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Loosli et al. Furthermore, many lipids provide sufficient EFA when included in the diet at these concentrations. Reeves et al. This amounts to approximately 3 percent soybean oil in the diet. However, to reach the plateau for maximal concentrations of these fatty acids in many tissues of growing rats, an amount of fat equivalent to percent soybean oil was required. Lee et al. Soybean oil is a source of dietary fat that may meet these criteria. The oil contains about 14 percent saturated fatty acids, 23 percent monounsaturated fatty acids, 51 percent linoleic acid, and 7 percent linolenic acid.

This gives a nn-3 ratio of seven, and a P:S ratio of approximately four. The fatty acid composition of commercial lipid sources must be monitored because of the widespread practice of hydrogenation and the emergence of new cultivars with different fatty acid compositions. Although no definite carbohydrate requirement has been established, rats perform best with glucose or glucose precursors such as other sugars, glycerol, glucogenic amino acids in their diets.

Diets containing 90 percent of dietary ME from fatty acids and 10 percent from protein were unable to support growth of young male rats. The substitution of neutral fats soybean oil for fatty acids or the addition of glycerol equivalent to that in the triglyceride allowed growth but not at rates equivalent to that achieved.

When carbohydrate-free diets containing 80 percent of dietary ME from fatty acids and 20 percent from protein were fed, rats were capable of weight gain, but growth increased when the diet was supplemented with glucose or neutral fats Goldberg, ; Akrabawi and Salji, Rats fed low-protein 10 percent of dietary ME , carbohydrate-free diets were hypoglycemic and demonstrated abnormal glucose tolerance curves Konijn et al.

When neutral fats replaced fatty acids in carbohydrate-free diets 20 percent of dietary ME from protein , growth did not improve when rats were allowed to eat ad libitum but was greater with diets containing the neutral fats when rats were meal-fed once daily Akrabawi and Salji, Over wide ranges of dietary fat:carbohydrate ratios 0.

A large number of carbohydrates can be used by the rat. Those most commonly used in rat diets include glucose, fructose, sucrose, starch, dextrins, and maltose. See "Fiber" section for a discussion of fiber sources. These carbohydrate sources support similar rates of growth; however, in diets adequate in other respects, fructose and sucrose as a source of fructose can lead to several abnormalities when compared to glucose or glucose-based polymers.

Because the initial metabolic steps in fructose utilization are mediated by fructokinase and aldolase B, fructose metabolism bypasses the control of glycolysis at phosphofructokinase and, thus, increases the flux through glycolysis.

Feeding of fructose or sucrose leads to increases in liver weight, liver lipid, liver glycogen, and activities of liver lipogenic enzymes: glucosephosphate dehydrogenase, malic enzyme, ATP citrate lyase, and fatty acid synthetase Worcester et al. Hypertriglyceridemia associated with fructose feeding has been attributed to both increased hepatic synthesis Herzberg and Rogerson, b and decreased peripheral clearance Hirano et al. Increases in kidney weight and nephrocalcinosis also were observed when diets containing 55 percent sucrose Kang et al.

Starch was more easily metabolized than sucrose by rats fed low-protein diets Essential fatty acid deficiencies may be exacerbated by high sucrose diets Trugnan et al. Xylose is toxic to rats; lens opacity and diarrhea were observed in rats fed diets containing 15 percent or more xylose Booth et al. Sorbose, a slowly absorbed sugar, decreases feed intake and growth rate when added to rat diets but appears to supply the rat with a significant amount of energy, presumably, in part, as end products of hindgut fermentation Furuse et al.

Mannose up to 8 percent of the diet improved growth of rats fed a carbohydrate-free diet, suggesting that it can be metabolized, at least in low concentrations Keymer et al. Of the sugar alcohols, lactitol and xylitol decrease feed intake and growth when added to diets at 16 percent of dry matter, although rats appear to adapt, at least in part, to these two sugar alcohols within 2 weeks Grenby and Phillips, Sorbitol can be metabolized by rat liver Ertel et al.

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A series of experiments defined the rats' need for carbohydrate for successful reproduction. In all these experiments a low-protein diet was required in order to demonstrate the need for carbohydrate. By day 12 of gestation, all embryos from rats fed carbohydrate-free diets had been resorbed Taylor et al. Survival was poor for pups from dams fed low-glucose diets 9. From dams fed 6 percent or less glucose, no pups survived 7 days postpartum. From those dams fed 8 or 12 percent glucose, pup survival at 7 days was 6 and 30 percent, respectively.

Control pups whose dams were fed 62 percent glucose diets had 93 percent survival Koski and Hill, Poor rat pup survival caused by feeding dams a low 4 percent -glucose diet 10 percent of calories from protein could be markedly improved by feeding dams a high-carbohydrate diet for the final 2 days of gestation and through lactation Koski and Hill, Lactation is not supported by carbohydrate-free diets.

Milk production can occur for rats fed 6 percent glucose diets, but the milk contains low concentrations of carbohydrate and lipid, which is associated with retarded postnatal growth of pups Koski et al. In general, fructose appears to be an adequate source of carbohydrate in diets fed to pregnant rats.

