Effects of homozygosity of the nude (rnu) gene in an inbred strain of rats: studies of lymphoid and non--lymphoid organs in different age groups of nude rats of LEW background at a stage in the gene transfer

Several age groups of nude homozygous rnu/rnu and heterozygous rnu/+ rats of the same genetic background at an early stage of back-crossing (LEW/Mol) were compared as to body and organ weights, histological appearance and cell density of lymphoid organs, haematological values and differential counts of bone marrow and peripheral blood. No thymic tissue was found in the nude animals. 7-week-old nudes were smaller than control animals and had relatively larger non-lymphoid organs and cell-depleted peripheral lymphoid organs. Other age groups showed little difference. Peripheral blood of nude rats showed no signs of lymphopaenia in contrast with the findings in nude mice. The number of thoracic duct lymphocytes was, however, significantly smaller in all age groups of the nude rats, and the bone marrow tended to contain fewer lymphocytes.     

Effects of four-week feed restriction on toxicological parameters in beagle dogs

This study was conducted to examine any changes caused by feed restriction in dogs to contribute to safety evaluation in toxicity studies. Two male 7-month-old beagle dogs/group were fed 300 (control), 150 (50% of control), or 70 g/animal of diet daily (23% of control) for 4 weeks. Effects of feed restriction, except for clinical signs, were noted depending on the feed dosage in almost all examinations. The principal outcomes were: decreased body weight and water consumption, ECG changes (decreased heart rate and prolonged QTc), and hematopoietic and lymphopoietic suppression (decreased reticulocyte ratio or white blood cell count in hematology, decreased nucleated cell count in bone marrow, decreased erythroid parameters in myelography, and hypocellularity of bone marrow and thymic atrophy in histopathology). In addition, some changes were noted in urinalysis (decreased urine volume and sodium and potassium excretion), blood chemistry (decreased ALP and inorganic phosphorus and increased creatinine), organ weights, and gastric histopathology. These results provide important reference data for distinguishing the primary effects of test compounds from secondary effects of decreased food consumption in toxicity studies in beagle dogs.     

封闭群五指山小型猪主要脏器重量与体重的相关性分析

目的测定封闭群五指山小型猪主要脏器重量和脏器系数,对脏器重量与体重的相关性进行分析,并计算出相应的直线回归方程和多元回归方程。方法实验选用6-10月龄普通级封闭群五指山小型猪30头（其中♂16头、♀14头）,分别测定体重和7个主要脏器重量,计算脏器系数,通过SAS软件进行脏器系数的性别间比较和各脏器重与体重间的相关与回归分析。结果性别间比较,小型猪仅有心脏的脏器系数差异有显著性（P〈0.05）。除公猪的胃脏和母猪的肺脏外,所测脏器重量与体重间均有明显的正相关线性关系;多因素分析显示公猪的肝脏和肾脏,母猪的心脏、肝脏和肾脏对各自体重有影响。结论封闭群五指山小型猪主要脏器系数性别间差异较小,其体重与某些脏器重量存在一定的线性关系。     

