Female Fischer-344 Research Articles

Effects of aging and long-term caloric restriction on hepatic microsomal monooxygenases in female fischer 344 rats: Alterations in basal cytochrome P-450 catalytic activities

The effects of aging and caloric restriction on uninduced levels of hepatic microsomal cytochrome P-450s and specific P-450-related catalytic activities were evaluated in female Fischer 344 rats. Microsomes were isolated from livers of ad libitum (AL) fed rats 1, 3, 6, 16 and 26 months of age, and from calorie-restricted (CR) rats 6, 16 and 26 months of age. The recovery of microsomal protein was higher in CR than AL rats at 6, 16 and 26 months of age. Between ages 3 and 26 months there was a gradual decline in recovered microsomal P-450, but the differences between successive age categories were not significant. A different trend was observed for total cytochrome P-450 per liver. AL rats showed a 2-fold decline in P-450/liver between 6 and 26 months of age, while P-450/liver of corresponding CR rats increased 1.7-fold. Neither cytochrome b5 nor NADPH cytochrome C reductase varied consistently as a function of increased age, with all age groups showing greater reductase activity for CR rats than for AL rats. Phenobarbital (PB) and methylcholenthrene (MC) inducible cytochrome P-450 catalytic activities (pentoxy [PROD] and ethoxy [EROD] resorufin O-deethylases) exhibited similar age-related alterations that were distinctly different from the two other enzymes examined. Both PROD and EROD showed dramatic declines in activity between 1 and 3 months of age, with a slight increase in activity at 6 months and maintenance of the activity levels through 26 months. Benzphetamine N-demethylase (BND) and aniline p-hydroxylase (APH) activities were also altered as a function of increased age, with CR rats exhibiting increased isozyme activity above that seen for aging AL rats. Calorie restriction appears to have a modulating effect, compensating for an age-related decline of hepatic microsomal monooxygenase activity in female Fischer 344 rats.

Rat model of perchloroethylene-induced renal dysfunctions

To investigate whether perchloroethylene (PCE) can induce renal disturbances and to compare morphological alterations with functional data, two groups of 12 male and female Fischer-344 mature rats were treated daily with PCE (500 mg/kg body wt in corn oil, p.o.) for 4 weeks. Sex- and age-matched control groups received corn oil only. Weekly, the urinary excretion of albumin (Alb), alpha 2 mu-globulin (alpha 2 mu) and retinol-binding protein (RBP) was measured in 24-hr urine samples using immunoassays specific for rat proteins. N-acetylglucosaminidase (NAG) activity was measured by a colorimetric assay. Electrophoretic analysis of proteinuria included SDS-PAGE and isoelectric-focusing of Alb purified from serum and urine. Weekly histopathology comprised light and electron microscopy. In the male rat, a trend toward progressive albuminuria (up to 15 times the pair-fed controls) was observed, together with transient increases in alpha 2 mu and NAG; RBP showed a twofold increase at the end of treatment. Histopathology failed to demonstrate glomerular changes, whereas it displayed alpha 2 mu accumulation and mild lesions in the S2 segment of proximal tubules. Thus, in the male rat, the selective damage to S2 was associated with "glomerular" proteinuria, the alpha 2 mu cortical content being closely correlated with albuminuria (n = 9, r = 0.92, P < 0.001). In the female rat, only minor, although statistically significant (P < 0.05), increases were recorded for Alb, whereas urinary alpha 2 mu reached up to four times the control values. As a whole, these findings suggest that PCE, like other hydrocarbons, selectively affects the tubular segment S2 in the rat. A competition with alpha 2 mu for tubular uptake could explain enhanced albuminuria. Owing to the species specificity of alpha 2 mu, caution should be exercised in extrapolating these findings to man.

