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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 3 Nutrient Requirements of the Mouse Mice (Mus musculus) have been used extensively as animal models for biomedical research in genetics, oncology, toxicology, and immunology as well as cell and developmental biology. The widespread use of this species can be attributed to the mouse's high fertility rate, short gestation period, small size, ease of maintenance, susceptibility or resistance to different infectious agents, and susceptibility to noninfectious or genetic diseases that afflict humans. Morse (1978) wrote a detailed history of the development of the mouse as a model for biomedical research. Estimating the quantitative nutrient requirements for mice is particularly challenging because of the large genetic variation within the species and the different criteria used to assess nutritional adequacy of diets. Research to determine nutrient requirements for reproduction, lactation, and maintenance of mice has received relatively little attention. A complicating factor in estimating the nutrient requirements for laboratory mice is that they are reared and maintained in conventional, specific-pathogen-free, or germ-free environments where the intestinal flora is undefined, defined, or absent, respectively. Because intestinal flora populations influence nutrient requirements, it is not valid to generalize data among these environments. GENETIC DIVERSITY Laboratory mice used in biomedical research represent noninbred stocks and inbred, congenic, and mutant strains. The number of individual stocks and strains of mice available for use in research is estimated to be near 500. In addition, there are numerous recently developed transgenic mouse strains; the exact number is not readily available, but estimates are as high as 20,000 strains. With this amount of genetic diversity within a mammalian species the probability is high that there would be differences in nutrient requirements among the different stocks and strains. Even though a small percentage of the existing stocks and strains of laboratory mice have been used in nutritional research, discussions of individual nutrients in this chapter indicate that mouse stocks or strains differ in their requirements for various nutrients. GROWTH AND REPRODUCTION The growth rates published by Poiley (1972) for 38 stocks and strains of mice show an approximately twofold difference between the slowest and fastest growing mice. Growth statistics for five stocks and strains representing this range of mouse genotype are shown in Table 3-1. This difference in growth suggests a marked difference in nutrient requirements among mouse genotypes. Considering this large variation in growth rates, expected or acceptable growth rates used as standards should come only from those individuals responsible for maintaining the breeding colony that provides a given genotype. Reproduction, too, varies among genotypes (National Institutes of Health, 1982). The reproductive performance of highly inbred strains is frequently low, particularly for strains that have been selected for a metabolic defect. The reproductive characteristics of representative inbred and outbred mouse genotypes are presented in Table 3-2. Because reproductive characteristics are specific to each mouse genotype, information in this regard should be obtained from those individuals who maintain the foundation colony of the strain or substrain of interest. ESTIMATION OF NUTRIENT REQUIREMENTS The nutrient requirements of mice have been defined by several different criteria including growth, reproduction, longevity, nutrient storage, enzyme activity, gross or histo-
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 TABLE 3-1 Average Growth of Commonly Used Strains of Laboratory Mice Weight, g Age (weeks) Swiss-Webster (OB) BALB/c (IB) DBA/2 (IB) B6C3F1 (HB) Female 3 12 12 11 9 4 14 14 15 14 5 23 16 18 16 6 24 17 19 17 7 26 18 20 18 8 26 18 21 20 9 27 10 29 Male 3 12 12 11 9 4 16 14 15 15 5 26 19 17 19 6 31 21 21 22 7 34 22 23 24 8 36 23 22 25 9 38 10 40 Abbreviations: OB, outbred; IB, inbred; HB, hybrid. SOURCE: Adapted from Poiley (1972). logical appearance of tissue lesions, and nucleic acid or protein content of tissue. The requirement for any nutrient may vary with the criteria used. Traditionally, rapid growth leading to maximum body size at maturity has been the basis for measuring dietary adequacy on the assumption that a diet promoting maximum growth would be adequate for reproduction, lactation, and maintenance. Data have been published that test the validity of this assumption for the mouse. Knapka et al. (1977) found that diets producing maximum postweaning growth did not support maximum rates of reproduction. Since the mouse achieves one-third of its total growth during the suckling period, lactation imposes a heavier nutritional burden on the dam; this may influence some nutrient requirements more than others. Dubos et al. (1968) reported that a casein-starch diet that contained 0.05 percent magnesium was adequate for growth of mice, but sudden death occurred in some lactating females when they consumed that diet. An additional 0.02 percent magnesium prevented this syndrome, indicating the need for an increase in the magnesium requirement during lactation. These results suggest that diets which support maximal growth are not optimal for reproduction. Therefore, for the mouse diet, the meaning of the term "adequate" may need to be expanded to indicate a range of nutrient intakes between minimal and harmfully excessive; the range will TABLE 3-2 Some Reproductive Characteristics of Representative Strains of Inbred and Outbred Mouse Colonies Maintained at the National Institutes of Health Strain Sterile Matings (%) Mean Litter Size Preweaning Mortality (%) Inbred strain NFR/N 3.0 7.6 7.0 FVB/N 1.0 7.8 8.7 I/STN 30.0 4.9 34.0 P 13.0 2.6 27.0 Outbred strain N:NIH 14.9 7.1 8.1 N:GP 16.3 6.7 6.1 SOURCE: Data summarized and provided by C. T. Hansen (Veterinary Resources Program, National Center for Research Resources, National Institutes of Health, personal communication, 1993). vary at different stages of the life cycle. Nutrition investigators generally focus on nutrient requirements as minimal dietary concentrations. For life-span studies with mice, however, optimum dietary concentrations of energy and nutrients may have to be established. Although many studies have been conducted on the effects of diet on longevity, there are insufficient published data to estimate the nutrient requirements for long-term maintenance of mice. Mice maintained in germ-free, gnotobiotic, or specific-pathogen-free environments, where the kinds and number of intestinal microorganisms are altered, may require different dietary concentrations of nutrients. Luckey et al. (1974) fed mice a sterilized diet, marginal in several vitamins, and observed decreased reproduction in germ-free as compared to conventionally reared mice. Allen et al. (1991) reported that adding 20 mg menadione sodium bisulfite/kg diet to the diets of hysterectomy-derived mice maintained in a specific-pathogen-free environment arrested a spontaneous outbreak of hemothorax. Considering the many genetic and environmental factors that influence the nutrient requirements of laboratory mice, too few controlled studies have been conducted, particularly in recent years, to identify the nutrient requirements of this species. As a result the estimates of nutrient requirements are based on data accumulated many years ago involving mouse strains fed dietary ingredients that are no longer available or cannot be identified, experimental results derived from studies that were not designed to establish nutrient requirements, nutrient consumption by mice fed diets producing "acceptable performance," and the assumption that mouse nutrient requirements are similar to those of the rat.
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 The estimated nutrient requirements presented in Table 3-3 provide guidelines for the adequate nutrition of mice maintained in conventional animal facilities. However, mice subjected to stress, such as drug testing or surgery, or mice maintained in a germ-free environment may have TABLE 3-3 Estimated Nutrient Requirements of Mice Nutrient Unit Amount, per kg diet Comment/Reference Lipid g 50.0 Linoleic acid g 6.8 Protein (N × 6.25) Growth g 180.0 Equivalent to 20% casein supplemented with 0.3% DL-methionine or 24% casein g 200.0 Casein (see text) Reproduction g 180.0 Natural-ingredients Amino acids Arginine g 3.0 See text Histidine g 2.0 See text Isoleucine g 4.0 See text Leucine g 7.0 See text Valine g 5.0 See text Threonine g 4.0 See text Lysine g 4.0 See text Methionine g 5.0 Cystine may replace 50-66.6% Phenylalanine g 7.6 Tyrosine may replace 50% Tryptophan g 1.0 Niacin may replace 0.025% (see text) Minerals Calcium g 5.0 Chloride g 0.5 Magnesium g 0.5 0.7 g/kg for lactation (see text) Phosphorus g 3.0 Potassium g 2.0 Higher concentrations may be required for lactation (see text) Sodium g 0.5 Copper mg 6.0 8.0 mg/kg for pregnancy and lactation Iron mg 35.0 Manganese mg 10.0 Zinc mg 10.0 30 mg/kg for reproduction and lactation Iodine µg 150.0 Molybdenum µg 150.0 Selenium µg 150.0 Selenite form of Se Vitamins A (retinol)a mg 0.72 Santhanam et al., 1987 D (cholecalciferol)b mg 0.025 Adequate; no quantitative data E (RRR-α-tocopherol)c mg 22.0 Yasunaga et al., 1982 K (phylloquinone) mg 1.0 Based on the requirement for the rat; Kindberg and Suttie, 1989 Biotin (d-biotin) mg 0.2 Adequate; Fenton et al., 1950 Choline (choline bitartrate) mg 2,000.0 Adequate; insufficient data to establish requirement Folic acid mg 0.5 Fenton et al., 1950; Heid et al., 1992 Niacin (nicotinic acid) mg 15.0 Based on the requirement for the rat; Hundley, 1949 Pantothenate (Ca) mg 16.0 Morris and Lippincott, 1941, suggest 36 mg/kg for reproduction and lactation Riboflavin mg 7.0 Adequate; insufficient data to establish requirement Thiamin (thiamin-HCl) mg 5.0 B6 (pyridoxine-HCl) mg 8.0 1 mg/kg for maintenance B12 µg 10.0 Adequate; insufficient data to establish requirement NOTE: Nutrient requirements are expressed on an as-fed basis for diets containing 10% moisture and 3.8 to 4.1 kcal ME/g (16–17 kJ ME/g) and should be adjusted for diets of differing moisture and energy concentrations. Unless otherwise specified, the listed nutrient concentrations represent minimal requirements and do not include a margin of safety. Higher concentrations for many nutrients may be warranted in natural-ingredient diets. a Equivalent to 2,400 IU/kg of diet. b Equivalent to 1,000 IU/kg of diet. c Equivalent to 32 IU/kg. altered nutrient requirements. The values in Table 3-3 may have to be adjusted to allow a margin of safety between the actual and estimated requirements. For most nutrients a single estimate has been made. It is recognized, however, that mice are similar to other