Effect of feed restriction on Hershberger and pubertal male assay endpoints

BACKGROUND: The Hershberger and male pubertal onset assays have been identified as possible Tier I screening tests to detect endocrine‐active compounds (EACs). Both tests rely on changes in reproductive and/or accessory sex gland (ASG) weights in young animals. Because chemical treatment may affect growth rate, the relationship between body weight and reproductive/ASG weights was examined using feed restriction (FR) to produce a targeted 10% decrease in body weight. METHODS: In the male pubertal onset assay, 23‐day‐old rats (12/group) were given ad lib feed or FR until euthanized at 45, 49, 52, 56, or 59 days of age. Despite a 10% body weight differential, pubertal onset was not significantly delayed and testes weights were conserved. Absolute prostate, ventral prostate, seminal vesicle, epididymides, and liver weights were decreased by FR. Relative weights for the prostate, ventral prostate, and seminal vesicles were similar to controls, but relative epididymides and liver weights still exhibited FR‐mediated changes. In the Hershberger assay, male rats (12/group) castrated at 36 days of age were given ad lib feed or FR in the presence or absence of testosterone propionate (T) from 46–55, 50–59, or 56–65 days of age. At 56, 60, and 66 days of age, rats were euthanized. In untreated animals, FR did not alter absolute ventral prostate, seminal vesicles, or Cowper's gland weights; however, absolute and relative weights of the levator ani‐bulbocavernosus muscles (LABC) were affected. In T‐treated animals, absolute organ weights (the ventral prostate, seminal vesicles, LABC, and glans penis) were relatively insensitive to FR. The weight of the Cowper's gland was affected only at 66 days of age. RESULTS: These data show that reproductive and ASG organ weight endpoints in the Hershberger and male pubertal onset assays can be influenced by FR levels that produce a 10% change in terminal body weight. CONCLUSIONS: The establishment of objective criteria for a positive or negative result is problematic due to the confounding effects of body weight on some endpoints. Furthermore, a 10% decrease in body weight seems to be excessive as a requirement for high‐dose toxicity in these assays due to possible indictment of agents that are not EACs, as well as potential masking of EAC effects coincident with body weight changes. Minimally, caution must be used in interpreting assay results in the presence of a 10% body weight change, recognizing the possible confounding effects of this degree of growth suppression. Birth Defects Res B 68:363–374, 2003. © 2003 Wiley‐Liss, Inc.     

The effects of feed restriction during organogenesis on embryo-fetal development in the rat

BACKGROUND: Given the role of nutrition and body weight gain in normal development, pharmaceuticals intended to reduce appetite and promote weight loss will generate safety data that may be challenging to interpret. To aid with this, the effects of feed restriction and subsequent body weight reductions on embryo-fetal development were investigated in the rat. METHODS: Groups of 20 timed pregnant female Sprague-Dawley rats were offered Certified Rodent Diet 5002 either ad libitum or in restricted amounts of 20, 15, 10, and 7.5 g/day from Gestation Day (GD) 6-17. Clinical signs, body weights, and food consumption were recorded. Cesarean sections were performed on GD 21 and fetuses were sexed, weighed, and examined for external, visceral, and skeletal development. RESULTS: Mean maternal body weights at the end of the feed restriction period, GD 18, were reduced 0.87 x, 0.80 x, 0.69 x, and 0.63 x control mean in the 20, 15, 10, and 7.5 g/day groups, respectively. Mean body weight gains for the restriction period inclusive, GD 6-18, were 0.49 x and 0.24 x control at 10 and 7.5 g/day, respectively, and a mean body weight loss occurred at 10 and 7.5 g/day (0.95 x and 0.85 x mean GD 6 body weight, respectively). Fetal body weights were reduced 0.95 x, 0.93 x, 0.90 x, and 0.76 x control at 20, 15, 10, and 7.5 g/day, respectively. This resulted in a reduction in gravid uterine weight at 10 and 7.5 g/day. There were no external, visceral, or skeletal malformations attributed to feed restriction. There was an increase in the skeletal variation of wavy ribs and a decrease in ossification at 7.5 g/day. CONCLUSIONS: These data demonstrate that feed restriction-induced reductions in maternal gestational body weight gain of approximately 50% compared to ab lib fed rats only caused a reduction in fetal body weight. Even up to a 15% maternal gestational body weight loss had no effect on embryo viability in rats, but retarded fetal growth significantly enough to induce minor changes in skeletal development. There were no external, visceral, or skeletal malformations associated with any of the levels of maternal body weight reduction or loss.     