However, when low 4 percent -carbohydrate diets are fed during lactation, neither fructose- nor glycerol-supplemented diets will support deposition of as much fetal liver glycogen as 4 percent glucose diets Fergusson and Koski, Essential fatty acid deficiencies may be more likely to occur in gestating rats fed sucrose-based In establishing the protein requirements at different stages of life, three factors must be considered: 1 energy concentration in the diet, 2 amino acid composition of the protein see Appendix Table 2 , and 3 bioavailability of the amino acids.

Protein requirements are most accurately expressed as a protein:energy ratio to take into account the large differences in energy concentration that may occur among diets. Similar results were obtained with pure amino acid mixtures Rose et al. The edition of this report concluded that the protein requirement for maximum growth of the rat is 12 percent when highly digestible protein of balanced amino acid pattern is used. Computation of the percentage of dietary protein required for maximum growth when the diet contains a mixture of proteins requires that both the content and bioavailability of the amino acids in the different proteins be considered.

Historically, most methods have assumed that protein quality is constant over a range of dietary protein concentrations. For example, in the slope-ratio procedure, test proteins are fed at several concentrations and the value of a protein is determined by linear regression Hegsted and Chang, However, the value of protein as used for maintenance differs from the value of protein as used for growth, and the difference is not linear Phillips, ; Finke et al.

Finke et al. Although 1. In another comparison, twice as much soybean protein as lactalbumin was required to support 95 percent of the maximum nitrogen gain, but only 1. Thus, use of nonlinear models to describe an animal's growth response to dietary protein or protein mixtures indicates that the relative value of protein is not constant and that the value of a protein for maintenance may not predict its value for growth.

This may be an expression of the different amino acid patterns required for maintenance versus growth. Finally, nonlinear response models, in which marginal efficiency response per unit input changes with response level, seem to be more accurate than linear constant marginal efficiency, i. In determining the relative value of proteins to support growth using nonlinear models, it is important to include test diets that produce a maximal response or response plateau so that the "diminishing-returns" portion of the response curve can be defined.

The weight gain response per unit of protein added diminishing-returns is expected to vary with type of dietary protein. By applying a saturation kinetics model, Mercer et al. Given that 1. Additional studies with nonlinear-response models and rapidly growing rat strains are needed to refine this requirement. In practice, natural-ingredient diets that contain 18 to 25 percent crude protein have supported high rates of postweaning growth. Although protein requirement declines with age after weaning, the problem has not been studied extensively Forbes and Rao, ; Hartsook and Mitchell, The higher value agrees with that calculated from analysis of rat milk Luckey et al.

Using carcass nitrogen as the dependent variable, Sheehan et al. Baldwin and Griminger were able to maintain nitrogen balance in and month-old male rats with an amino acid mixture simulating casein provided in the diet at 4. Dibak et al. Therefore the maintenance requirement is about 5 percent protein when the source is of high-quality. In natural-ingredient diets a concentration of 7 percent crude protein is suggested by Bricker and Mitchell As with estimation of the protein requirement, it is necessary to consider the energy concentration of the diets when estimating the amount of each amino acid needed to support growth Wretlind and Rose, ; Rosenberg and Culik, The sample amino acid patterns given in Table are intended for use in a diet that contains 5 percent fat.

Extrapolation of the requirements to diets of different caloric densities can probably be safely made by maintaining a constant amino acid:energy ratio and allowing for variations in amino acid digestibility Kornberg and Endicott, ; Guthneck et al. Amino acid requirements are related to dietary protein concentration Grau, ; Almquist, ; Brinegar et al. In general, the requirement for an amino acid, expressed as a percent of the diet, tends to increase as dietary protein. As with protein quality assessment, a nonlinear model best describes the growth response of rats fed varying amounts of amino acids Yoshida and Ashida, ; Heger and Frydrych, ; Gahl et al.

A nonlinear model most accurately describes the diminishing-returns portion of the response curve. Heger and Frydrych and Gahl et al. Gahl et al. The test amino acid was incorporated into the amino acid mixture at a concentration 35 percent below that of the other amino acids. Addition of incremental amounts of the mixture to the diet was used to obtain a growth response to the test amino acid.

This approach ensured that the limiting amino acid remained first limiting. Figure shows the response curves for nitrogen gain as a function of lysine and sulfur amino acid intake. These curves were generated from data reported by Gahl et al. Similar curves for each indispensable amino acid were used to generate the requirement estimated to support growth Table Estimates were also made for the amount of amino acid required for nitrogen gain based on carcass nitrogen gain. The estimated amino acid requirements based on nitrogen gain were 1.

Because weight gain per se does not reflect a change in body composition, nitrogen gain may be a more dependable response criterion. The substitution value of tyrosine for phenylalanine and cystine for methionine could not be estimated from the results used to generate the requirements shown in Table The replacement of phenylalanine by tyrosine was determined by Stockland et al.

They found the requirement for phenylalanine alone was 0. Tyrosine without phenylalanine would not support growth, and at least 0. Tyrosine could provide 45 percent of the aromatic amino acid requirement. Estimates of the replacement value of cystine for methionine have been made Sowers et al. The requirement for methionine alone was 0.