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 mammalian species in that optimum nutrient requirements differ for growth, reproduction, lactation, and maintenance. Unfortunately, published data are not available for estimating nutrient requirements for each stage of the life cycle. EXAMPLES OF DIETS FOR LABORATORY MICE Mice are omnivorous; they consume a wide variety of seeds, grains, and other plant material as well as feedstuffs of animal origin. Natural-ingredient diets for mice maintained in conventional and barrier environments are commercially available. The formulations for conventional and autoclavable natural-ingredient diets that have been used successfully for many years are presented in Table 2-3 (Knapka et al., 1974; National Institutes of Health, 1982; Knapka, 1983). Note that alterations of these formulations may be appropriate to accommodate changes in ingredient availability or nutrient composition. The purified diet formulations presented in Table 2-5 have been developed and evaluated by a committee of the American Institute of Nutrition (AIN) as new standard reference diets (Reeves et al., 1993b). These diets replace the widely used purified diet referred to as AIN-76A shown in Table 2-4 (American Institute of Nutrition, 1977). Chemically defined diets are another option (Pleasants et al., 1970). The type of diet used depends on production or experimental objectives. ENERGY Troelson and Bell (1963) found that mice consumed an average of 3.5 g diet/day during 14 days postweaning. Calvert et al. (1986) reported that male mice consumed an average of 3.75 g diet/day during the 21 days postweaning and that mice with an increased genetic potential for growth because of (1) an apparent single-gene mutation that increased postweaning weight gain, (2) a genetic selection for growth, or (3) a combination of the single-gene plus genetic selection consumed 4.81, 4.57, and 6.18 g diet/day, respectively. The metabolizable energy (ME) content was estimated to be 3.9 kcal/g diet (16.2 kJ/g diet). It was not possible to determine whether the maintenance energy requirement differed for the different strains. Canolty and Koong (1976) reported that a line of mice selected for rapid postweaning growth consumed 5.0 g diet/day [18 kcal ME/day (75 kJ ME/day)] from 21 to 42 days of age while a line of mice from the same strain, but not selected for rapid growth, ate 3.8 g diet/day (57.7 kJ ME/day). The energy requirement for maintenance was exactly the same for both lines—176 kcal ME/BWkg0.75/day (736 kJ ME/BWkg0.75/day). Bernier et al. (1986) examined the effect of growth rate on maintenance energy requirements in two lines of mice with similar genetic backgrounds with the exception that one line had a single-gene mutation that increased body weight gain without altering body composition. They reported that the normal mice consumed 12.7 kcal ME/BWkg0.75/day (53.3 kJ ME/BWkg0.75/day) from 21 to 42 days of age and gained 17.2 g BW, while mice with the gene for rapid growth consumed 17.4 kcal ME/BWkg0.75/day (72.8 kJ ME/BWkg0.75/day) and gained 29.8 g BW. On the basis of a comparative slaughter experiment, the rapidly growing mice had a maintenance energy requirement of 155 kcal ME/BWkg0.75/day (648 kJ ME/BWkg0.75/day) as compared to 164 kcal ME/BWkg0.75/day (686 kJ ME/BWkg0.75/day) in the normal mice. These values are slightly lower than the 176 kcal ME/BWkg0.75/day (736 kJ ME/BWkg0.75/day) reported by Canolty and Koong (1976). It is likely that this difference is the result of an error of 7 percent in the ME of glucose (Canolty and Koong, 1976). The estimated maintenance energy requirement reported by Bernier et al. (1986) is similar to that reported by Webster (1983). He found that the maintenance energy requirement of adult mice maintained at 24° C was 161 kcal ME/BWkg0.75/day (673 kJ ME/BWkg0.75/day). It is not possible to specify a maintenance energy requirement for the average growing mouse without sufficient information about the mouse and its environment. Genetics and diet can have a substantial influence on the estimated maintenance energy requirement. Lin et al. (1979) reported that when fed a high-carbohydrate diet, obese (ob/ob) mice had an estimated maintenance energy requirement averaging 73 kcal ME/BWkg0.75/day (305 kJ ME/BWkg0.75/day), while lean mice required 118 kcal ME/BWkg0.75/day (493 kJ ME/BWkg0.75/day). Although the genetic background of these mice is different than those discussed previously, other factors influence estimates of maintenance energy requirements. Lin et al. (1979) maintained mice at an environmental temperature of 30° C for the first 2 weeks postweaning and 26° C for the following 2 weeks. Webster (1983) reported that when room temperature was increased from 24° to 28° C, heat production in mice decreased 21 percent, thus decreasing observed maintenance energy requirement. Diet composition also can alter the maintenance energy requirement. Lin et al. (1979) reported that lean mice fed a high-carbohydrate diet had a maintenance energy requirement of 118 kcal/BWkg0.75/day (493 kJ/BWkg0.75/day); when fed a high-fat diet, their estimated maintenance energy requirement increased to 130 kcal/BWkg0.75/day (544 kJ/BWkg0.75/day)—a 10 percent increase. This effect of diet was not observed in obese mice (Lin et al., 1979). Thus, environmental temperature, diet composition, and genetic background must be considered when predicting maintenance energy requirements. Sex must also be considered. Bull et al. (1976) report that female rodents appear to have a lower maintenance energy requirement than males. Based on their ob-
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 servations it is estimated that the daily ME requirement for maintenance is 160 kcal/BWkg0.75/day (670 kJ ME/BWkg0.75/day) in mice that have no obvious genetic or stress-induced abnormalities or pathologies. A diet containing 3.9 kcal ME/g (16.2 kJ ME/g) should meet this requirement. As with determining a specific energy requirement for maintenance, developing a specific energy requirement for a given growth rate or to support lactation or pregnancy is difficult at best. In the case of growth, the composition of gain must be considered. Gain as fat is an energetically more efficient process than gain as lean (see "Energy" section in Chapter 2). Further, the energetic efficiency with which a diet is used to support gain depends, in part, on the composition of the diet. It is energetically more efficient to produce body fat from dietary fat than it is to produce body fat from dietary carbohydrate. Still, there may be value in estimating the efficiency of ME used for fat energy gain and that used for lean energy gain. Kielanowski (1965) proposed that total ME intake (MEI) of growing animals could be partitioned into three portions: one proportional to body weight (representing energy requirement for maintenance), a second proportional to fat energy gain, and a third proportional to lean energy gain. Several problems have been identified relative to the use of this model. Generally, body weight is scaled using the interspecific relationship of adult basal heat production to body weight (BWkg0.75). Such scaling, however, was intended to describe a relationship among species, not within species (Webster, 1988). Bernier et al. (1987) demonstrated that the body weight exponent affects the proportions of heat production assigned to maintenance and growth. Thus it is important, when using the Kielanowski (1965) model, that the body weight exponent chosen to represent basal heat production be appropriate for the given species. Using the Kielanowski (1965) model and data generated by Bernier et al. (1986, 1987), the estimated energetic efficiencies of fat energy gain in two lines of mice would be 189 and 161 percent, obviously a biological impossibility. Use of regression techniques to estimate the efficiency of lean energy gain also leads to results that are impossible (Bernier et al., 1986, 1987; Thonney et al., 1991). A more precise estimate of energy requirements will be possible only with the development and testing of mechanistic models. Given the concerns raised above, it is likely that the average daily ME requirement of growing mice from 21 to 42 days of age will be met by their consuming 263 kcal ME/BWkg0.75 (1,100 kJ ME/BWkg0.75). During early gestation the energy requirement is likely less but may be as high as 358.5 kcal ME/BWkg0.75 (1,500 kJ ME/BWkg0.75) during the third trimester. Although specific data on energy requirement and support of lactation for mice are notably lacking, from other rodent data it is estimated that peak lactation could require a daily MEI of 311 to 430 kcal ME/BWkg0.75 (1,300 to 1,800 kJ ME/BWkg0.75) to support the dam and large litters. LIPIDS Lipids are required by the mouse to provide essential fatty acids (EFA). Dietary fat is another concentrated energy source and a carrier for fat-soluble vitamins. It aids absorption of fat-soluble vitamins and enhances diet acceptability. DIETARY FAT CONCENTRATION Bossert et al. (1950) demonstrated that weanling (Dohme and Swiss-Webster strains) mice gained weight equally well when fed diets containing 0.5 to 40 percent fat; all diets contained 0.5 percent corn oil with the remainder of the fat supplied by hydrogenated cottonseed oil. A decrease in growth was noted when the dietary fat content exceeded 40 percent. Fenton and Carr (1951) demonstrated that the effect of dietary fat concentration on weight gain of mature mice depended on the strain. Strains A and C3H had higher rates of gain when dietary fat was increased from 5 to 47 percent, while strains C57 and I showed no further increases in weight gain when the fat content of the diet was increased to more than 15 percent. Knapka et al. (1977) found a significant strain × fat interaction in reproductive capability (number of pups born per litter, pups weaned per litter) when diets containing 4, 8, and 12 percent crude fat were fed to four different strains of mice (BALB/cAnN, C3H/HeN, C57BL/6N, and DBA/2N). For example, the mean number of pups born to and weaned by each BALB/cAnN mouse over the reproductive lifetime increased from 38 to 46 when crude fat was increased from 4 to 8 percent, while the number of pups born to and weaned by DBA/2N mice decreased from 13 to 8 with increasing concentrations of crude fat. The other two strains had responses similar to (although less dramatic than) those of the DBA/2N strain, indicating that the absolute concentration of dietary crude protein and crude fat in diets for production of these inbred mouse strains is not as important as the ratio of these nutrients. Mouse reproduction also was affected by protein × fat interactions. Knapka and co-workers (1977) suggested that optimal crude protein and crude fat concentrations should be lower than 18 percent and 10 to 11 percent, respectively. Olson et al. (1987) described an increase in mammary tumorigenesis, reduced T-cell blastogenesis, and lowered cell-mediated immunity when fat (soybean oil) fed to C3H/OUJ female mice was increased from 5 to 20 percent of the diet. Birt et al. (1989) noted that dimethylbenzanthracene-induced skin papillomas grew more rapidly in SENCA mice fed 24.6 percent versus 5 percent dietary corn oil. Kubo et al. (1987) observed that longevity of (NZB × NZW)F1 female mice whose feeding was restricted was greater than that of controls allowed to feed ad libitum. Of the diets fed on a restricted basis, high-fat (69.8 percent