Difference in response of hepatic glutathione S-transferase activities to protein-free diet between young and old C57/BL male mice

Responses of hepatic glutathione S-transferase (GST) activities to protein-free diet (PFD) and normal diet (ND) refeeding were compared for young (6-month-old) and old (22-month-old) C57/BL male mice. Enzyme activities toward 1-chloro-2,4-dinitrobenzene (CDNB) were not significantly different between young and old rat livers in the basal condition without diet manipulation. When animal were fed PFD for 1 week, GST activities toward CDNB significantly declined in both age groups in comparison to respective basal values, but there was no significant difference in activities between the two age groups after a 7-day PFD. When they were refed with ND for 2 days (on day 2 of ND), the activities in young mice rose to a level significantly higher than the corresponding basal value. In contrast, in old animal livers, the activity slightly but further tended to decline on day 2 of ND. Activities in old rat livers returned to the basal level on day 5 of ND, while activities in young animal livers that increased to levels higher than basal levels due to the overshoot returned to the basal level on day 7 of ND. Enzyme activities toward 1,2-dichloro-4-nitrobenzene (DCNB) were significantly higher in young rat livers than in old ones at the basal period. However, enzyme activities also overshot the basal level on day 2 of ND after 7-day PFD in young mouse livers, while in old mouse livers the activities were lowest on this day. Activities returned to the basal level on day 7 of ND in both age groups. Thus, the greatest difference in enzyme activities between young and old mouse livers for both substrates was observed on day 2 of ND after 7-day PFD, rather than at either the basal period or immediately after 7-day PFD. The results essentially agree with our previous findings on female C57/BL mice as well as female Fischer-344 rats, suggesting that the age-induced changes in the GST system become clearly manifest after diet manipulation of PFD followed by ND refeeding, rather than in values during a basal period without diet manipulation, regardless of sex or species of animal.

Diaphragmatic fiber type specific adaptation to endurance exercise

Recent evidence suggests that exercise training results in a significant improvement in the oxidative capacity of the mammalian diaphragm; however, limited data exist concernin g which diaphragmatic fiber types are metabolically altered due to training. To test the hypothesis that exercise training increases the oxidative capacity of diaphragmatic type I and IIa fibers only, we examinedthe effects of endurance training on the fiber type specific changes in oxidative capacity, cross-sectional area, and capillarity of the costal diaphragm. Female Fischer-344 rats (agc ca 180 days) were divided into either a sedentary control group ( n = 6) or an exercise training group ( n = 6). The trained animals exercised for 10 wks on a motor-driven treadmill (60 min·day −1; days·wk −1) at a work rate equal to ca 55–65%s% V̇ o 2max . Capillaries were identified histologically and fiber types determined using ATPase histochemistry. Fiber cross-sectional area (CSA) and succinate dehydrogenase (SDH) activity in individual fibers were measured using a computerized image analysis system. Compared to control animals, training did not increase the capillary to fiber ratio in any diaphragm fiber typc ( P > 0.05); however, training increased capillary density (capillary No. /CSA) in type lla fibers due to a reduction in cell CSA ifP > 0.05. Further, training resulted in significant ifp > 0.05 1 increases in total diaphragmatic SDH activity ( Δ increase = 17.5%) and an increase in SDH activity in both type I (Δ increase = 14%) and lla fibers ( Δ increase = 17.4%). In contrast, training did not alter ( P > 0.05) SDH activity in type llb fibers. These data support the hypothesis that endurance training results in significant improvements in the oxidative capacity of type I and lla fibers in the costal diaphragm of rodents. However, the increase in relative SDH activity and capillary density in type lla fibers is achieved primarily via a reduction in fiber CSA.

Exercise training-induced alterations in skeletal muscle oxidative and antioxidant enzyme activity in senescent rats.

Limited data exist concerning exercise training-induced alterations in skeletal muscle oxidative and antioxidant enzyme activity in senescent animals. Therefore, the purpose of this study was twofold: 1) to examine the exercise training-induced changes in oxidative and antioxidant enzyme activity in skeletal muscle of old rats; and 2) to critically analyze the relationship between oxidative and antioxidant enzyme activities in skeletal muscle in both trained and untrained senescent rats. Female Fischer-344 rats (approximately 24-mo-old) were divided into 1) exercised trained (ET; n = 10) and 2) sedentary (S; n = 6) groups. The ET rats performed a 10-week training program of treadmill exercise (approximately 60 min, 5 days/wk). Training significantly (p less than 0.05) improved VO2max (delta 22.8%) in the ET rats above their age-matched controls. Further, the ET group had significantly elevated (p less than 0.05) activities of succinate dehydrogenase (SDH) in the soleus and red gastrocnemius (RG) muscles as well as greater (p less than 0.05) 3-hydroxyacyl-CoA dehydrogenase (HADH) activity in the RG when compared to the S group. However, training did not alter (p greater than 0.05) HADH activity within the white gastrocnemius (WG) or soleus muscles. Activity of the antioxidant enzyme, glutathione peroxidase (GPX) was higher (p less than 0.05) in the soleus and RG in ET rats when compared to the S rats; in contrast, training did not alter (p less than 0.05) GPX activity in the WG. Finally, the correlation coefficients between SDH and GPX activities (combined ET and S groups) for the RG, WG, and soleus muscles were r = .73, .17 and .36, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Feeding studies in rats with mineral hydrocarbon food grade white oils.