The diet had to have at least 0. Rat growth was between 4 and 5. The estimates. Each data point represents the mean SEM for four rats. The estimates for indispensible amino acids reported in earlier editions of this publication are, on average, 23 percent lower than the current estimates see Table for comparisons. The reasons for this difference is the methods used to estimate the requirement. Estimates reported earlier National Research Council, , were based on significant differences between means by use of a multiple-range test, which produced values similar to results obtained with broken-stick models.

Estimates made in this way will be lower than those made by the four-parameter logistical model and, as observed in the guinea pig Chapter 5 , may underestimate the requirement for indispensable amino acids by about 20 percent. A reanalysis of the original data of Benevenga et al.

Table of Contents

Gahl and N. Benevenga, University of Wisconsin, personal communication, The difference between the total nitrogen requirement and the essential amino acid nitrogen requirement should be made up with mixtures of nonessential amino acids. Stucki and Harper reported that amino acid diets that contained both essential and nonessential amino acids supported greater growth in rats than diets that contained only essential amino acids. Ratios of essential amino acid nitrogen to nonessential amino acid nitrogen of 0. Arginine, asparagine, glutamic acid, and proline must be included in the nonessential amino acid mixture to support maximum growth Breuer et al.

The responses to these amino acids are presumed to reflect the inability of the rat to synthesize the quantities required for rapid growth. However, as pointed out by Breuer et al. It is evident that specific requirements for the nonessential amino acids cannot be given because of the metabolic relationships among them. Therefore, the values given in Table represent a pattern that has been used successfully in studies with purified diets. The value of Bradley and Breuer et al. To raise the dietary crude protein limit to that planned, a mixture of alanine, glycine, and serine can be used.

Amino acid imbalances and antagonisms can result in increased requirements for individual amino acids, an area reviewed by Harper et al. The effects of imbalances and antagonisms on the requirement for maximum growth may be small or nonexistent if dietary protein concentration is adequate, but the effect in diets that contain suboptimal concentrations of protein may be considerable. The immediate response of an imbalance is decreased food intake Harper et al. The determination of amino acid requirements for adult rats is difficult because of the flat dose-response curves that occur for many amino acids Smith and Johnson, ; Said and Hegsted, The indispensable amino acid requirements for maintenance of adult rats are based on reports by Benditt et al.

Nelson and Evans reported that 5 percent protein as unsupplemented casein was the minimum amount needed to support reproduction, while optimal performance occurred at 15 to 20 percent. Later, Nelson and Evans reported that 18 percent casein supported maximum growth in suckling young but that 24 percent was required to provide for weight gain in the dam during lactation. Supplementary cystine was added to both diets. Sucrose was used as the source of carbohydrate, a factor that may have influenced food intake, and thus protein utilization, at the lower protein concentrations in their studies Harper and Elvehjem, ; Harper and Spivey, Gander and Schultze reported that 15 to 16 percent protein derived from a combination of casein, methionine, and mixed cereals supported reproduction and lactation in rats.

More recently, Turner et al. Protein intakes of 8. Concentrations of Subsequent response surface analysis revealed that a concentration of 21 percent would have been needed for maximum responses with a minimum concentration of between 9 to 11 percent whole-egg powder. It seems that the net protein requirement for gestation and lactation as a percentage of the diet does not differ significantly from that for growth of weanling rats see Table The amino acid requirements for gestation and lactation have not been studied in depth.

A concentration of 0. Nelson and Evans reported that the sulfur amino acid requirement for lactation was 1 percent of the diet, one-half of which could come from cystine. Newburg and Fillios reported an apparent requirement for dietary asparagine in pregnant rats because its omission from the diet may have been associated with impaired neurological development of pups. Data are inadequate at this time to conclude that the concentration of amino acids in the diet required to support gestation and lactation exceed that required for growth in young rats.

Protein deficiency in young rats results in reduced growth, anemia, hypoproteinemia, depletion of body protein, muscular wasting, emaciation, and, if sufficiently severe, death. In adults a loss of weight and body nitrogen occurs Cannon, , and chronic deficiency may lead to edema Alexander and Sauberlich, Estrus becomes irregular and may cease, fetal resorption occurs, and newborns are weak or dead. A lack of protein for pregnant and lactating rats may result in offspring that are stunted in growth Hsueh et al. Low-protein diets also result in reduced food intake Black et al.

The reproductive capacity of the male is impaired by consumption of diets with inadequate concentrations of protein Goettsch, Removal of a single indispensable amino acid results in an immediate reduction in feed consumption, a situation that can return to normal within a day after replacement of that amino acid.

A lack of an indispensable amino acid in the diet tends to be reflected in the concentration of the amino acid in the blood plasma Longnecker and Hause, ; Kumta and Harper, Lack of specific amino acids has been reported to manifest as specific signs:. The accumulation of a porphyrin-like pigment on the nose and paws has been observed in rats deficient in tryptophan, methionine, and histidine Cole and Robson, ; Forbes and Vaughan, , but this condition is also observed in other deficiency states.