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 fat) diets increased longevity only two-thirds as well as low-fat (4.5 percent fat) diets. For these reasons, a diet with a fat concentration of 5 percent is recommended, similar to that suggested for the rat. This concentration is adequate but may not support maximal growth and reproduction of all mouse strains. ESSENTIAL FATTY ACIDS (EFA) n-6 Fatty Acids The mouse, like the rat, requires linoleic acid to avoid classical signs of EFA deficiency; however, the precise requirement for n-6 fatty acids has not been determined. Cerecedo et al. (1952) reported that 5 mg linoleate/day alleviated clinical signs of EFA deficiency in three mouse strains (C57, DBA, C3H) that had become EFA-deficient after eating a fat-free diet for more than 50 days postweaning. The n-6 stores of the mice were unknown; it is likely that the requirement is higher in the young growing mouse. The rate of depletion of tissue linoleate is biphasic (Tove and Smith, 1959) with the most rapid loss occurring when linoleate comprised more than 20 percent of the depot fat. Also, female and immature male mice lose linoleate more quickly than mature males during the slower, second phase of depletion. The linoleate requirement for pregnant and lactating mice is unknown, although it should increase during lactation as in the rat. The previous recommendation (National Research Council, 1978) was 0.3 percent dietary linoleate, based on the n-6 requirement of the rat. However, the present recommendation for a standard rat diet is 0.68 percent of dietary ME as linoleate; therefore, the current recommended amount of dietary linoleic acid for mice is 0.68 percent. n-3 fatty acids As in the rat and other mammals, n-3 fatty acids are sequestered in certain tissues in the mouse; thus, an essential function is likely. Two studies (Rivers and Davidson, 1974; Wainwright et al., 1991) have attempted to demonstrate a need for n-3 fatty acids. No attempt is made here to indicate a specific requirement. Gross depletion of tissue 22:6(n-3) in conjunction with abnormalities of the retina have been demonstrated in other species only when fed diets that contain oils with extremely high ratios (150:1) of n-6:n-3 fatty acids (as found in safflower, sunflower, and peanut oil) (Neuringer et al., 1988). Diets containing other common oils with more moderate ratios of n-6:n-3 fatty acids will not result in a depletion of n-3 fatty acids. (See Appendix Table 1 for fatty acid composition of common dietary fats and oils.) Signs of EFA Deficiency EFA deficiency in the mouse was first described by White et al. (1943) and later by Decker et al. (1950) using weanling mice inbred in their respective laboratories (strain was not reported). Cercedo et al. (1952) produced EFA deficiency in three strains of weanling mice (C57, DBA, C3H), all of which were reported to have dermatitis of the thorax and extremities, scaliness of the ears, alopecia, and growth retardation. Mice fed a fat-free diet also developed lighter colored hair in the lower dorsal region. A "spectacle" eye condition was reported in two-thirds of the DBA mice but only noted occasionally in the C57 mice. The DBA mice developed the EFA deficiency syndrome more rapidly than did the C57 mice. Berkow and Campagnoni (1983) reported reduced myelination and abnormal myelin composition in C57BL/6J female mice fed EFA-deficient diets during the rapid growth phase. CARBOHYDRATES Typical diets fed to mice contain high concentrations of carbohydrate, although diets containing no carbohydrate (83 percent protein) have been shown to support growth rates of 0.1 g/day from 4 to 16 weeks of age in normal mice (Leiter et al., 1983). Mice fed high-fat diets (49 percent fat, 20 percent protein, 15 percent carbohydrate) grew at rates similar to those fed high-carbohydrate diets (4 percent fat, 20 percent protein, 65 percent carbohydrate; 0.13 and 0.09 g/day, respectively; Robeson et al., 1981). Similar growth rates were observed in normal mice fed high-carbohydrate (≥50 percent) diets in which glucose, fructose, sucrose, or starch was the primary carbohydrate source (Leiter et al., 1983; Seaborn and Stoecker, 1989). Diets with high concentrations of fructose or sucrose increased liver fatty acid synthesis and decreased extrahepatic fatty acid synthesis as opposed to diets high in glucose or starch (Herzberg and Rogerson, 1982). PROTEIN AND AMINO ACIDS PROTEIN The requirement for protein to support maximal growth or reproduction depends on the content and digestibility of the amino acids in the diet and the growth and reproductive potential of the mice in question (Keith and Bell, 1988). Growth rates of mouse strains used in research range from 0.6 to 1.2 g/day and litter size may vary from three to seven. The estimated protein requirements are based on strains with high growth and reproductive potential under
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 the assumption that these requirements should meet the needs of strains with lower growth and reproductive potential. Growth Of the studies reviewed, none used natural-ingredient diets to estimate the protein requirements of growing mice. For male mice, purified diets will support growth rates up to 1.2 g/day for the 2-week period following weaning. The AIN-76 purified diet (American Institute of Nutrition, 1977), which contains 20 percent casein supplemented with 0.3 percent DL-methionine, will support gains of 0.98 to 1.2 g/day in Carworth Farms No. 1 X Swiss male mice (Bell and John, 1981; Keith and Bell, 1989) (Table 3-4). Others (Maddy and Elvehjem, 1949; Hirakawa et al., 1984; Toyomizu et al., 1988) using either Swiss or Y strain mice have reported growth rates of 0.8 g/day, 1 g/day, and 1 to 1.1 g/day when 19, 22.7, and 27 percent casein diets, respectively, were used. Improving the dietary amino acid pattern by supplementing casein with an equivalent amount of nitrogen as a mixture of indispensable amino acids lowers the protein required for CD-1 mice that gain 1.3 g/day to 15.5 or 16.5 percent of the diet (Bell and Keith, 1992). Females grow more slowly, and lower dietary protein concentrations are needed to maximize growth. Goettsch (1960) found that a diet containing 20 percent casein would support a growth rate of 0.73 g/day in male Swiss mice but that 14 percent would support the growth rate of 0.59 g/day in female Swiss mice. Thus, diets containing 18 percent crude protein, equivalent to 20 percent TABLE 3-4 Protein Requirements for Growth for Various Strains of Mice Strain Sex Growth, g/day Sourcea Comment Reference Carworth Farms No. 1 X Swiss Male 0.98 Casein (20%) + DL-Met (0.3%) Bell and John, 1981 ICR Male 1.0 Casein (22.3%) Hirakawa et al., 1984 Swiss-STM Male, female 0.73, 0.57 Casein 14% (female), 20% (male) Goettsch, 1960 Swiss-Webster Male 0.82 Casein (19%) Maddy and Elvehjem, 1949 Swiss-Webster Male 0.93 20% casein + 0.3% L-Cys Reeves et al., 1993 Female 0.71 20% casein + 0.3% L-Cys Reeves et al., 1993 Y Male 1.0-1.1 Casein (0, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, and 100%) Multiple Toyomizu et al., 1988 Carworth Farms No. 1 X Swiss Male 1.2 ± 0.05 (7 reps) Casein (20%) + DL-Met (0.3%) 20% Keith and Bell, 1989 CD-1 Male 1.15-1.3 Casein (56% of crude protein) 15.5% crude protein + IAA and DAA Bell and Keith, 1992 Male 1.3 Casein (20%) + DL-Met (0.3%) a Values in parentheses are amount of ingredient expressed as percent of the diet. casein supplemented with methionine or casein alone at 23 to 27 percent of the diet, support growth rates of more than 1 g/day in male mice. Reproduction Both casein-based purified and natural-ingredient diets have been used in studies of the protein requirement for reproduction and lactation. In a study limited to the first gestation/lactation, a diet containing 16.7 percent casein resulted in the lowest age at first estrus (30.5 days versus 36.7 days) and largest litter size (7.5 versus 7.1), while a diet containing 20 percent casein was needed to support lactation, as demonstrated by the weight of the dam and litter at 21 days in Swiss-STM mice (Goettsch, 1960) (Table 3-5). Natural-ingredient diets varying in composition but containing 18 to 24 percent crude protein have been used to evaluate the protein requirement for mice over 6- to 9-month periods (Bruce and Parkes, 1949; Hoag and Dickie, 1962) or over four to seven litters for five strains [BALB/cAnN, C3H/HeN, C57BL/6N, N:NIH(S), and DBA/2N] (Knapka et al., 1974, 1977). Although strain differences were observed, a natural-ingredient diet containing 18 percent crude protein supported litter sizes of six to seven and a weaning percentage of 80 to 85 percent over four to five litters (Knapka et al. 1974, 1977). Thus natural-ingredient diets containing 18 percent crude protein from a mixture of animal and plant proteins will meet the protein needs of gestating/lactating mice through several pregnancies.