This investigation compared the effects of feeding rats diets containing food grade white oil processed by either conventional oleum treatment or the more modern method of catalytic hydrogenation. In two separate experiments, male or female Fischer-344 rats were given free access for 90 days to diets containing 0, 10, 100, 500, 5,000, 10,000, or 20,000 ppm of either oleum-treated white oil (OTWO) or hydrotreated white oil (HTWO). There were no mortalities and no adverse clinical signs associated with feeding either white oil. Treatment-related effects evidenced by hematological, clinical chemical, and pathological changes were generally dose-related and more marked in female than in male rats, and the OTWO caused a greater pathological response than the HTWO. Tissue residues of saturated hydrocarbons were up to 5.2 times higher in female rats than in males. Rats fed 5,000 ppm or more of either white oil showed dose-related alterations in several hematological and clinical chemistry variates associated mainly with hepatic damage or functional alteration. At necropsy, mesenteric lymph nodes were enlarged, and increases in weight of liver, kidney, and spleen were significant. Microscopic changes were characterized by multifocal lipogranulomata in mesenteric lymph node and liver. No changes were observed in rats fed OTWO or HTWO for 90 days at dietary concentrations of 10 or 100 ppm, equivalent to a minimum intake of 0.65 and 6.4 mg/kg/day, respectively. Differences in degree of pathological response associated with each oil may have been due to their differences in specification rather than processing method.

The effect of age on the biliary transport maximum ( Tm) of bile salts in rats

Age-related differences in the biliary transport maxima ( T m) values for taurocholate (TC) and tauroursodeoxycholate (TUDC) were examined in female Fischer-344 rats as well as Wistar-derived rats of both sexes. The T m values for TUDC were more than two times higher than corresponding values for TC in young (3-month-old) rats of both sexes. T m values for both bile salts tended to decline with age, demonstrating a significant negative correlation between the T m (μmol/min per g liver) and rat age (months) for all rat groups. The decline in T m value was, however, dominant in the first year with little significant change after 1 year. The results in the present study coupled with our previous observations for T m values of sulfobromophthalein (BSP) and conjugated BSP support our hypothesis that the transport capacity for bile canalicular membrane generally declines with age in rats.

Influence of aging on rat liver enzymes involved in glutathione synthesis and degradation

The purpose of this study was to determine the effects of aging on the activities of rat liver enzymes involved in the synthesis and degradation of glutathione, as well as those important for maintaining glutathione in its reduced form. γ-Glutamylcysteine synthetase, γ-glutamyltransferase, glutathione reductase, and glucose-6-phosphate dehydrogenase activities were measured in liver fractions prepared from male and female Fischer-344 rats at the ages 4, 14, and 29 months. The activity of γ-glutamylcysteine synthetase, the rate-limiting enzyme in GSH synthesis, and overall rates of glutathione synthesis were unaffected by aging. In contrast, the activity of γ-glutamyltransferase, the key enzyme in glutathione degradation, was markedly influenced by animal age; activity increased with age in male rats and decreased with age in female rats. Age-associated alterations also were observed in activities of hepatic enzymes needed to maintain glutathione in its reduced form. Glutathione reductase activity was greater in old female rats and glucose-6-phosphate dehydrogenase activity was greater in old male rats than in young and middle-aged rats of the same sex. Age-dependent changes in glutathione metabolizing enzymes could have important toxicological implications.