Recommended mineral intakes have often been based on estimates of the amounts of minerals that promote maximum growth in short-term studies with little consideration of potential toxicological problems and of nutrient interactions. However, high safety margins added to recommended intakes of one mineral may affect requirements for another. For example, ingestion of extra calcium has been found to decrease absorption of iron and zinc Greger, , , and excess intake of manganese may decrease iron utilization as these two elements are antagonistic Davis et al. Because of concerns about the consequences of feeding purified diets to rats for more than 6 months in studies on aging, hypertension, and cancer, a separate discussion of the role of dietary minerals in the development of nephrocalcinosis follows the discussions of the individual minerals.

Six mineral elements occur in living tissues in substantial amounts and are commonly called ''macrominerals" to distinguish them from mineral elements present in lesser quantities and designated as "trace elements. The dietary requirements for calcium and phosphorus are closely linked and depend on the availability of each mineral from the dietary source. This gives a Ca:P molar ratio of 0. However, Bernhart et al.

They held the dietary molar ratio of Ca:P to 0. Several groups of investigators have observed normal growth and tissue concentrations of calcium and phosphorus in bones and other tissues of rats RIVm:TOX and Sprague-Dawley strains fed from 2. Ritskes-Hoitinga et al. They found that 2.

Kaup et al. These studies suggest that dietary concentrations of calcium and phosphorus at 3. However, other studies have shown that a larger Ca:P ratio is required to prevent specific abnormalities in Sprague-Dawley rats. Draper et al. Variations in calcium and phosphorus intake have been associated with soft tissue calcification, especially nephrocalcinosis, in rats. However, a variety of other dietary factors can influence the development of nephrocalcinosis.

The recommendations for calcium and phosphorus intakes reflect the somewhat conflicting needs to maximize growth and maximize bone calcium and phosphorus concentrations without inducing nephrocalcinosis. A Ca:P molar ratio of 1. However, a dietary phosphorus concentration of more than 2.

Therefore, the recommended concentrations of dietary calcium and. Considering the demands placed on the dams during lactation, it might be prudent to increase the amount of dietary calcium and phosphorus during this period. It has been estimated that a lactating dam will produce 70 mL of milk per day Brommage, This amounts to approximately mg calcium and mg phosphorus transferred to milk in a hour period. Brommage showed that this demand for calcium and phosphorus was compensated for by increases in food intake and dramatic increases in intestinal absorption of these minerals.

To help relieve some of the stress of lactation, it is recommended that the dietary calcium and phosphorus be increased by 25 percent 6. This could be especially helpful for those females used in continuous-breeding programs. It should be mentioned, however, that when lactating and nonlactating rats were given a choice of diets containing various concentrations of calcium and phosphorus, the lactating rats chose a diet that contained a Ca:P molar ratio of 2, whereas the nonlactating rats chose a diet that contained a ratio of 1.

Factors Affecting Calcium and Phosphorus Requirements Certain dietary factors can affect the biological availability of calcium and phosphorus and thus affect requirements for them in the diet. When these factors are present in the diet, appropriate adjustments to the dietary concentrations of calcium or phosphorus should be made. Low concentrations of vitamin D in the diet will reduce the absorption of calcium. High dietary phosphorus will in turn reduce the apparent absorption of calcium Schoenmakers et al. Increasing the amount of fat in the diet from 5 to 20 percent reduced phosphorus absorption in older rats but not young rats Kaup et al.

High-fat diets also have been shown to decrease the absorption of calcium in mature rats but not young rats Kane et al. Calcium absorption is decreased in rats fed diets containing sources of oxalate Weaver et al. Some protein sources, including soybean protein isolates and other plant products, contain phytate. Phosphorus availability from these products should be considered when they are used in an animal's diet.

Other factors enhance calcium or phosphorus absorption. Bergstra et al. Dietary disaccharides such as lactose and sucrose stimulate calcium absorption in rat intestine Armbrecht and Wasserman, However, dietary lactose was better than sucrose in improving bone growth and development in intact vitamin D-deficient rats Miller et al. Buchowski and Miller showed that 20 percent lactose added to diets containing a variety of calcium sources such as calcium carbonate, milk, and cheese significantly increased the amount of calcium in the tibia compared to rats fed diets without lactose.

The enhancement was evident in day-old rats fed the diets for 8 days but not in older rats. Protein sources contain varying amounts of phosphorus, and the bioavailability of this phosphorus may not be the same in all sources. It is advisable, therefore, to analyze the source before using it in the diet and to be aware of whether the phosphorus is biologically available. Although few data are available in rats Moore et al. The rats exhibited growth retardation, decreased food consumption, increased basal metabolic rate, reduced activity and sensitivity, osteoporosis, rear leg paralysis, and internal hemorrhage.

Males failed to mate; females did not lactate properly. Day and McCollum fed 0. The animals survived up to 9 weeks and exhibited lethargy, pain, and cessation of bone growth with massive losses of calcium in urine. When Sprague-Dawley rats were fed diets with moderate restrictions in calcium 2. Improved calcium absorption and reduced urinary calcium losses allowed the rats to compensate for these marginally low calcium intakes, but these mechanisms would not be sufficient to prevent growth retardation if lesser amounts of calcium had been fed.