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 TABLE 3-5 Protein Requirements for Reproduction for Various Strains of Mice Strain Diet Pups in Litter, no. Comment Reference Swiss-STM Casein 7 16.7% Goettsch, 1960 Gestation 20% Lactation C57BL/6J; DBA/2N; AKR/J Natural-ingredient 7.5; 80% weaned 20% crude protein Hoag and Dickie, 1962 BALB/cAnN; C3H/HeN; C57BL/6N; DBA/2N Natural-ingredient 6; 85% weaned 18% and 24% crude protein Knapka et al., 1977 C57BL/6N; BALB/cAnN; N:NIH Natural-ingredient 6-8; weaned 24% crude protein Knapka et al., 1974 6-8 over 5-6 litters; 70-85% weaned AMINO ACIDS The estimated requirement for a single amino acid depends on the amounts of other amino acids in the diet and the rate of growth. With the exception of D-lysine (Friedman and Gumbmann, 1981) and probably D-threonine, the L-indispensable amino acid requirement may be met, in part, by D-amino acids. The efficiency of use of individual D-amino acids depends on the activity (Konno and Yasumura, 1984) and specificity of D-amino acid oxidase (Konno et al., 1982) as well as the amount and distribution of other D-amino acids in the diet because of competition for the enzyme (Marrett and Sunde, 1965). Growth rates similar to those obtained with intact protein (0.7 to 1.0 g/day) have been obtained with L-amino acid diets in 14-day growth studies (Maddy and Elvehjem, 1949; Hirakawa et al., 1984; Reicks and Hathcock, 1989). The concentration of amino acids in these diets exceeds the estimated requirement (National Research Council, 1978) by 25 to 200 percent. Growth Differences in growth potential among strains have been observed (see Table 3-6). Mice of the C57BL/6 strain gained 0.44 g/day, while CD-1 mice gained 0.68 g/day (Olejer et al., 1982); and Swiss-Webster mice gained 0.4 g/day, while the Rockland strain gained 0.78 g/day (Maddy and Elvehjem, 1949). Few studies have focused on estimating amino acid requirements of mice (John and Bell, 1976; Bell and John, 1981). The requirement for L-arginine is suggested to be less than 0.1 percent for mice gaining 0.8 g/day (Bell and John, 1981) and less than 0.3 percent for mice gaining 0.9 g/day (John and Bell, 1976). Milner et al. (1975) report evidence of arginine deficiency in BFDSCH mice that gained 0.4 g/day when fed a diet devoid of L-arginine. Bauer and Berg (1943) found that arginine could be deleted from the DL-amino acid diet of mice gaining 0.11 g/day. A level of 0.3 percent arginine should meet the requirements of mice with a growth potential of 1 g/day. The requirement for L-histidine is 0.2 percent of the diet for mice gaining more than 1 g/day (John and Bell, 1976). Olejer et al. (1982) showed that 0.1 percent would meet the needs of C57BL/6 mice growing 0.4 g/day but that 0.2 percent was required for CD-1 mice, which grew 0.7 g/day. L-carnosine at 0.29 percent can replace 0.2 percent L-histidine (Olejer et al., 1982). Parker et al. (1985) showed that deletion of L-histidine from the amino acid mixture resulted in weight loss and that the single-test concentration of 0.33 percent L-histidine met the needs of Swiss-Webster mice gaining 0.3 g/day. The L-histidine requirement for growing mice seems to be met at 0.2 percent of the diet. The L-isoleucine requirement is 0.4 percent of diet for mice gaining 1.0 g/day (John and Bell, 1976). Diets containing 0.7 percent and 0.5 percent L-leucine and L-valine, respectively (John and Bell, 1976), meet the needs of mice growing 1 g/day; therefore, these concentrations are set as the requirements. The requirement for L-threonine is set at 0.4 percent of diet since it will support a gain of 1.1 g/day in Carworth Farms No. 1 X Swiss mice (John and Bell, 1976). The L-lysine requirement of 0.4 percent of diet for mice gaining 0.9 g/day (John and Bell, 1976) was confirmed (Bell and John, 1981). The L-methionine requirement is 0.5 percent of diet for mice gaining 1 g/day (John and Bell, 1976). L-cysteine may replace as much as one-half to two-thirds of methionine in diets of mice gaining 1 g/day, and D-cysteine does not spare L-methionine (Friedman and Gumbmann, 1984a). D-methionine may have a value as high as 60 percent that of L-methionine in mice gaining 1 g/day (Friedman and Gumbmann, 1984a). The L-phenylalanine requirement of 0.4 percent of diet is supported by the work of John and Bell (1976) and Bell and John (1981). In estimates of the requirement for L-phenylalanine, dietary L-tyrosine must be taken into account as it may replace as much as 50 percent of L-phenylalanine (Friedman and Gumbmann,
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 TABLE 3-6 Amino Acid Requirements for Growth for Various Strains for Mice Strain Sex Growth, g/day Amino Acid Amount, % of diet Reference Carworth Farms No. 1 X Swiss Male 0.92 Arg at 40, 60, 80, 100, 120% of rat requirement ≤0.3 John and Bell, 1976 1.08 His added to 5% casein 0.2 1.00 Ile added to 5% casein 0.4 1.10 Leu added to 5% casein 0.7 0.93 Lys added to 5% casein ≤0.4 0.97 Met added to 5% casein 0.5 1.15 Phe added to 5% casein ≤0.4 1.13 Thr added to 5% casein 0.4 0.92 Trp added to 5% casein ≤0.1 0.93 Val added to 5% casein 0.5 Carworth Farms Male 0.75 Arg 0.1, 0.2, 0.3, 0.4, and 0.7% <01 Bell and John, 1981a No. 1 X Swiss 0.87 Lys 0.4, 0.5, and 1.0% 0.4 0.90 Trp 0.10, 0.13, and 0.17% 0.1 0.81 Phe 0.3, 0.55, and 0.89% 0.4 ICR Male 1.0 L-amino acid mixture, 16% of diet — Hirakawa et al., 1984 Swiss-Webster Male, female 0.3–0.4 Mixture of 16 L- and DL-amino acids — Maddy and Elvehjem, 1949 Rockland Male 0.7–0.78 Diet 39 VII — Maddy and Elvehjem, 1949 Swiss-Webster Male 0.84 L-amino acids, 14.1% — Reicks and Hathcock, 1989 C57BL/6 Male 0.44 L-amino acids, 12.0% — Olejer et al., 1982 CD-1 Male 0.68 L-amino acids, 12.0% — Olejer et al., 1982 C3HeJ Male 0.7 Casein (6%) + gelatin (6%) ± 0.065% D- or L-Trp ± 0.05% niacin — MacEwan and Carpenter, 1980 Swiss-Webster Male 1.0–1.1 L-amino acid diet (other amino acids up to 2 × rat requirement) — Friedman and Gumbmann, 1984a,b Male 1.1 0.59% L-Met — 0.29% L-Met + 0.29% L-Cys — a Based on purified proteins. 1984b). Growth rates of 1.2 g/day in Swiss-Webster mice required 0.76 percent of L-phenylalanine or 0.38 percent L-phenylalanine + 0.38 percent L-tyrosine (Friedman and Gumbmann, 1984b). D-phenylalanine has a growth promoting value that is one-third that of L-phenylalanine. Based on the above discussion, the requirement of L-phenylalanine + L-tyrosine is set at 0.76 percent of the diet (where L-tyrosine may replace 50 percent of L-phenylalanine). The requirement for L-tryptophan of 0.1 percent of diet for mice gaining 0.9 g/day (John and Bell, 1976) was confirmed (Bell and John, 1981). MacEwan and Carpenter (1980) showed that 0.05 percent niacin reduced the L-tryptophan requirement from 0.125 percent to 0.1 percent of the diet in C3HeJ mice gaining 0.7 g/day. The requirement for L-tryptophan is retained at 0.1 percent of the diet. Reproduction No studies were found regarding estimated amino acid requirements for gestation and lactation. Concentrations similar to those listed for growth can be expected to meet the requirements for gestation. Higher concentrations may be required for lactation. MINERALS MACROMINERALS Calcium and Phosphorus Reports regarding the quantitative calcium and phosphorus requirements of mice have not been published; therefore, the estimated requirements for these minerals are based on the dietary concentrations that have resulted in acceptable performance in mice. Purified diets that contain 4.0 g Ca/kg diet and 3 to 12 g P/kg diet (Morris and Lippincott, 1941; Mirone and Cerecedo, 1947), 5.0 g Ca/kg diet (Wolinsky and Guggenheim, 1974), and 8.0 g Ca/kg diet and 4.0 mg P/kg diet (Bell and Hurley, 1973) have been shown to support growth and reproduction in mice. Natural-ingredient diets containing 12 g Ca/kg and 8.6 g P/kg (Knapka et al., 1974, 1977) also have been reported to support growth and reproduction in BALB/cAnN, C57BL/6N, N:NIH(S), C3H/HeN, and DBA/2N mice. Limiting dietary phosphorus to 3.0 g P/kg appears to promote bone calcification in mice. Bell et al. (1980) found that female B6D2F1 mice had higher concentrations of
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 calcium and phosphorus in their bones when fed 6.0 g Ca/kg diet with 3.0 g P/kg diet than when fed 6.0 to 24.0 g Ca/kg diet with 12.0 g P/kg. Further work demonstrated that female B6D2F1 mice grew better when fed 15 percent casein with 6.0 g Ca/kg and 3.0 g P/kg diet (basal diet) than when fed 15 percent or 30 percent protein with 6.0 g Ca/kg and 12.0 g P/kg diet (Yuen and Draper, 1983). Moreover, bone calcium concentrations were higher when mice were fed the basal diet than when they were fed the diets containing elevated concentrations of phosphorus. Little has been written about the problem of nephrocalcinosis in mice. However, Yuen and Draper (1983) observed that calcium concentrations in the kidneys of B6D2F1 mice more than doubled when dietary phosphorus was increased from 3.0 g P/kg to 12.0 g P/kg and protein was held constant at 15 percent of the diet. This suggests that excess dietary phosphorus has the same negative effects in mice as in rats; and as regards calcium, there is no evidence to indicate that the requirements for calcium are greater for mice than rats. Therefore, the 5.0 g Ca/kg diet and 3.0 g P/kg diet estimated as the requirements for the rat are also the estimated requirements for the mouse. Signs of Calcium and Phosphorus Deficiency Wolinsky and Guggenheim (1974) and Ornoy et al. (1974) reported that Swiss mice consuming a diet containing only 0.2 g Ca/kg experienced decreased weight gain, bone ash, and serum calcium. These effects were much less marked in mice than in rats, however. Mice increased the concentration of calcium-binding protein in the duodenal mucosa and reduced skeletal growth. Decreased growth rather than osteoporosis was the more prominent sign of deficiency. Chloride (See ''Sodium and Chloride" section.) Magnesium Magnesium has been shown to be a dietary essential for mice, but the optimal intake for this species has not