Age-related alterations of enzyme activities and subunits of hepatic glutathione S-transferases in male and female Fischer-344 rats

Enzyme activities of glutathione S-transferases (GSTs) toward five different substrates (benzalacetone (PBO), styrene oxide (STOX), sulfobromophthalein (BSP), 1,2-dichloro-4-nitrobenzene (DCNB) and 1-chloro-2,4-dinitrobenzene (CDNB)) as well as concentrations of four subunits of GST isozymes (1, 2, 3 and 4) were determined using cytosol fractions obtained from livers of young (6 months )and old (26 months) Fischer-344 rats of both sexes. Values for enzyme activities for three substrates (DCNB, BSP and PBO) in young male rats were significantly higher than the corresponding values in female rats. In old male rats, values were generally lower than the corresponding values in young male rats, becoming close to corresponding values in young female rats. Old female rats, however, exhibited values close to those in young female rats, except for DCNB and STOX values, which were slightly lower in old female rats. GST subunits 3 and 4, as determined by high-performance liquid chromatography after purification by affinity chromatography using S-hexyl-glutathione, were predominant in young males, whereas concentrations of subunits 1 and 2 were higher in females than in males. In male rat livers, concentrations of subunits 3 and 4 decreased considerably with age while those of subunits 1 and 2 increased, so that the subunit pattern in old male rats tended to be similar to that of young female rats. In old females, a decrease in the concentration of subunits 3 and 4 and an increase in the concentration of subunit 1 were also observed as in old male rats, while the subunit 2 concentration tended to decline. Furthermore, the elution pattern of affinity chromatography changed with age, yielding an earlier elution of most subunits in old male rats and of subunit 1 in old female rats. The result suggest that age-related changes that occur with GSTs in livers of male rats are essentially a feminization of the isozyme pattern. However, despite rather unremarkable changes in enzyme activities with age in females, considerable changes of subunit pattern (a general decrease in concentration of subunits 2, 3 and 4 and an increase in the concentration of subunit 1) were also observed in female rats, and these were much greater than could be predicted from enzyme activity changes with age in this sex.

Facilitation of dimethylbenz[a]anthracene-induced rat mammary tumorigenesis by restraint stress: role of β-endorphin, prolactin and naltrexone

In order to investigate the involvement of opioid peptides and prolactin in stress-facilitated mammary cancer, we studied the effect of chronic restraint stress on dimethylbenz[a]-anthracene (DMBA)-induced mammary tumorigenesis and the effect of an opiate antagonist, naltrexone, on this process. Female Fischer-344 rats (n = 160) were administered 15 mg DMBA/ml of sesame oil/rat by intragastric intubation. Eighty rats were subjected to daily 30 min restraint stress in a plastic cylinder, and 80 rats served as control not subjected to the stressor. Half of the rats from each group received naltrexone (1 mg/kg, i.p. daily). Five rats from each group (restraint stress +/- naltrexone and control +/- naltrexone) were killed every 2-3 weeks. Rats subjected to restraint stress developed a greater number of tumors earlier. Naltrexone decreased the tumor incidence in the stressed animals from 32 to 12% (P less than 0.001) and in unstressed rats from 27 to 15% (P less than 0.001) at the end of 18 weeks. Stressed rats showed a decrease of 48% (P less than 0.001) in the level of hypothalamic beta-endorphin. Plasma prolactin increased from 4-13 ng/ml in the control rats to 109-396 ng/ml (P less than 0.001) in the stressed rats throughout the 18 week period. The beneficial effect of naltrexone was associated with 42% (P less than 0.01) increase in T cell proliferation, but greater than 90% (P less than 0.001) decrease in plasma prolactin level was observed in naltrexone-treated rats compared to the untreated animals. Rats subjected to restraint stress showed a 15% (P less than 0.001) decrease in weight gain at the end of the experiment (18 weeks). Neither restraint stress nor naltrexone administration affected the caloric intake of rats during this period. Thus, we believe that restraint stress facilitates DMBA-induced mammary tumors by releasing beta-endorphin and prolactin, and naltrexone shows a beneficial effect by opposing the effect of beta-endorphin on prolactin release in the stressed animals.

