepatic peroxisomal beta-oxidation and decreased hepatic lipid synthesis resulting from treatment with DEHP. TCDD treatment produced a fatty liver, as determined by gravimetric analysis of extracted lipid and microscopic examination of liver sections which revealed extensive cytoplasmic vacuolization that stained positive with Oil Red 0, but did not induce peroxisomal beta-oxidation. Thus, an increase in hepatic or serum lipid levels is not sufficient for induction of peroxisome proliferation. Neither TCDD nor DEHP treatment affected mitochondrial beta-oxidation. Pretreatment of rats with DEHP, followed by daily exposure to this hypolipidemic agent after treatment with TCDD, had a partial protective effect against TCDD-induced fatty liver, body weight loss and mortality. Microscopic examination of liver sections confirmed the suppression of TCDD-induced fatty liver by pretreatment with DEHP. When DEHP treatment was initiated after the TCDD dose, there was less protection against the above parameters of TCDD toxicity. This study demonstrates that TCDD-induced fatty liver, hyperlipidemia and mortality can be antagonized by treatment with a hypolipidemic agent such as DEHP.     

Reversible ischemic inhibition of F(1)F(0)-ATPase in rat and human myocardium

The physiological role of F(1)F(0)-ATPase inhibition in ischemia may be to retard ATP depletion although views of the significance of IF(1) are at variance. We corroborate here a method for measuring the ex vivo activity of F(1)F(0)-ATPase in perfused rat heart and show that observation of ischemic F(1)F(0)-ATPase inhibition in rat heart is critically dependent on the sample preparation and assay conditions, and that the methods can be applied to assay the ischemic and reperfused human heart during coronary by-pass surgery. A 5-min period of ischemia inhibited F(1)F(0)-ATPase by 20% in both rat and human myocardium. After a 15-min reperfusion a subsequent 5-min period of ischemia doubled the inhibition in the rat heart but this potentiation was lost after 120 min of reperfusion. Experiments with isolated rat heart mitochondria showed that ATP hydrolysis is required for effective inhibition by uncoupling. The concentration of oligomycin for 50% inhibition (I(50)) for oxygen consumption was five times higher than its I(50) for F(1)F(0)-ATPase. Because of the different control strengths of F(1)F(0)-ATPase in oxidative phosphorylation and ATP hydrolysis an inhibition of the F(1)F(0)-ATPase activity in ischemia with the resultant ATP-sparing has an advantage even in an ischemia/reperfusion situation.     

Sex and dietary fat modulate hepatic prostaglandin F2 alpha in F344/N rats.

The study was designed to determine whether sex and fat calories altered hepatic prostaglandin (PG) F2 alpha status; a factor which may reflect susceptibility to cancer development. For 4 weeks, groups of 8 male and 8 female F344/N rats were fed diets with 9% of energy (en%) from linoleate and 15.5, 20, 30 or 40 en% fat. Females had greater hepatic stearate, arachidonate and PGF2 alpha whereas males had greater hepatic myristate, palmitate and oleate. Females also had greater plasma stearate levels. Greater hepatic arachidonate may have stimulated PG production in females. Hepatic oleate increased and hepatic palmitate decreased with increasing en% fat (p < 0.05). Hepatic stearate was greater and hepatic linoleate less when 40 en% fat was fed compared with other levels of dietary fat (p < 0.05). Plasma oleate was greater at 30 or 40 en% fat than at lower levels of fat, whereas plasma linoleate was less at 40 en% than at 15.5% en% fat. The ability of a 30 en% fat diet, containing equal proportions of linoleate and oleate, to suppress hepatic PG production may be related to the effects of dietary fat content and composition on plasma fatty acid profiles. Because suppressed PG production has been linked with suppression of cancer development, dietary recommendations to consume 30 en% fat with a P:M ratio of 1:1 may be cancer-protective.