Response of animals to dietary gramine. II. effects of feeding high‐gramine yellow lupin seeds on reproductive performance of rats and on selected hematological and biochemical parameters in offspring

Two groups of 26 male and 26 female rats at the initial age 30 ± 2 days were fed during 31 weeks on diets containing 20 percent of yellow lupin seeds having low (LG) or high (HG) gramine content. The animals were mated twice within nutritional groups, 1 male: 1 female, and their main reproductive parameters were recorded. In both reproductive cycles body weight of females at mating, after parturition and after 21‐days lactation was lower in HG than in LG group. Fertility rate and body weight of neonates were not affected by the diet while number of neonates per litter tended to be lower by 0.7 and 0.8 pups in HG than in LG group. Body weight of weaners was also substantially smaller in dams fed on HG than LG diet. Relative weight of spleen but not of liver, kidney and heart was significantly greater in HG females. Four weeks old males and females issued from the first litters born to LG and HG animals (ten males and ten females per treatment) were fed individually on respective diets during 3 weeks. Feed intake and growth rate did not differ between the treatments. In males relative weight of liver and testicles was greater, while hematocrit and red blood count were lower in HG than in LG group. In females organ weights did not differ. Activity of liver enzymes determined in males was not affected by the diet. It may be concluded that high‐gramine lupin affects negatively lactational performance, probably via lower feed intake, but it does not induce apparent teratogenic effects in the progeny.     

Relationship of food intake to the induction of plasma sex steroid-binding protein and testicular activity in immature male little brown bats (Myotis lucifugus lucifugus)

Immature male little brown bats were aroused prematurely from their first hibernation and fed ad libitum (Group AL) or given a restricted diet (Group FR). All animals were weighed daily and the food intake of Group FR males was restricted to maintain their body weights at or near initial post-arousal values (5.3-6.8 g). The average body weights of Group AL males increased during the first week after arousal and then stabilized at a level which was 20% higher than those of Group FR males. The post-arousal induction of plasma SBP was similar in Groups FR and AL: plasma SBP activity was significantly increased 1 week after arousal and by 3 weeks had reached levels which were more than 10-fold higher than those of immature hibernating males which served as controls. Although food restriction had no effect on plasma SBP levels, it did inhibit reproductive development. Arousal-induced increases in testicular and epididymal (head/body) weights in Group FR males were less than 50% of those in Group AL males. However, histological examination of the testes revealed similar degrees of spermatogenic activation in both groups. Plasma testosterone concentrations were increased markedly in Groups FR and AL; values were generally lower in Group FR but wide individual variations were observed. Despite these elevated peripheral testosterone values, the accessory sex glands in both groups remained unstimulated.     

Sex-related differences in energy balance in response to caloric restriction

Sex-related differences in energy balance were studied in young Wistar rats fed standard chow pellets either ad libitum or in restricted amounts (60% of ad libitum intake) for 100 days. Caloric intake, indirect calorimetry, organ and adipose tissue weights, energy efficiency, liver mitochondrial respiration rate, and brown adipose tissue (BAT) uncoupling protein-1 (UCP1) content were measured. Ad libitum-fed females showed greater oxygen consumption (Vo(2)) and carbon dioxide production (Vco(2)) and lower energy efficiency than males. Caloric restriction induced a chronic drop of Vo(2) and Vco(2) in females but not in males over the period studied. Restricted females showed a better conservation of metabolic active organ mass and a greater decrease in adipose depots than restricted males. Moreover, changes of BAT size and UCP1 content suggest that BAT may be the main cause responsible for sex differences in the response of energy balance to caloric restriction. In conclusion, our results indicate that females under caloric restriction conditions deactivate facultative thermogenesis to a greater degree than males. This ability may have obvious advantages for female survival and therefore the survival of the species when food is limiting.     

Sibutramine alters the central mechanisms regulating the defended body weight in diet-induced obese rats

Chronic administration of sibutramine lowers body weight, presumably by altering brain monoamine metabolism. Here the effect of sibutramine on sympathoadrenal function (24-h urine norepinephrine and epinephrine levels) and arcuate nucleus (ARC) neuropeptide Y (NPY) and proopiomelanocortin (POMC) expression was assessed in diet-induced obese rats fed a low-fat diet. Chronic (10 wk) sibutramine [5 mg. kg(-1). day(-1) ip; rats fed ad libitum and injected with sibutramine (AS)] lowered body weight by 15% but only transiently (3-4 wk) reduced intake compared with vehicle-treated controls [rats fed chow ad libitum and injected with vehicle daily (AV)]. Other rats food restricted (RS) to 90% of the weight of AS rats and then given sibutramine restored their body weights to the level of AS rats when allowed libitum food intake. After reequilibration, RS rats were again energy restricted to reduce their weight to 90% of AS rats, and additional vehicle-treated rats (RV) were restricted to keep their body weights at the level of AS rats for 3 wk more. Terminally, total adipose depot weights and leptin levels paralleled body weights (AV > AS = RV > RS), although AS rats had heavier abdominal and lighter peripheral depots than RV rats of comparable body weights. Sibutramine treatment increased sympathetic activity, attenuated the increased ARC NPY, and decreased POMC mRNA levels induced by energy restriction in RV rats. Thus sibutramine lowered the defended body weight in association with compensatory changes in those central pathways involved in energy homeostasis.     