Resistance of female Fischer-344 rats to the hepatonecrogenic and hepatocarcinogenic actions of a choline-devoid diet

A series of experiments was performed to investigate the response of female Fischer-344 rats to a choline-devoid (CD) diet. In contrast to findings previously made in male Fischer-344 rats, hepatocellular carcinomas did not develop in females chronically fed the diet. Their liver actually showed only minimal histopathological changes. For these reasons, the steatogenic and hepatonecrogenic actions of a CD diet were compared in male and female Fischer-344 rats. Young adult females were found to be largely resistant to both. The results were taken as further evidence of the primary and essential role played by an enhanced cell turnover in the pathogenesis of the carcinomas induced in male Fischer-344 rats by this non-chemical, nutritional model of hepatocarcinogenesis. A high incidence of preneoplastic and benign lesions developed in breast, pancreas or stomach of females chronically fed the CD diet. However, a similar spectrum and high incidence of lesions was observed in control rats fed a choline-supplemented diet. These findings were attributed to an enhanced occurrence of spontaneous lesions, most likely due to the high fat content (15%) of the two diets used.

Induction of 6‐thioguanine‐resistant lymphocytes in fischer 344 rats following in vivo exposure to n‐ethyl‐n‐nitrosourea and cyclophosphamide

We have developed a limiting dilution clonal assay for determining the frequency of 6-thioguanine-resistant (TGr) lymphocytes produced in rats by in vivo exposure to genotoxic agents. Spleen lymphocytes were isolated from female Fischer 344 rats and were cultured with 1 microgram/ml of phytohemagglutinin (PHA) for 40 hr. Northern blot analysis revealed that this procedure resulted in increased hprt and beta-actin mRNA synthesis. Conditions for optimum cloning were established by culturing four PHA-primed lymphocytes/well in 96-well round-bottom microtiter plates containing a medium supplemented with interleukin-2. These cultures also contained autologous and/or TK6 feeder cells inactivated with different doses of irradiation. Lymphocyte cloning efficiencies (CEs) were highest in plates containing both irradiated TK6 cells (5 x 10(3) cells/well; 90 Gy) and irradiated autologous feeder cells (5 x 10(4) cells/well; 50 Gy). CE did not depend on the number of primed lymphocytes/well when four or fewer target cells/well were cloned. To measure the effects of chemical mutagens on the frequency of TGr lymphocytes, rats were given a single i.p. injection of 0-150 mg/kg of N-ethyl-N-nitrosourea (ENU), a direct-acting alkylating agent, or 0-50 mg/kg of cyclophosphamide (CP), an indirect acting alkylating agent. Lymphocytes were isolated, primed, and cloned at 4 weeks after CP treatment and at 1, 2, 4 and 6 weeks after ENU treatment. CE in these cultures ranged from 12% to 27%. Cultures were also established for measuring CE in the presence of 6-thioguanine (TG) and these contained 5 x 10(3) irradiated TK6 cells and 5 x 10(4) primed rat lymphocytes/well. The frequency of TGr lymphocytes was calculated by correcting the CE in the presence of TG with the CE measured in its absence. ENU exposure produced a higher frequency of TGr lymphocytes than CP, but both chemicals produced a dose-dependent increase in TGr cells. In addition, the frequency of ENU-induced TGr lymphocytes increased with time after treatment. The TGr cells are presumed to be hprt mutants, but further analysis at the DNA level is required to establish this. The dose-dependent responses obtained with both ENU and CP treatments suggest that rat lymphocytes are sensitive to direct- and indirect-acting alkylating agents administered in vivo and that the rat lymphocyte assay is a useful complement to the in vivo/in vitro mouse assay for determining the mutagenicity of environmental toxicants.