been well established. Alcock and Shils (1974) reported that mice fed diets containing 20 mg Mg/kg diet developed signs of deficiency, but these signs did not develop when the diet contained 400 mg Mg/kg diet. Fahim et al. (1990) reported that mice fed a diet containing 111 mg Mg/kg diet grew more slowly and had lower concentrations of magnesium in their serum than mice fed a diet containing 335 mg Mg/kg diet. A purified diet containing 730 mg Mg/kg diet supported normal growth and development of mice (Bell and Hurley, 1973). Dubos et al. (1968) reported sudden death in lactating mice fed a diet containing 500 mg Mg/kg diet but not in mice fed a diet containing 700 mg Mg/kg. This parallels the finding for rats (Hurley et al., 1976) that the magnesium requirement for lactation is higher than for growth. Natural-ingredient diets containing 1,800 and 2,600 mg Mg/kg diet provided for good growth and reproduction in three mouse strains (Knapka et al., 1974). The magnesium concentration in the widely used AIN-76 (American Institute of Nutrition, 1977) purified diet is 500 mg/kg. Since the data regarding the quantitative magnesium requirements for mice are inconsistent and not definitive, 500 mg Mg/kg diet is the estimated requirement for this species, and the requirement for lactation may be as high as 700 mg/kg, at least for some strains. Signs of Magnesium Deficiency Alcock and Shils (1974) reported magnesium-deficient mice developed rapid and usually fatal convulsions without previous hyperirritability. Soft tissue calcification resulting from magnesium deficiency has been reported in the hereditarily diabetic KK mouse strain (Hamuro et al., 1970). Phosphorus (See "Calcium and Phosphorus" section.) Potassium Bell and Erfle (1958) found that mice (Carworth Farms No. 1) fed purified diets with potassium concentrations of 2.0 g/kg diet did not exhibit signs of potassium deficiency, such as poor growth, inanition, lusterless eyes and hair, and dry scaly tails. A natural-ingredient diet containing 8.2 g K/kg diet (Knapka et al., 1974) and a purified diet containing 8.9 g K/kg (Bell and Hurley, 1973) supported good growth and reproduction in mice. Based on these results, the estimated required potassium concentration for mice is 2.0 g K/kg diet. Sodium and Chloride Sodium and chloride requirements of mice have not been studied. Two natural-ingredient diets containing 3.6 and 4.9 g Na/kg diet (Knapka et al., 1974) and a purified diet containing 3.9 g Na/kg diet (Bell and Hurley, 1973) are known to support good growth and reproduction. However, the estimated requirement for sodium and chloride is 0.5 g Na/kg diet and 0.5 g Cl/kg diet, which is identical to that estimated for rats. The actual requirements may be lower for mice. Rowland and Fregley (1988) observed that adrenalectomized mice are not as dependent as adrenalectomized rats on supplemental sodium. Mice are also less likely than rats to ingest saline solutions. TRACE MINERALS Based on work with the rat, it seems reasonable to sug-
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 gest that the mouse might have similar requirements for the trace elements. Until further work is completed with the mouse, the requirements established for the rat will suffice as estimates for the mouse. For a more in-depth discussion of the trace element requirements, see Chapter 2. Copper Specific studies to determine copper requirement of young growing mice have not been published. Knapka et al. (1974) reported satisfactory growth and reproduction by feeding mice a natural-ingredient diet containing 16 mg Cu/kg diet. Hurley and Bell (1974) reported adequate growth and development in young mice when they were fed a purified diet containing 4.5 mg Cu/kg diet. Mulhern and Koller (1988) showed that C57BL/6J weanling male and female mice fed an egg white-glucose-based purified diet containing 2 mg Cu/kg diet maintained values for serum ceruloplasmin activity and immune response for 8 weeks that were not significantly different from mice fed diets containing 6 mg Cu/kg diet; however, 1 mg/kg was not sufficient. Reeves et al. (1994) used nonlinear modeling techniques to estimate the copper requirement of adult male Swiss-Webster mice fed the AIN-93M purified diet. By feeding mice a range of dietary copper, from 0.8 to 6.5 mg/kg for 12 weeks, they estimated that minimal dietary concentrations of 2.5 and 4 mg Cu/kg diet were required to maintain maximal concentrations of serum copper and serum ceruloplasmin activity, respectively. However, under other environmental and dietary conditions the copper requirement for adult male mice might be more than 4 mg/kg diet. Based on these limited results, the estimated minimal requirement for both immature and adult mice is set at 6 mg Cu/kg diet. No information is available about the requirements for pregnancy and lactation. However, because of the similarity between the estimated requirement for copper in young rats (Johnson et al., 1993; Klevay and Saari, 1993) and adult mice (Reeves et al., 1994), the estimated requirement for pregnancy and lactation in mice is similar to that for rats; 8 mg Cu/kg diet. High dietary concentrations of zinc, cadmium, and ascorbic acid may increase the dietary requirement for copper (Davis and Mertz, 1987). Signs of Copper Deficiency Copper-deficient mice have low plasma copper concentrations, low plasma ceruloplasmin activity, anemia, enlarged hearts, altered catecholamine metabolism, thymus and spleen atrophy, and low hepatic cytochrome P-450 concentrations (Prohaska and Lukasewycz, 1989a,b; Gross and Prohaska, 1990; Prohaska, 1990; Phillips et al., 1991; Arce and Keen, 1992). Signs of Copper Toxicity Mice are relatively resistant to copper toxicosis. Pregnant mice fed diets containing 2,000 mg Cu/kg diet throughout gestation did not carry litters to term; when the high-copper diet was restricted to days 7 to 12 of gestation, the resorption frequency was higher than 50 percent and surviving fetuses were normal. The diet's toxicity to embryos was apparently caused by an indirect effect of reduced food intake rather than by a direct effect of excess copper on the fetus (Keen et al., 1982). Iron Sorbie and Valberg (1974) reported that iron concentrations of 25 to 100 mg Fe/kg diet supported normal growth and hematopoiesis in male C57BL/6J mice, although, liver iron storage in these animals was low compared to mice fed natural-ingredient diets containing between 220 to 240 mg Fe/kg diet. When the dietary iron concentration was increased to 120 mg Fe/kg diet, liver iron stores were similar to those obtained with the natural-ingredient diet. The 120 mg Fe/kg diet supported good reproduction for three generations. The requirement for iron is set at 35 mg/kg diet based on the concentration in the widely used purified diet, AIN-76 (American Institute of Nutrition, 1977). Higher concentrations may be necessary for reproduction. Two natural-ingredient diets known to provide good health and reproduction in three mouse strains contained between 198 and 255 mg Fe/kg diet (Knapka et al., 1974). Signs of Iron Deficiency Compared to controls fed a diet containing 122 mg Fe/kg diet, male CD-1 mice fed a low-iron diet (2 mg Fe/kg) for 30 days were characterized by low body weights, anemia, and suppressed T-lymphocyte-dependent functions associated with antibody production and blastogenesis (Blakley and Hamilton, 1988). Kuvibidila et al. (1990) reported similar T-cell abnormalities in female C57BL/6 mice fed low-iron diets (10 mg Fe/kg) for 40 days; in addition, these investigators noted a reduction in mature B-cell populations. Signs of Iron Toxicity NMR1 mice fed high-iron diets (ranging from 0.5 to 3.5 percent Fe-fumarate) for 4 weeks were characterized by iron concentration-dependent increases in liver and colon iron concentrations and tissue lipid peroxidation (Younes et al., 1990). Manganese Manganese concentrations of 3 mg/kg diet or less are clearly inadequate for optimal growth and development of several mouse strains, while diets containing 45 to 50 mg Mn/kg diet are adequate for all criteria tested (Hurley and
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 Control mice in these studies were fed selenium concentrations ranging from 330 to 500 µg Se/kg diet (Wendel and Otter, 1987; Otter et al., 1989; Toyoda et al., 1989; Weitzel et al., 1990; Peterson et al., 1992). Based on these works, it seems reasonable to suggest that the minimal requirement of selenium and iodine for the mouse might be at least as much as for the rat. Data for molybdenum requirements of the mouse are even more sparse than those for selenium or iodine, and it is suggested that those values established for the rat are good estimates for the mouse (see Table 3-3). VITAMINS FAT-SOLUBLE VITAMINS Vitamin A It has been shown by Wolfe and Salter (1931) that vitamin A is required by the mouse, and the mouse has been used extensively in studies of vitamin A metabolism and of the role of vitamin A in the prevention of cancer. Little work has been done to establish the vitamin A requirement of mice, however, and depleting the mouse of its vitamin A stores is difficult (McCarthy and Cerecedo, 1952). If rapid depletion is desired, it is necessary to use the pups from a pregnant female fed a vitamin A-deficient diet from about day 10 of gestation; this will produce very low vitamin A stores in the pups (Smith, 1990). Young mice weaned from dams fed a standard diet may require up to 1 year to show overt signs of deficiency. Santhanam et al. (1987) have explored methods to slowly produce vitamin A deficiency in mice. Both BALB/c and Swiss mice eventually developed deficiency signs when fed a cereal grain-based diet calculated to contain 1,200 IU vitamin A/kg (roughly equivalent to 1.2 µmol retinol/kg diet). BALB/c mice maintained good health, showed good growth, and stored modest liver reserves of retinyl esters when fed a diet calculated to contain 2,400 IU vitamin A/kg (2.5 µmol/kg). The AIN-76 diet was formulated to contain 4,000 IU vitamin A/kg (4.2 µmol retinyl esters/kg). This diet