Voris and Thacker obtained a reduction of 25 percent in growth in a week, paired-feeding comparison of rats fed 0. On the basis of these limited studies, the estimated requirement is 0. Signs of Chloride Deficiency The rat tenaciously conserves its supply of tissue chloride by reducing drastically the urinary excretion within hours of consuming a diet deficient in the element. As a result, the signs of deficiency develop slowly.

Rats fed 0. Signs of Chloride Toxicity Rats are also relatively insensitive to excess dietary chloride as judged by growth and tissue composition. Dahl salt sensitive and Sprague-Dawley rats fed excess chloride However, the Sprague-Dawley rats fed Dahl salt sensitive rats fed 4. Magnesium is required for numerous physiological functions in the rat. The amount required in the diet for adequate nutrition of the rat depends on numerous factors that affect availability of magnesium—the most important being the amount of dietary calcium, phosphorus, and vitamin D present.

McAleese and Forbes found that a diet containing 0. However, a diet containing 0. More recently, Brink et al. On the other hand, rats fed only 0. Previously, Martindale and Heaton reported that 0. Other studies have shown questionable extremes for magnesium requirement. For example, Smith and Field estimated that a diet containing 0. These extremes may be the result of dietary factors that affect magnesium bioavailability. Brink et al.

Apparently this effect was caused by the presence of phytate in the soybean protein because when phytate was added to a casein diet, there was a similar reduction in absorption of magnesium. On the other hand, when lactose was added to the casein diet, magnesium absorption was enhanced. Dietary calcium and phosphorus also affect magnesium requirement. O'Dell et al. Bunce et al. High dietary calcium also will depress magnesium absorption O'Dell et al. They showed that calcium was ineffective when phosphorus was not present and vice versa.

However, if diets contain factors, such as phytate, that might reduce the absorption of magnesium, a slightly higher dietary concentration might be required. In addition, because of the demands of lactation, an increase in dietary magnesium during this period is recommended. Wang et al. Signs of Magnesium Deficiency Signs of magnesium deficiency in growing Sprague-Dawley rats include vasodilation, hyperirritability, cardiac arrhythmias, spasticity, and fatal clonic convulsions.

Vasodilation occurred after about 1 week and often disappeared and reappeared spontaneously. Convulsions occurred between 21 and 30 days Kunkel and Pearson, ; Ko et al. In Sprague-Dawley rats renal calcification was common and was detected within 2 days after initiating a markedly deficient diet Reeves and Forbes, Tufts and Greenberg reported that lactating females fed a deficient diet bred successfully but did not. Hurley et al. In two studies, rats grew normally when fed 1.

Studies to determine potassium requirements for the rat are limited. Until more extensive research has been done, the minimal requirement is estimated to be 3. The potassium requirement of different strains of rats may vary. Sato et al. However, Sprague-Dawley rats developed elevated blood pressure when fed Signs of Potassium Deficiency Insufficient potassium markedly reduces appetite and growth.

Animals become lethargic and comatose and may die within 3 weeks. They have an untidy appearance, cyanosis, short fur-like hair, diarrhea, distended abdomens with ascites, and are frequently hydrothoracic. Pathological lesions are widespread with potassium depletion Schrader et al. The initial noninflammatory degeneration of myocardial fibers is followed by necrosis and cellular infiltration. Renal lesions include cast formation in proximal convoluted tubules, sloughing of tubular epithelium in the medulla, and accumulation of hyalin droplets in the epithelium of the collecting tubules.

Signs of Potassium Toxicity Pearson fed weanling rats 5 percent potassium in the diet as potassium bicarbonate, and after 3 weeks observed reduced growth rate. More than 60 percent mortality was observed when dietary magnesium was low and only 17 percent when magnesium was adequate. Drescher et al. Potassium toxicity can cause hypertrophy of the adrenal zona glomerulosa, sodium depletion, and increased density of mitochondrial cristae in the kidney tubules Hartroft and Sowa, ; Sealey et al. Grunert et al. Forbes found that 0.

Intermediate concentrations were not tested. Pregnant Sprague-Dawley females fed low-sodium diets 0. Ganguli et al. The estimated requirement for growth, maintenance, gestation, and lactation is 0. Signs of Sodium Deficiency The classic sodium deficiency syndrome was described by Orent-Keiles et al.

The Laboratory Rat: Relating Its Age With Human's

Males became infertile after 2 to 3 months, and sexual maturity was delayed in females. Death ensued in 4 to 6 months. Signs of Sodium Toxicity Rats are relatively insensitive to excess sodium as indicated by growth and tissue composition. Sprague-Dawley rats fed However, ingestion of excess sodium as NaCl is associated with elevated blood pressure in several different rat strains, including Sprague-Dawley, Dahl salt sensitive , Dahl salt resistant treated with deoxycorticosterone acetate , and spontaneously hypertensive rats SHR Kaup et al. Of the many trace mineral elements found in foods, only seven—copper, iodine, iron, manganese, molybdenum, se-.

Although there is some evidence that other mineral elements such as chromium, lithium, nickel, sulfur, and vanadium may be required, further research is needed to establish requirement amounts. These other elements are treated in the discussion "Potentially Beneficial Dietary Constituents. Johnson et al. Studies by Klevay and Saari showed similar results. When weanling male rats were fed dietary copper ranging from 0.