Effects of subchronic D-fenfluramine (d-FEN) on splenic and blood NK activity in young and old male and female fischer 344 rats

Effects of subchronic D-fenfluramine (d-FEN) on splenic and blood NK activity in young and old male and female fischer 344 rats

Analgesic nephropathy in fischer 344 rats: comparative effects of chronic treatment with either aspirin or paracetamol

This study has compared the relative nephrotoxicity of chronic treatment with aspirin or paracetamol in an animal model. Changes in renal structure and urinary concentrating ability were examined in female Fischer 344 rats after continuous treatment with either aspirin (120-230 mg/kg body wt/day), or paracetamol (140-210 mg/kg body wt/day), and were compared with age-matched untreated control rats. Renal morphological changes were examined after 40-83 weeks of analgesic treatment, using light and electron microscopy. Aspirin caused renal papillary necrosis and a decrease in urinary concentrating ability, whereas paracetamol alone did not cause significant renal damage. Aspirin produced damage to the interstitial cells and matrix, particularly in the mid-papillary region, followed by changes to the thin limbs of the loop of Henle and medullary capillary endothelium. These structural changes were similar to those described previously, when continuous treatment with combined aspirin and paracetamol was studied in the same animal model.

Effects of subchronic d-fenfluramine on splenic immune functions in young and old male and female fischer 344 rats

The present study was designed to demonstrate age- and sex-related differences in immune functions, and to determine whether subchronic elevations in serotonin (5-HT) availability in vivo would alter immune functions assessed subsequently in vitro. Male and female F344 rats (5 and 21 months of age) were administered the 5-HT releaser and reuptake inhibitor, d-fenfluramine ( d-Fen), in their drinking water for 30–38 days then killed. The young animals received a higher dose (1.8 mg/kg/day) of d-Fen than the old rats (0.6 mg/kg/day) in order to compensate for age-related decreases in drug biotransformation and clearance. Brain and spleen d-Fen and metabolite concentrations, however, were considerably higher in the young than in the old rats. d-Fen treatment did not affect body weight or fluid intake. Although substantial sex differences in immune function were not discerned, age-related decreases were observed in absolute splenic cellularity, recombinant interleukin-2 (rIL-2) stimulated natural killer (NK) cytotoxicity, LPS stimulated B-cell mitogenesis, and in the level of Ox19 (CD5) positive cells. d-Fen caused an increase in absolute spleen weight and a decrease in absolute splenic cellularity only in the old rats of both sexes. Spleen cells from young male and old female rats receiving d-Fen had relatively more large granular lymphocytes and enhanced baseline and rIL-2 activated killing of YAC-1 cells than their vehicle matched or opposite sex counterparts. The drug also increased Con A-induced T-cell proliferation in young males and LPS induced B-cell proliferation in old females. d-Fen decreased Ox39 (CD25) levels by 19%, but did not affect any of the other phenotypes examined. The results suggest that 5-HT has a selective stimulatory effect on young male and old female NK activity, and that old female rats are more sensitive to the immunological effects of d-Fen than old male rats.

Effect of protein-free diet on activities and subunits of glutathione S-transferase in livers of young and aged female rats

Female Fischer-344 rats of different ages (8 and 25 months old) were fed a protein-free diet (PFD) for 7 days and refed a normal diet (ND) (23% protein) thereafter. Rats were killed immediately after the PFD was stopped (day 0) and at different time intervals during refeeding of a ND. Four subunits (1,2,3 and 4) and activities of glutathione S-transferases (GSTs) toward five different substrates, [styrene oxide (STOX), 1,2-dichloro-4-nitrobenzene (DCNB), 1-chloro-2,4-dinitro benzene (CDNB), sulfobromophthalein (BSP) and benzalacetone (PBO)] were determined. There were no significant differences between young and old rats in the liver enzyme activities before the PFD. The PFD caused significant decreases in activities for three substrates (DCNB, BSP and STOX) in both age groups, with no significant differences between young and old rats at day 0. During recovery from the PFD, activities for the three substrates exceeded basal levels in young rats but at different time intervals (STOX, day 2; BSP, day 5; DCNB, day 9), while enzyme values in old rats tended to return slowly to basal values with no “overshoot.” Concentrations of subunits 3 and 4 in young rat livers that were depressed by the PFD did not recover until day 9 of the ND, while subunits 2 and especially 1 increased during the ND refeeding, overshoting the basal levels. In contrast, in old rat livers the only change was a reduction of subunit 1 by the PFD and its gradual recovery during ND refeeding. These results demonstrate that our previous observation of overshooting of enzyme activities in mice is reproducible in rats but with certain substrate specificities. Furthermore, changes in subunit concentrations caused by aging and a PFD are more complex than what was predicted from changes in enzyme activities of GSTs.