has been adequate for normal growth and reproduction in mice (American Institute of Nutrition, 1977). When fed a natural-ingredient diet that contained 13,371 IU/kg (roughly 14 µmol/kg), A/J mice were found to accumulate vitamin A reserves in their livers as they increased in age from 9 to 216 days old (Sundboom and Olson, 1984). However, 644-day-old A/J mice were found to have about one-half the liver vitamin A stores observed in mice 216 days old. Based on these limited data, the vitamin A (retinol) requirement of the mouse seems to be similar to the requirement of the rat. Therefore, a dietary concentration of 2,400 IU/kg diet (2.5 µmol/kg diet; 0.72 mg/kg diet) is adequate to meet the requirements of the mouse. Ideally, retinyl esters should be added to animal diets in stabilized gelatin beadlets, which will protect the vitamin A from oxidation. An alternative procedure is to slowly dissolve the retinyl esters in the dietary lipid, which contains an antioxidant, before the lipid is mixed into the diet. If the second procedure is used, the diet should be freshly prepared at least every other week. Dissolving the retinyl esters in a solvent and adding them directly to the other dietary constituents without the protection afforded by the dietary oils or by gelatin beadlets will result in substantial oxidative destruction of the vitamin. The storage and treatment of the diet are also very important. Zimmerman and Wostmann (1963) reported that vitamin A activity was decreased by 20 percent as a result of steam sterilization. Signs of Vitamin A Deficiency One of the early and significant consequences of vitamin A deficiency is impairment of the functional immune system (Smith et al., 1987). If conditions are sanitary the main overt sign observed early in deficiency is a decreased rate of weight gain. As the deficiency progresses many epithelial tissues become keratinized, including those of the seminal vesicles, testes (Van Pelt and De Rooij, 1990), bladder, kidney, trachea, esophagus, salivary glands, and lungs (McCarthy and Cerecedo, 1952). Xerophthalmia of the eye occurs if the mice are exposed to unsanitary conditions or are subjected to stress. Signs of Vitamin A Toxicity The studies of vitamin A toxicity in mice focused on the teratological aspects of the toxicity. Kochhar et al. (1988) have found that a single dose of 349 µmol/kg BW on day 10.5 of gestation produced cleft palates and limb deformities in ICR mice. A lower dose of 175 µmol/kg BW did not produce the deformities. Giroud and Martinet (1962) reported that three doses of 6.5 µmol vitamin A/kg BW on days 8, 9, and 10 of gestation caused death or resorption of 63 percent of the fetuses and malformations in others. Vitamin D The AIN-76 diet was formulated to contain 0.025 mg cholecalciferol/kg (0.65 µmol or 1,000 IU/kg) (American Institute of Nutrition, 1977). This amount of vitamin D is adequate and may represent a considerable excess. However, a lesser amount cannot be recommended until the more sensitive criterion of vitamin D status has been evaluated at lower intakes. Signs of Vitamin D Deficiency The mouse is quite resistant to the development of rickets—a disease caused by vitamin D deficiency. Beard and Pomerene (1929) found that mice fed vitamin D-deficient diets developed signs of
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 rickets within 7 to 14 days. Rickets spontaneously healed between days 20 to 27 without vitamin D supplementation, but osteoporosis was present in many of the animals after healing. Delorme et al. (1983) found that both the 10,000 and 25,000 molecular weight kidney vitamin D-dependent calcium binding proteins were reduced to about one-third the normal concentrations in vitamin D-deficient Swiss mice. In contrast, milk production and the calcium content of the milk were normal in CD-1 mice fed a vitamin D-deficient diet (Allen, 1984). Signs of Vitamin D Toxicity The LD50 of a single intraperitoneal injection of cholecalciferol for CF1 mice was found to be 355 µmol/kg BW (Hatch and Laflamme, 1989). No toxicity was found after the injection of 104 µmol/kg (1.7 × 106 IU/kg). In contrast, only 5.5 nmol 1,25-dihydroxycholecalciferol/kg was required to produce toxicity in C57BL/6J mice (Crocker et al., 1985). Vitamin E Bryan and Mason (1940) observed fetal resorption in vitamin E-deficient female mice similar to that observed in rats but observed no evidence of testicular injury in vitamin E-deficient males. They reported that administration of 81 nmol all-rac-α-tocopherol daily for the first 10 days of gestation was adequate to maintain the first pregnancy. This corresponds to a dietary concentration of 10 IU RRR-α-tocopherol/kg diet (15.7 µmol/kg). Goettsch (1942) found that a single dose of vitamin E equivalent to 1.8 IU to 2.4 IU RRR-α-tocopherol (1.16 to 1.55 µmol) given at the start of the gestation period was adequate to maintain pregnancy in mice between 3 and 6 months old. Mice 7 to 12 months old required a larger dose equivalent to 5 IU RRR-α-tocopherol (7.78 µmol) to maintain pregnancy. Trostler et al. (1979) found that male C57BL/6J mice fed a diet containing the equivalent of 62 µmol RRR-α-tocopherol/kg diet (lower dose not used) had a growth rate equal to or greater than that observed with mice fed 124 µmol/kg diet. However, more than 124 µmol/kg diet was required to prevent the accumulation of malondialdehyde in liver and adipose tissue. Yasunaga et al. (1982) gave daily intraperitoneal injections of all-rac-α-tocopherol to BALB/c mice and measured their response to mitogens. The best responses were obtained in mice injected with amounts equivalent to 7.8 to 28 µmol RRR-α-tocopherol/kg BW. The lower dose is equivalent to 50 µmol RRR-α-tocopherol/kg diet. Based on these data the vitamin E requirement for mice is estimated to be 22 mg/kg or 32 IU/kg RRR -α-tocopherol/kg diet (50 µmol/kg diet) when lipids comprise less than 10 percent of the diet. When all-rac-α-tocopheryl acetate is used as the dietary source, the equivalent amount would be 32 mg/kg diet. Signs of Vitamin E Deficiency Pappenheimer (1942) reported muscular dystrophy and hyaline degeneration in vitamin E-deficient mice but at a lower incidence than was observed in rats. No lesions were found in the central nervous system. Davies et al. (1987) did not find an accumulation of lipofuscin in neural tissues. The only tissue to show lipofuscin accumulation in vitamin E deficiency was the liver (Csallany et al., 1977). Spermatogenesis remained active in vitamin E-deficient mice for up to 439 days (Pappenheimer, 1942). Signs of Vitamin E Toxicity Yasunaga et al. (1982) found that male C3H/He mice injected intraperitoneally daily with 212 µmol all-rac -α-tocopherol/kg BW showed a weight loss by day 7. Injections of 846 µmol/kg BW/day were lethal. α-Tocopheryl quinone, a major metabolite of α-tocopherol, has been found to interfere with the mouse's ability to metabolize vitamin K and resulted in bleeding (Woolley, 1945). Vitamin K Vitamin K has not been considered essential for mice reared under conventional conditions because of the substantial contribution from coprophagy. However, with the increased use of specific-pathogen-free animals for research, this is probably no longer true. Both specific-pathogen-free CF1 mice (Fritz et al., 1968) and germ-free ICR/JCL mice (Komai et al., 1987) were reported to die quickly from hemorrhagic diathesis when fed vitamin K-free diets. Addition of 16 µmol menadione/kg to the diet prevented hemorrhaging problems in the specific-pathogen-free mice. Studies using the more sensitive criterion of vitamin K status have not been conducted with mice as they have been with rats (Kindberg and Suttie, 1989). Therefore, the estimated requirement of vitamin K for mice is 1 mg phylloquinone/kg diet (2.22 µmol/kg diet), based on the requirement of the rat. WATER-SOLUBLE VITAMINS Vitamin B12 Intestinal bacteria in mice synthesize undetermined amounts of vitamin B12 that can be utilized by the host. The presence of endogenous vitamin B12 generally confounds attempts to determine the quantitative requirements of this vitamin for mice. Jaffé (1952), however, reported a vitamin B12 requirement in excess of 5 µg/kg diet for growth and between 4 and 5 µg/kg diet for reproduction and lactation. Lee et al. (1962) demonstrated that mice require vitamin B12 for gestation. The widespread use of the AIN-76 (American Institute of Nutrition, 1977) purified diet containing 10 µg vitamin B12/kg has not resulted in
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 any reports of vitamin B12 deficiency signs. This indicates that the vitamin B12 concentration in the AIN-76 diets is adequate for mice. In the absence of more recent and definitive data regarding the vitamin B12 requirements for mice, 10 µg vitamin B12/kg diet is the estimated requirement for this species. However, it is noted that lower dietary concentrations may be adequate for mice with conventional intestinal flora, but higher concentrations may be required when the availability of endogenous B12 is limited under conditions such as antibiotic feeding, germ-free environments, or coprophagy prevention. Signs of Vitamin B12 Deficiency Young mice deficient in vitamin B12 show retarded growth and renal atrophy (Lee et al., 1962). Deficiency causes death both before and after birth. Biotin In contrast to other rodent species, mice fed purified casein-based diets appear to have a requirement for biotin that exceeds the amount obtained from coprophagy. Several investigators have observed signs of biotin deficiency or suboptimal weight gain when mice were fed biotin-deficient diets (Nielsen and Black, 1944; Fenton et al., 1950; Lakhanpal and Briggs, 1966). Fenton et al. (1950) found that 0.823 µmol biotin/kg diet was adequate for the mouse, but they did not use other concentrations. The AIN-76 diet was formulated to contain 0.2 mg biotin/kg diet (0.82 µmol biotin/kg). In the absence of more recent and definitive data regarding the dietary requirements of mice, the concentration of 0.2 mg biotin/kg diet is the