However, Failla et al. When similar rats were fed diets with sucrose instead of starch, indicators of copper status were significantly reduced at dietary concentrations up to 2. The functional significance of the higher tissue copper concentrations was not investigated. It should be noted that the requirement for growth and maintenance has not changed from that reported in the edition of this volume.

High dietary concentrations of zinc, cadmium, and ascorbic acid may increase the dietary requirement for copper Davis and Mertz, The copper deficiency develops more rapidly when fructose or sucrose is fed than when starch is fed, and males show a greater sensitivity to copper deficiency than females with respect to both the severity of signs and the duration of time until the onset of signs of deficiency Fields et al. Lewis et al. Copper deficiency during early development can result in significant abnormalities in the cardiovascular, nervous, skeletal, reproductive, immune, and hematopoietic systems Keen et al.

Weanling and adult rats fed copper-deficient diets can develop alternations in platelet function, impairments in both the acquired and innate arms of the immune system, altered exocrine pancreatic morphology and function, anemia if dietary iron is marginal , alterations in thromboxane and prostaglandin synthesis, and impaired cardiovascular function Cohen et al. Weanling rats fed diets containing less than 2. Signs of Copper Toxicity Rats are particularly tolerant of high concentrations of dietary copper. Boyden et al.

Iodine is regarded as essential for the rat. Utilization of dietary iodine is very high, and absorption occurs all along the gastrointestinal tract. It is concentrated by many tissues Gross, but functions primarily as an integral part of the thyroid hormones.

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  • Parker et al. Many commercially available natural-ingredient diets contain this amount and support adequate growth and reproductive performance in rats. There have been no recent studies to suggest that this concentration should be changed. Signs of Iodine Deficiency The most obvious sign of iodine deficiency in the rat is enlargement of the thyroid glands with the formation of trabecular-type nodules Taylor and Poulson, Iodine-deficient rats also had more coarse and less dense hair than controls.

    Iodine deficiency results in impaired reproduction Feldmann, One biochemical sign of iodine deficiency is a decrease in serum concentrations of the thyroid hormone thyroxine T 4 Abrams and Larsen, ; another is a dramatic increase in the concentrations of serum thyrotropin Pazos-Moura et al. An increase in the activity of liver type I iodothyronine deiodinase also occurs in iodine-deficient rats. Arthur et al.

    Signs of Iodine Toxicity The rat has a relatively high tolerance for dietary iodine. For reproduction McCall et al. Shepard et al. Signs of Iron Deficiency In addition to anemia, iron-deficient rats can be characterized by multiple abnormalities including hyperlipidemia and low tissue carnitine concentrations Bartholmey and Sherman, , growth failure, elevated resting metabolic rate Tobin and Beard, ; Borel et al. Signs of Iron Toxicity The general term used to describe iron toxicity in animals is "iron overload.

    Wu et al. Within 2 weeks of feeding the high-iron diet, young rats had stopped gaining weight and old rats had lost 12 percent of their body weight. Weight of the old rats continued to decrease for up to 10 weeks of feeding. Large increases in the concentrations of iron in liver and spleen were seen in both age groups.

    Reductions in concentrations of serum, liver, and heart copper were also observed in the iron-overloaded rats. Britton et al. These large amounts of tissue iron result in lipid peroxidation and cellular damage Houglum et al. There is a paucity of studies that address manganese requirements in rats. The manganese requirement for reproduction has not been firmly established.

    Keen, University of California, Davis, personal communication, However, because there is a significant difference in how different strains respond to dietary manganese intake Hurley and Bell, ; Kawano et al. High concentrations of dietary iron, calcium, phosphorus, and copper have been reported to increase the requirement for dietary manganese Hurley and Keen, ; Johnson and Korynta, Reproduction can be impaired and is characterized by testicular degeneration in the male and by a delay in the opening of the vaginal orifice and defective ovulation in the female.

    If reproduction occurs, litters are characterized by ataxia, skeletal defects, marked abnormalities in glucose and lipid metabolism, and a high frequency of early postnatal death Hurley and Keen, Manganese deficiency in weanling and adult rats can result in significant alterations in pancreatic exocrine and endocrine functions Baly et al.

    The mechanisms underlying the cellular toxicity of manganese have not been clearly identified but may involve manganese-initiated oxidative damage, disturbances in carbohydrate metabolism, and altered intracellular iron metabolism Keen and Hurley, Molybdenum metabolism was reviewed by Mills and Davis Similar criteria used to establish selenium as an essential nutrient also can be used to establish the essentiality of molybdenum. These enzymes catalyze redox reactions.

    When rats are fed diets with very low concentrations of molybdenum, activities of these enzymes in various tissues are depressed. However, it has not been demonstrated that this is detrimental to the animal. On the other hand, if rats are fed tungsten, an antagonist to molybdenum, the activities of molybdenum-dependent enzymes are scarcely measurable and signs of deficiency then become apparent.

    Genetic deficiencies of sulfite oxidase in humans have been shown to result in numerous pathologies Mudd et al. Early studies used the effect of low dietary molybdenum on liver and intestinal XDH activities to establish the requirement for molybdenum. Studies by Higgings et al. Xanthine oxidase activity was impaired, however.