Gender-dependent differences in serum profiles of insulin and leptin in caloric restricted rats

In the present study, we have investigated whether differences between male and female rats described in response to 40% caloric restriction (CR) were influenced by circulating level variations of sex hormones and/or insulin and leptin. Body weights (BW), organ weights, and adipose depot weights (ADW) were also measured. The most affected tissues by CR were the fat depots. Metabolically active organs were the least affected, especially more in females than in males (male weight lost: 24.3% vs. female: 17.3%). Testosterone and estradiol circulating levels did not show changes by CR. Insulin levels were decreased by CR in both genders, but was more evident in female rats than males. Leptin serum levels were higher in male rats than in females, and CR caused a circulating leptin level reduction only in males. In conclusion, our results indicate that leptin and insulin could be one of the keys of the different hormonal control of energy homeostasis in response to CR between female and male rats. In this sense, leptin serum levels correlated statistically with BW and with individual ADW only in male rats, whereas insulin serum levels correlated statistically with BW and with any of the ADW studied only in females.     

Quantitative studies of lymphoid organs, blood and lymph in inbred athymic and euthymic LEW rats under germfree and specified-pathogen-free conditions

Four groups of inbred male LEW rats were examined: A, germfree athymic; B, specified pathogen free (SPF) athymic; C, germfree euthymic; D, SPF euthymic. All animals were killed at 18 weeks and compared with respect to body weight, histological appearance and cell density of the lymphoid organs, haematological values and differential counts of bone marrow, peripheral blood and lymph. Athymic rats had a lower body weight, less densely populated lymphoid organs, and fewer lymphocytes in the blood and lymph compared with euthymic animals. No difference was seen between athymic rats under germfree and SPF conditions, and in general the differences between athymic and euthymic animals were less pronounced under germfree conditions.     

Programmed metabolic syndrome: prenatal undernutrition and postweaning overnutrition

Maternal nutrient restriction results in intrauterine growth restriction (IUGR) newborns that develop obesity despite normal postweaning diet. The epidemic of metabolic syndrome is attributed to programmed "thrifty phenotype" and exposure to Western diets. We hypothesized that programmed IUGR newborns would demonstrate greater susceptibility to obesity and metabolic abnormalities in response to high-fat diet. From day 10 to term gestation and lactation, control pregnant rats received ad libitum (AdLib) food, whereas study rats were 50% food restricted (FR). Cross-fostering techniques resulted in three offspring groups: control (AdLib/AdLib), FR during pregnancy (FR/AdLib), and FR during lactation (AdLib/FR). At 3 weeks, offspring were weaned to laboratory chow or high-fat calorie diet (9% vs. 17% calorie as fat). Body composition, appetite hormones, and glucose and lipid profiles were determined in 9-mo-old male and female offspring. High-fat diet had no effect on body weight of AdLib/AdLib, but significantly increased weights of FR/AdLib and AdLib/FR offspring. High-fat diet significantly increased body fat, reduced lean body mass, and accentuated plasma leptin but not ghrelin levels in both sexes in all groups. In males, high-fat diet caused a significant increase in glucose levels in all three groups with increased insulin levels in AdLib/AdLib and AdLib/FR, but not in FR/AdLib. In females, high-fat diet had no effect on glucose but significantly increased basal insulin among all three groups. High-fat diet caused hypertriglyceridemia in all three groups although only food-restricted females exhibited hypercholesterolemia. Sex and offspring phenotype-associated effects of high-fat diet indicate differing pathophysiologic mechanisms that require specific therapeutic approaches.     