Perinatal d, 1-amphetamine exposure: Behavioral development and striatal dopamine levels in male and female fischer 344 rats

Perinatal d, 1-amphetamine exposure: Behavioral development and striatal dopamine levels in male and female fischer 344 rats

The Determination of the Repeated Oral Toxicity of Halocarbon Oil, Series 27-S

Halocarbon 27-S (HC 27-S), a polymer of chlorotrifluoroethylene (CTFE), is used as a lubricating oil for pumps in hyperbaric chambers. Although monomeric CTFE has been shown to produce renal lesions in rats, the toxicity of CTFE polymers have not been investigated. To assess the toxicity of repeated exposure to HC 27-S, three groups (N = 6/group) of male and female Fischer-344 rats were dosed with 2.5 g HC 27-S/kg for 7 or 21 consecutive days. Groups were sacrificed at 7, 21, and 35 days (14 days after the 21-day dosing). Corresponding control groups (N = 6) were dosed with deionized water. Decreased water consumption and urine output were apparent in all test groups. Statistically significant increases in fluoride excretion were noted in 24-hr urine samples assessed periodically during the study. Neurotoxic signs were observed in female rats but not in male rats. Significant increases in liver and kidney weights were seen in all rats, regardless of number of dosing days. The increased fluoride burden in treated animals appeared sufficient to alter bone calcium/phosphate ratios in male rats but not female rats. Gross liver enlargement and hepatocellular cytomegaly indicated that the liver was probably the primary target organ following repeated administration of HC 27-S.

Experimental analgesic nephropathy: changes in renal structure and urinary concentrating ability in fischer 344 rats given continuous low doses of aspirin and paracetamol

Long-term treatment with aspirin and paracetamol produced renal papillary necrosis in female Fischer 344 rats. Aspirin (230 mg/kg body weight/day) and paracetamol (380 mg/kg body weight/day) were dissolved in drinking water and given continuously for up to 65 weeks. Renal morphological changes were examined between 21 weeks and 65 weeks of commencement of analgesic treatment using light and electron microscopy, and were compared with age-matched controls. Structural damage initially occurred in the mid-papillary region, and specifically involved the interstitial cells and interstitial matrix. Necrosis of the epithelium of the thin limbs of the loop of Henle was present only after interstitial changes were well established. Cortical interstitial fibrosis and tubular atrophy occurred after renal papillary changes were observed. There was no evidence of significant vascular damage. Urinary concentrating ability was measured sequentially during the period of analgesic treatment. A decrease in urine concentrating ability was present when early changes to the interstitial cells and matrix were observed, and concentrating ability continued to decrease in parallel with increasing morphological damage. This study describes an animal model of analgesic-induced nephropathy, enabling early morphological changes to be studied and correlated with renal functional changes.

Effect of long-term caloric restriction on brain monoamines in aging male and female fischer 344 rats

The present study examines the changes in central monoamines and their metabolites in aged male and female rats after long-term caloric restriction. Fischer 344 rats of both sexes ( n = 5–10/ group) were maintained on one of two dietary regimens: ad libitum NIH 31 diet or 60% by weight of the ad lib. intake (restricted), supplemented with vitamins and minerals. Animals received these diets from the age of 14 weeks until killed at 22.25 months of age. Caudate nucleus (CN), hypothalamus (HYPO), olfactory bulb (OB) and nucleus accumbens (NA) were assayed for content of norepinephrine (NE), dopamine (DA) and its metabolites (dihydroxyphenylacetic acid, DOPAC, and homovanillic acid, HVA) and serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) using HPLC/EC. Relative to the ad lib, group, restricted rats of both sex showed significant decreases in NE content in CN, HYPO and OB. DA and 5-HT content were decreased significantly in the CN and HYPO. No significant changes were found in the levels of DA metabolites in all brain regions studies. While the 5-HIAA level was significantly reduced in the HYPO and NA of the female restricted rats, it was increased several-fold in the OB of the male restricted animals. These preliminary results suggest that long-term caloric restriction alters brain monoamine concentrations, an effect which may in turn modify the normal rate of aging.