estimated safe and adequate dietary concentration. Signs of Biotin Deficiency Watanabe and Endo (1989, 1991) observed teratogenic effects of biotin deficiency in mice fed a spray-dried egg white diet (containing avidin). The teratogenic effects were much more severe in the fast-growing ICR and C57BL/6N strains than in the slower growing A/Jax mice. The other signs of deficiency include alopecia, achromotrichia, and growth failure, as well as decreased reproduction and lactation efficiency (Nielsen and Black, 1944). Choline Choline was first recognized as a dietary essential for the mouse by Best et al. (1932), who observed fatty livers in choline-deficient mice. Since choline can be synthesized from methionine (see Chapter 2), and its metabolism is influenced by folic acid and vitamin B12 , a minimum requirement for choline is difficult to establish. Meader and Williams (1957) found that mice fed a diet containing 80 g casein/kg and 400 g lard/kg required 5 g choline chloride/kg diet (35,800 µmol/kg) to support growth and prevent lipid accumulation in the liver. However, Williams (1960) found this level of choline to be toxic in long-term studies. Therefore, caution should be exercised in adding high concentrations of choline to the diet. The widely used AIN-76 diet was formulated to contain 2 g choline bitartrate/kg (7,900 µmol/kg). This amount provides an adequate concentration of choline for diets containing optimal concentrations of methionine. Thus 2 g choline bitartrate/kg diet (7,900 µmol/kg) is the estimated safe and adequate dietary concentration. Signs of Choline Deficiency Choline-deficient mice had fatty livers with modular parenchymal hyperplasia and lower conception rates with low viability of the young (Mirone, 1954; Buckley and Hartroft, 1955; Meader and Williams, 1957). In contrast to earlier descriptions of fibrosis, Rogers and MacDonald (1965) observed that C57BL mice, unlike rats, did not develop cirrhosis or fibrosis of the liver but only fatty livers. There were acute and chronic inflammations on necrosis of individual hepatic cells. Proliferation of parenchymal cells increased with fat deposition. There was increased thymidine uptake by endothelial, perivascular, and parenchymal cells. Fifty-four percent of the choline-deficient mice died during a 24-week period. Signs of Choline Toxicity Choline is a very toxic nutrient with a narrow margin of safety. Williams (1960) observed that a dietary concentration of 5 g choline chloride/kg diet (35,800 µmol/kg) induced weight loss in BALB/c mice after they were fed that diet for 6 months, and there were no survivors after 9 months. After 15 weeks 52 percent of the mice had myocardial lesions and by 33 weeks 100 percent of the mice had myocardial lesions. The lesions were most frequently fibrosis with limited necrosis of muscle fibers and fibroid necrosis of coronary arteries (Thomas et al., 1968). Folates Weir et al. (1948) documented the essentiality of folic acid in growing mice. Fenton et al. (1950) obtained satisfactory growth in mice fed defined diets containing 0.5 mg folic acid/kg diet (1.1 µmol/kg). Heid et al. (1992) found that 0.4 to 0.5 mg/kg diet (0.9 to 1.1 µmol/kg) was necessary for successful pregnancy outcome in Swiss-Webster mice. Based on these results, 0.5 mg folic acid/kg diet (1.1 µmol/kg) is the estimated requirement for mice. Signs of Folate Deficiency Weir et al. (1948) observed the following effects after feeding mice a folate-deficient diet for 50 days: a decrease in white cell count from 6,000 to 4,000/mm3, disappearance of megakaryocytes and nucleated cells from the spleen and hemosiderin accumulation,
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 and disappearance of normal cell types from bone marrow. Other signs of deficiency reported include impaired antibody response (Rothenberg et al., 1973), decreased organ growth—particularly brain and liver (Shaw et al., 1973)—and decreased fetal implantations and increased resorption (Heid et al., 1992). Niacin Adequate data are not available to estimate the niacin requirement of mice. Male BK albino mice have been shown to convert [14C]tryptophan to N-methyl-nicotinamide, a urinary metabolite of niacin (Bender et al., 1990). The mouse may require increased niacin when tryptophan is fed at suboptimal concentrations. Based on the requirements of the rat, a dietary concentration of 15 mg nicotinic acid/kg diet (120 µmol/kg) is the estimated requirement for mice under the most adverse conditions (Hundley, 1949). Pantothenic Acid Sandza and Cerecedo (1941) found that subcutaneous injections of 63 nmol Ca-d-pantothenate 6 days each week would maintain an optimal growth rate in albino mice. Morris and Lippincott (1941) reported that a diet containing 21 µmol Ca-pantothenate/kg produced growth equivalent to a diet containing 168 µmol/kg in C3H mice. Fenton et al. (1950) obtained maximal growth in C57 mice with diets containing 13 µmol/kg diet, but more than 17 µmol/kg diet was required for optimal growth in the A and C3H strains of mice. Based on these limited data, 10 mg Ca-d-pantothenate/kg diet (21 µmol/kg) seems to be adequate for optimal growth in most strains of mice, but some strains may have higher requirements. Data on the requirement for pregnancy and lactation are not available, but the AIN-76 diet was formulated to contain 16 mg Ca-d-pantothenate/kg diet (33.6 µmol/kg). This diet has been shown to be adequate to support pregnancy and lactation in mice. Signs of Pantothenic Acid Deficiency The following pantothenic acid-deficiency signs in growing mice were reported by Morris and Lippincott (1941): loss of weight; loss of hair, particularly of the ventral surface, flanks and legs; dermatosis; partial posterior paralysis; other neurological abnormalities; and achromotrichia. Vitamin B6 (Pyridoxine, Pyridoxal, Pyridoxamine) According to Miller and Baumann (1945) and Morris (1947), mice grew satisfactorily when fed diets containing 1 mg pyridoxine-HCl/kg diet. Pyridoxamine and pyridoxal were found to be less active than pyridoxine. Bell et al. (1971) found 0.2 mg pyridoxine-HCl/kg diet limited growth in two strains, whereas 8.2 mg/kg supported normal growth. A comparison of reproductive performance of C57BL and I strains found that concentrations of 1 to 6 mg/kg diet resulted in fewer productive matings, smaller litters, and a lower survival rate in the I strain. Increasing dietary pyridoxine concentrations to 8 to 12 mg/kg improved the reproductive performance, but further improvement was not obtained using concentrations of 410 or 1,230 mg/kg diet; however, these concentrations did improve the survival rate of C57BL mice over a concentration of 1 to 6 mg/kg (Hoover-Plow et al., 1988). The concentrations of pyridoxal-5'-phosphate and pyridoxamine-5'-phosphate were determined in female mice fed purified diets containing 0.5, 1.0, 2.0, 3.0, 5.0, and 7.0 mg/pyridoxine-HCl/kg diet for 5 weeks. Plasma, erythrocyte, whole blood, liver, and brain pyridoxal-5'-phosphate and liver and brain pyridoxamine-5'-phosphate concentrations correlated with dietary concentrations (r = 0.81 to 0.94) and did not plateau over the entire dietary ranges of values (Furth-Walker et al., 1990). During pregnancy mice fed open-formula diets containing 8.13 mg pyridoxine-HCl/kg had increased erythrocyte and whole blood (2.9- and 1.6-fold) and decreased plasma (50 percent) pyridoxal-5'-phosphate. Liver pyridoxal-5'-phosphate, and pyridoxamine-5'-phosphate decreased 25 percent, but brain concentration remained unchanged (Furth-Walker et al., 1989). The recommended concentration of vitamin B6 for reproduction is set at 8 mg/kg diet. The concentration of 1 mg/kg set by Miller and Baumann (1945) and by Morris (1947) seems to be adequate for maintenance and growth. Signs of Vitamin B6 Deficiency Vitamin B6 deficiency signs include poor growth, hyperirritability, posterior paralysis, necrotic degeneration of the tail, and alopecia (Beck et al., 1950). Investigators (Keyhani et al., 1974) observed in B6-deficient CF1 mice a progressive hypochromic microcytic anemia with hypersideremia. It was accompanied by an increase in reticulocyte count not observed in vitamin B6 deficiencies of other species. Riboflavin Based on data reported by Fenton and Cowgill (1947a,b) and Wynder and Kline (1965), mice require 4 mg riboflavin/kg diet for normal growth. However, diets resulting in normal reproduction in mouse colonies generally contain 6 or 7 mg riboflavin/kg diet (American Institute of Nutrition, 1977). In the absence of more definitive data regarding the requirements for reproduction, the estimated riboflavin requirements for this species is 7 mg/kg diet. Signs of Riboflavin Deficiency Ariboflavinosis in the