Effect of diet on condition indices in black-tailed jackrabbits

Changes in blood, urine and physical condition indices in 23 adult male black-tailed jackrabbits (Lepus californicus) with ad libitum feeding and 25% feed restriction were measured over a 2 wk period from 30 May to 12 June 1988. Feed restricted jackrabbits had (1) lower post-trial body weights and kidney fat indices, (2) higher femur marrow fat, serum bilirubin and cortisol concentrations, and adrenal cortex width, and (3) depressed immune function. No single index alone could best measure the nutritional status of these jackrabbits.     

Organ weights and organ:body weight ratios of the African white-tailed rat (Mystromys albicaudatus).

Fifty-three adult female and 51 adult male white-tailed rats (Mystromys albicaudatus) were killed with ether and weighed; the spleen, kidneys, liver, heart, lung, pancreas, brain and gonads were dissected free of adhering tissue and weighted. The mean absolute organ weight and organ:body weight ratios by sex and organ were calculated and compared. The male rats were significantly (p less than or equal to 0.05) heavier. The mean weight of the males was 110.0 +/- 23.8 g versus 82.9 +/- 16.1 g for the females. The absolute weights of the heart, liver and kidneys were significantly (p less than or equal to 0.05) greater for the males. The organ:body weight ratios, except for heart and brain (excluding ovary and testicle), were unaffected by sex. The heart to body weight ratio and the brain to body weight ratio were significantly (p less than or equal to 0.05) larger in female rats.     

Physiological profile of juvenile rats: effects of cage size and cage density

Although there is a general consensus that housing conditions affect the well-being of laboratory animals, the ideal cage size and density for housing laboratory rodents has not been established. The authors investigated the effects of cage size and cage density on growth, organ development, metabolic profile, and hemogram in juvenile Sprague-Dawley rats. Larger cages and increased cage density were associated with depressions in body weight and in the weights of several organs. In general, increasing group size and density correlated more strongly with detrimental effects on the growth of females than males, although hemogram values indicated that males are more prone to emotional stress and immune suppression than females in response to increasing group size and crowding.     

The micronucleus test in rat erythrocytes from bone marrow, spleen and peripheral blood: the response to low doses of ionizing radiation, cyclophosphamide and vincristine determined by flow cytometry

The frequency of micronucleated polychromatic erythrocytes (fMPCE) was determined in samples from bone marrow, spleen and peripheral blood of rats exposed to low doses of X-rays, cyclophosphamide or vincristine. The fMPCE values were lower in the peripheral blood than in bone marrow or spleen. This is due to the elimination of MPCE from the circulating blood, which was confirmed by the results from prolonged exposure of rats to gamma-radiation. When the analysis was restricted to the youngest PCE in peripheral blood, the sensitivity of the assay was considerably improved. This can be reproducibly achieved with the flow cytometric analysis.     

A subchronic toxicity study of elemental Nano-Se in Sprague-Dawley rats

The subchronic toxicity of Nano-Se was compared with selenite and high-selenium protein in rats. Groups of Sprague-Dawley rats (12 males and 12 females per group) were fed diets containing Nano-Se, selenite and high-selenium protein at concentrations of 0, 2, 3, 4 and 5 ppm Se, respectively, for 13 weeks. Clinical observations were made and body weight and food consumption were recorded weekly. At the end of the study, the rats were subjected to a full necropsy, blood samples were collected for hematology and clinical chemistry determination. Histopathological examination was performed on selected tissues. At the two higher doses (4 and 5 ppm Se), significant abnormal changes were found in body weight, hematology, clinical chemistry, relative organ weights and histopathology parameters. However, the toxicity was more pronounced in the selenite and high-selenium protein groups than the Nano-Se group. At the dose of 3 ppm Se, significant growth inhibition and degeneration of liver cells were found in the selenite and high-selenium protein groups. No changes attributable to administration of Nano-Se at the dose of 3 ppm Se were found. Taken together, the no-observed-adverse-effect level (NOAEL) of Nano-Se in male and female rats was considered to be 3 ppm Se, equivalent to 0.22 mg/kg bw/day for males and 0.33 mg/kg bw/day for females. On the other hand, the NOAELs of selenite and high-selenium protein in males and females were considered to be 2 ppm Se, equivalent to 0.14 mg/kg bw/day for males and 0.20 mg/kg bw/day for females. In addition, studies have shown that Nano-Se has a similar bioavailability in rat, and much less acute toxicity in mice compared with selenite. In conclusion, Nano-Se is less toxic than selenite and high-selenium protein in the 13-week rat study.     