    More recent studies showed that not all criteria affected by dietary molybdenum are maximized by the same concentrations of molybdenum. However, it may not be valid to use tissue concentra-. In many instances, the element accumulates in the tissue above a certain concentration but does not have a physiological function. There is a strong interaction among molybdenum, copper, and sulfur; thus the dietary requirement of molybdenum might depend on the amount of copper and sulfur in the diet.

    Signs of Molybdenum Deficiency Outward signs of deficiency are difficult to produce when rats are fed purified diets with only molybdenum absent. Even when an antagonist of molybdenum, tungsten, was fed at a ratio of 2, tungsten:molybdenum there were no detrimental effects on weight gain, but the animals had very low activity concentrations of molybdenum-dependent enzymes in liver. Signs of Molybdenum Toxicity The occurrence of signs of molybdenum toxicity when rats and other species are fed high concentrations depends on the amount of copper and sulfate in the diet.

    Miller et al. Molybdenum toxicity also causes elevated liver copper, decreased serum ceruloplasmin, and increased tissue concentrations of molybdenum. Selenium is found in living organisms as an integral part of selenoproteins Sunde, in the form of selenomethionine or selenocystine.

    There are also selenium binding proteins. A number of important selenoenzymes have been discovered in mammalian systems—glutathione peroxidase GSH-Px; Rotruck et al. GSH-Px is found in most tissues and cells and catabolizes hydrogen peroxide and other free and membrane associated hydro- and phospholipid peroxides. ITD-I is found in liver, kidney, and thyroid and catalyzes the generation of 3,5,3'-triiodothyronine T 3 , the metabolically active thyroid hormone, from T 4 , the main circulating thyroid hormone.

    Other functions for selenium are probable but have not been adequately defined Beckett et al. Dietary sources of selenium can be of two forms—inorganic, represented by selenite or selenate, and organic, represented by selenomethionine or selenocystine. Because of the complex metabolic fate of these different forms, and because of the influence of other possible antioxidants in the diet, it is difficult to establish an exact dietary requirement for selenium.

    Selenium is more readily transported across the intestinal cells as selenate than as selenite. Selenium from selenomethionine is more readily transported than either selenate or selenite Vendeland et al. Various criteria have been used to assess the requirement for selenium. Hafeman et al. More recent studies Arthur et al. However, liver and plasma GSH-Px activities decreased significantly after only 2 weeks on low-selenium diets. In this regard Eckhert et al.

    They fed male rats diets high in sucrose to induce an elevation in blood triglycerides and cholesterol—a feeding regimen used by Lockwood and Eckhert to cause insult to the microvascular system. The results showed that dietary selenium concentration had no effect on GSH-Px activity in the erythrocytes; however, there was a marked effect on the microvasculature of the retinae.

    In addition, the inner retinal pericyte:endothelial cell ratio of the vessels was increased in rats fed the higher concentration of selenium. These authors interpreted these results to suggest that the higher concentration of dietary selenium protected the retinal microvasculature, particularly the pericyte cells, from sucrose-induced metabolic insult.

    It has been suggested that GSH-Px activity might be the best criterion for establishing a dietary requirement for selenium. However, recent investigations by Sunde et al. Vadhanavikit and Ganther used liver and thyroidal 5'-deiodinase type I activities as well as GSH-Px activities to determine selenium requirements for the rat. Thyroidal 5'-deiodinase activity was not significantly affected even at the lowest concentration of dietary selenium.

    This concentration may also be used for maintenance. At 15 days of gestation, erythrocyte selenium concentrations and GSH-Px activities of the dams were not different among the three highest concentrations of dietary selenium. At this period, selenium concentration and GSH-Px activity in the liver of nonpregnant controls was not different among the three highest concentrations of selenium.

    In the lactating females, however, liver selenium concentration and GSH-Px activity were different among all groups. GSH-Px activity in the liver of day-old pups was 1. Smith and Picciano also found that the form of dietary selenium could influence selenium bioavailability and dietary requirement. Studies by Lane et al. GSH-Px activity in the livers of dams was not different between the two sources.

    Whanger and Butler and Vendeland et al. If the dietary source of selenium is selenate or selenomethionine, the requirement could be less. Signs of Selenium Deficiency Outward signs of selenium deficiency are difficult to produce in rats fed diets adequate in vitamin E. However, one report McCoy and Weswig, demonstrated selenium deficiency signs in rats fed Torula yeast diets with adequate vitamin E. These signs included poor growth, sparse-hair coats, cataracts, and reproductive failure when the diets were fed for two generations.

    Caution should be exercised when interpreting these results, however. Male rats fed the Torula yeast diet with added selenium only gained about two-thirds as much as rats fed a commercial natural-ingredient diet during the first generation and less than one-half as much during the second.

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    This indicates that the diet may have been lacking in other essential nutrients. Biochemical signs of selenium. Signs of Selenium Toxicity Studies by Harr et al. Many of the animals did not live beyond days. The increased requirement for zinc with soybean protein-based diets is primarily attributed to the phytic acid content of these diets Berger and Schneeman, An increased requirement for dietary zinc during pregnancy is also supported by the observation of Fosmire et al.

    The dietary requirement for zinc can be significantly influenced by an animal's housing conditions. It should be noted that high concentrations of dietary cadmium, iron, phosphorus, and tin have been reported to increase the requirement for dietary zinc Hambidge et al. Signs of Zinc Deficiency The pathologic signs of zinc deficiency depend on the length and severity of the deficiency, the age and sex of the animal, and environmental surroundings.

    An inadequate intake of zinc can be reflected by marked reductions in plasma zinc concentrations within 24 hours and by mild-to-severe anorexia within 3 days Hambidge et al.

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    Esophageal lesions can occur in weanling rats within 7 days of the introduction of a zinc-deficient diet Diamond et al. For weanling males, the prolonged consumption of a diet containing less than 0. Zinc deficiency in females results in a disruption of the estrous cycle, a reduced frequency of mating, and a low implantation rate if mating occurs.

    The consumption of a zinc-deficient diet after mating can result in severe embryonic and fetal pathologies including prenatal death; a high incidence of central nervous system, soft tissue, and skeletal system defects; and abnormal biochemical development of the lung and pancreas. Zinc-deficient dams are characterized by severe parturition difficulties and the offspring are characterized by lower-than-normal growth rates, a high incidence of early postnatal death, and behavioral abnormalities Apgar, ; Bunce, ; Keen and Hurley, Nephrocalcinosis is histologically demonstrable in the rat as deposits of stainable calcium salts in the kidney, usually in the corticomedullary region.

    Urolith formation causes increased kidney calcium and phosphorus concentrations and eventually results in renal hypertrophy and heavier kidneys Woodard and Jee, Sometimes kidney function is reduced Ritskes-Hoitinga, The etiology is complex. Females are more susceptible than males, and Sprague-Dawley and Wistar strains may be more susceptible than other strains Ritskes-Hoitinga, Dietary factors are also important. Generally, rats.

    As yet no common mechanism has been identified that explains all the dietary factors that have been related to the incidence of nephrocalcinosis. Thus a brief review of potential factors is warranted. For example, Schoenmakers et al. Male rats were not affected. The amount of calcium consumed and the ratio of dietary calcium to phosphorus are also important. Woodard and Jee found that ingestion of additional calcium 5. In contrast, Schaafsma and Visser observed that Zucker rats fed diets with low concentrations of calcium 2.

    Moreover, Hoek et al. This may reflect the ratio of dietary calcium to phosphorus. Investigators have noted that a dietary calcium:phosphorus molar ratio below 1. The Ca:P molar ratio in all diets was 1. They found that the concentrations of calcium and phosphorus in the tibia of both male and female rats were similar to those in rats fed a commercial natural-ingredient diet that contained higher concentrations of calcium and phosphorus.

    In addition, there were no indications of nephrocalcinosis in female rats after they consumed these diets for 16 weeks. Nephrocalcinosis is a sign of magnesium deficiency in laboratory rats. This suggests that the rats were not magnesium-deficient per se. The ingestion of additional 25 or 30 percent versus 15 percent protein was found to prevent phosphorus-induced nephrocalcinosis in rats in several studies Hitchman et al.

    Similarly, Shah et al. The substitution of lactalbumin for casein in semipurified diets, even if dietary phosphorus amounts are similar, also is associated with less accumulation of calcium in kidneys of Sprague-Dawley rats Greger et al. Zhang and Beynen found that an increased intake of protein, provided in the diet by soybean isolate or casein, reduced the incidence of calcinosis in female rats; however, protein from fish meal did not.

    They concluded that the antinephrocalcinogenic effect of the soybean protein was related to lower urinary phosphorus, and the effect of casein was the result of lower urine pH and elevated urinary magnesium. This was related to fructose stimulating greater concentrations of urinary phosphorus and magnesium and lowering the pH. Levine et al. Kootstra et al. Supplementation of diets with fluoride has also been observed to decrease the accumulation of calcium in the kidneys of Sprague-Dawley rats in several studies Shah et al.

    In the conversion of many of the values to moles from international units or mass that appeared in the original literature, the values reported may not be an exact conversion. The molar values have been rounded to reflect the degree of precision present in the original published estimates. Conversion factors for molar, mass, and IU units of the vitamins are presented in Appendix Tables 3 and 4. Vitamin A is essential for many critical functions of the body such as vision, which requires cis -retinaldehyde bound to the photoreceptor pigments.

    Many cellular differentiation processes are mediated by all- trans -retinoic acid and 9- cis -retinoic acid bound to their respective nuclear.

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    The retinol, irrespective of its source, is esterified primarily with palmitate or stearate. The esters are transported to the parenchymal cells of the liver as components of the chylomicrons. The esters are either hydrolyzed and transported out of the liver to the target tissues in combination with a specific transport protein, retinol-binding protein, or they may be transferred to the stellate cells of the liver for storage.

    Vitamin A can be stored in the liver in large amounts. This investigation was supported in part by Cancer Research funds of the University of California, and was conducted in cooperation with the Animal Husbandry Research Division, A. Cite Citation. Permissions Icon Permissions. Issue Section:. Download all figures. View Metrics. Email alerts New issue alert. Advance article alerts. Article activity alert.

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