Effects of dietary fat content on adiposity during energy restriction in genetically obese rats.

The effects of the amount of fat provided in a restricted diet on weight loss and body composition were studied in this work. Lean male (Fa/?) Zucker rats were fed a control diet ad libitum. Obese (fa/fa) Zucker rats were divided into three groups: one group was fed a control diet ad libitum and the other two groups were fed 75% energy-restricted diets, which provided 10 or 50% of calories as fat. After 4 weeks, energy restriction normalized body weight but not body composition in the genetically obese rats. Reductions in adipose tissue weights and adipocyte size, without changes in the cellularity, were observed. Differences only reached statistical significance in subcutaneous adipose tissue. A standard fat content in the diet induced the same fat-free mass reduction as a higher amount of this macronutrient, but a greater body fat reduction. This suggests that the restriction of dietary fat, as well as energy, is necessary to achieve dietary management in obesity.     

Some aspects of haematology of an Indian grass snake Natrix stolata in relation to sex and size.

Studies have been made on the erythrocyte counts per mm3 of blood, total differential leucocyte counts per mm3 of blood, concentration of haemoglobin per 100 ml of blood, haematocrit values and nucleocytoplasmic ratio in a common Indian grass snake, Natrix stolata, in relation to body weight of both the sexes in the same month of the year (during breeding phase). Logarithmic transformations have been used in case of erythrocyte counts and haemoglobin concentrations. From log/log calculation it seems that the correlation between body weight and erythrocyte is more prounounced in females than in males. The concentration of haemoglobin shows a very high degree of correlation in both the sexes. The haematocrit values show a clear trend of increase with increasing body weight in both the sexes. The nucleocytoplasmic ratio does not show much variation in different weight groups whereas in females the variation is well marked in different weight groups and the size of erythrocyte also becomes larger in higher weight groups. In both the sexes the leucocyte counts have been found that along with the increase in body weights, the number of leucocyte increases in juveniles but in adults the leucocyte number decreases with the increasing body weights.     

Effect of deoxynivalenol (vomitoxin) on fertility, pregnancy, and postnatal development of Sprague-Dawley rats

A diet containing 20 ppm (micrograms/g) of purified deoxynivalenol (DON) was fed to male and female Sprague-Dawley rats for 60 and 15 days, respectively, before breeding. Rats consuming feed amended with DON throughout pregnancy and lactation showed no clinical signs of toxicity, nor did the control or pair-fed control groups. Male rats in the DON treatment group showed no feed refusal but were less efficient than males in control groups in converting feed into body mass. Feed refusal in female rats varied with stage of pregnancy. Before breeding, overall feed consumption was similar in all groups, but in the DON treatment group there was significant feed refusal for the first 2 days. Feed conversion efficiency was reduced in the DON treatment group. Pregnant and lactating rats fed DON-treated feed ate 6% less than did control rats fed solvent-treated feed. Although pair-fed control rats ate 14 to 21% less than rats in the DON treatment group, their body weights were greater than those of the DON group rats throughout most of the feeding trials, indicating that DON has a toxic effect. Only 50% of the matings between DON group rats resulted in pregnancy, compared with 80% in the control groups. There were no differences detected among groups in ratio of male to female pups, survival rate, or average litter number and weight. Pup weight gains in all groups were comparable through postnatal day 14.(ABSTRACT TRUNCATED AT 250 WORDS)