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 mouse was described by Lippincott and Morris (1942). They reported the development of either atrophic or hyperkeratotic epidermis with normal sebaceous glands, myelin degeneration in the spinal cord, and corneal vascularization with ulceration. Morris and Robertson (1943) found that adult mice lost weight and young mice grew poorly and died within 9 weeks when fed diets containing 0.4 to 0.6 mg riboflavin/kg diet. Kligler et al. (1944) showed that riboflavin-deficient mice had lowered resistance to Salmonella infection. Hoppel and Tandler (1975) reported striking increases in the size of hepatic mitochondria and a greatly decreased capacity for ADP-stimulated respiration in riboflavin-deficient mice. In some animals, livers were yellow and the cytoplasm of the cells was engorged with small lipid droplets. In other animals, the livers were redder than normal, and their hepatocytes contained few lipid droplets. Genetically diabetic (KK) mice had a higher riboflavin requirement than Swiss albino mice based on activity coefficients of erythrocyte glutathione reductase (Reddi, 1978). Riboflavin deficiency during gestation led to brain, orofacial, limb and gastrointestinal malformations in the offspring. The degree of severity and malformation pattern varied with the strain of mice studied (Kalter, 1990). Thiamin Hauschildt (1942) established the minimum requirement of thiamin for normal growth of mice at 10 µg/day. This would correspond to a concentration of approximately 3 mg/kg diet. Morris and Dubnik (1947) later found the growth requirement to be 4 to 6 µg/day for mice fed a diet containing 22 percent fat. Results of studies on the specific requirements for reproduction and lactation have not been reported, but Mirone and Cerecedo (1947) found that 20 mg/kg diet were adequate. The purified diet (American Institute of Nutrition, 1977) containing 6 mg thiamin-HCl/kg diet has been used in numerous mouse colonies resulting in normal growth and reproduction. In the absence of more definitive data the concentration of 5 mg thiamin-HCl/kg diet that was the estimated requirement in the previous issue of this report (National Research Council, 1978) is being retained. Signs of Thiamin Deficiency Morris (1947) and Jones et al. (1945) reported violent convulsions, especially when the animal was held a few seconds by the tail; cartwheel or circular movements; brain hemorrhages; decreased food intake; poor growth; early mortality; silvery-streaked muscle lesions; and testicular degeneration. The onset of ataxia in thiamin-deficient Swiss-Webster mice was preceded by a rapid rise in brain α-ketoglutarate (Seltzer and McDougal, 1974). Deficiency (4 to 21 days) led to increased activity in hepatic thiamin pyrophosphatase, alkaline phosphatase, and acid phosphatase (Tumanov and Trebukhina, 1983). Exposure of thiamin-deficient mice to ethanol resulted in brain damage that was more severe than either treatment alone (Phillips, 1987). POTENTIALLY BENEFICIAL DIETARY CONSTITUENTS FIBER A fiber source is routinely included to increase bulk in diets for mice, but at high concentrations it depresses performance. Dilution of diets with cellulose at concentrations of 15, 30, and 50 percent increased feed intake by 3.5, 12.0, and 26.9 percent, respectively, resulting in consumption of noncellulose constituents of 88.4, 78.4, and 63.5 percent of what mice fed the undiluted diet consumed (Dalton, 1963). Bell (1960) diluted mouse diets with wheat bran, alfalfa, beet pulp, oat hulls, wheat straw, corn cobs, or cellulose in amounts designed to dilute digestible energy (DE) to concentrations ranging from 2.2 to 3.4 kcal/g diet (9.2 to 14.2 kJ/g diet). In general, growth rate decreased when DE was less than 2.9 kcal/g diet (12.1 kJ/g diet). Fiber sources produced different effects. Mice fed 33 to 39 percent wheat straw died. Mice performed poorly when their diets consisted of 38 to 45 percent beet pulp. However, mice fed up to 68 percent wheat bran or up to 43 percent oat hulls grew at rates similar to those fed lower fiber concentrations. When cornstarch was replaced by barley bran, oat bran, rice bran, or soybean fiber in amounts supplying 7 percent fiber (TDF) to diets containing 30 percent ground beef, growth of mice was not affected (Hundemer et al., 1991). Addition of 10 percent guar gum, bagasse, or wheat bran to a natural-ingredient diet did not affect feed intake or growth of mice, although guar increased and bagasse decreased liver lipogenic enzymes (Stanley and Newsholme, 1985a,b; Stanley et al., 1986). VITAMINS Ascorbic acid The successful maintenance of mouse colonies fed diets devoid of ascorbic acid has confirmed the demonstration by Ball and Barnes (1941) that the mouse requires no dietary source of vitamin C. The plasma concentration of dehydroascorbate in mice fed graded concentrations of ascorbic acid (from 0 to 80 g/kg diet) increased with greater dietary concentrations; ≥10 g/kg resulted in significantly greater dehydroascorbate concentration in heart, kidney, lung, and spleen. Concentrations in eyes, were only slightly increased; and brain, adrenal gland, and leukocyte concentrations were unchanged in mice consuming diets containing 80 g/kg (Tsao et al., 1987; Tsao and Leung, 1989).
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Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995 During the first 8 days of pregnancy an inverse relationship was found between ascorbic acid intake and the concentration of peroxidase in the corpus luteum, blastocyst, and endometrium (Agrawal and Laloraya, 1979). A diet of 10 g ascorbic acid/kg increased average life span by 8.6 percent, decreased body weight by 6 to 7 percent, and increased the maximal life span 2.9 percent (from 965 to 993 days) in C57BL/6J male mice (Friedman et al., 1987). Myo-inositol Although Woolley (1941) reported that myo-inositol would alleviate a condition characterized by hair loss, other studies (Martin, 1941; Cerecedo and Vinson, 1944; Fenton et al., 1950; Shepherd and Taylor, 1974a) did not confirm the essentiality of myo-inositol for growth of mice. Studies with other rodent species indicate that they require myo-inositol under conditions of microbial suppression and physiological stress. Shepherd and Taylor (1974b) found that myo-inositol enhanced intestinal lipid transport in rats fed a 31 percent fat diet. Burton and Wells (1977) observed that rats fed 0.5 percent dietary phthalysulfathiazole required myo-inositol to prevent fatty liver during lactation; 500 mg myo-inositol/kg diet was sufficient. Anderson and Holub (1976) found that either tallow or the highly unsaturated canola oil caused liver fat accumulation in myo-inositol-deficient rats fed succinyl sulfathiazole, whereas corn oil or soybean oil did not; 0.5 percent myo-inositol was protective. Unlike rats (Bondy et al., 1990), the peripheral nerves of mice fed diets containing galactose (20 percent) were not depleted of myo-inositol (Calcutt et al., 1990). If gnotobiotic, germ-free, or antibiotic-treated mice are fed diets containing tallow or the highly saturated rapeseed oil, then myo-inositol may be required in the diets. A purified diet fed to germ-free rats and mice contained 1,000 mg myo-inositol/kg diet (Wostmann and Kellogg, 1967). Chemically defined diets that supported growth and limited reproduction in germ-free CFW or C3H mice contained 238 mg myo-inositol/kg diet (Pleasants et al., 1970, 1973). A concentration of 500 mg/kg diet was adequate for any combination of antibiotics, lactation, and unusual fat intake in rats and gerbils and seemed to be the upper limit of the myo-inositol requirement. However, conventionally reared mice fed ordinary diets have not been found to require dietary myo -inositol since the early studies of Woolley (1941, 1942). REFERENCES Agrawal, P., and M. M. Laloraya. 1979. Ascorbate and peroxidase changes during pregnancy in albino rat and Swiss mouse. Am. J. Physiol. 5:E386–E390. Alcock, N. W., and M. E. Shils. 1974. Comparison of magnesium deficiency in the rat and mouse. Proc. Soc. Exp. Biol. Med. 146:137–141. Allen, A. M., C. T. Hansen, T. D. Moore, J. Knapka, R. D. Ediger, and P. H. Long. 1991. Hemorrhagic cardiomyopathy and hemothorax in vitamin-K-deficient mice. Toxicol. Pathol. 19(4-Part II):589–596. Allen, J. C. 1984. Effect of vitamin D deficiency on mouse mammary gland and milk. J. Nutr. 114:42–49. American Institute of Nutrition. 1977. Report of the American Institute of Nutrition Ad Hoc Writing Committee on standards for nutritional studies. J. Nutr. 107:1340–1348. Anderson, D. B., and B. J. Holub. 1976. The influence of dietary inositol on glyceride composition and synthesis in livers of rats fed different fats . J. Nutr. 106:529–536. Arce, D. S., and C. L. Keen. 1992. Reversible and persistent consequences of copper deficiency in developing mice. Reprod. Toxicol. 6:211–221. Aughey, E., L. Grant, B. L. Furman, and W. F. Dryden. 1977. The effects of oral zinc supplementation in the mouse. J. Comp. Pathol. 87:1–14. Ball, Z. B., and R. H. Barnes. 1941. Effect of various dietary supplements on growth and lactation in the albino mouse. 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A comparison of fibrous feedstuffs in non-ruminant rations: Effects on growth responses, digestibility, rates of passage and ingesta volume. Can. J. Anim. Sci. 40:71–82. Bell, J. M., and J. D. Erfle. 1958. The requirement for potassium in the diet of the growing mouse. Can. J. Anim. Sci. 38:145–147. Bell, J. M., and A.-M. John. 1981. Amino-acid requirements of growing mice: Arginine, lysine, tryptophan and phenylalanine . J. Nutr. 111:525–530. Bell, J. M., and M. O. Keith. 1992. Effects of levels of dietary protein and digestible energy on growth, feed utilization and body composition of growing mice. Nutr. Res. 12:375–383. Bell, L., and L. S. Hurley. 1973. Ultrastructural effects of manganese deficiency in liver, heart, kidney and pancreas of mice. Lab. Invest. 29:723–736. Bell, R. R., C. A. Blanshard, and B. E. Haskell. 1971. Metabolism of vitamin B6 in the I-strain mouse. II. Oxidation of pyridoxal. Arch. Biochem. Biophys. 147:602–611. Bell, R. R., D. Y. Tzeng, and H. H. Draper. 1980. Long-term effects of calcium, phosphorus, and forced exercise on the bones of mature mice. J. Nutr. 110:1161–1168. Bender, D. A., E. N. M. Njagi, and P. S. Danielian. 1990. Tryptophan metabolism in vitamin B6-deficient mice. Br. J. Nutr. 63:27–36. Berkow, S. E., and A. T. Campagnoni. 1983. Essential fatty acid deficiency: Effects of cross-fostering mice at birth on myelin levels and composition . J. Nutr. 113:582–592. Bernier, J. F., C. C. Calvert, T. R. Famula, and R. L. Baldwin. 1986. Maintenance energy requirement and energetic efficiency of mice
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No. 19 . London: Butterworths. Burton, L. E., and W. W. Wells. 1977. Characterization of the lactation-dependent fatty liver in myo-inositol deficient rats. J. Nutr. 107:1871–1883. Calcutt, N. A., D. R. Tomlinson, and S. Biswas. 1990. Coexistence of nerve conduction deficit with increased Na+-K+-ATPase activity in galactose-fed mice: Implications for polyol pathway and diabetic neuropathy. Diabetes 39:663–666. Calvert, C. C., T. R. Famula, J. F. Bernier, N. Khalaf, and G. E. Bradford. 1986. Efficiency of growth in mice with a major gene for rapid postweaning gain. J. Anim. Sci. 62:77–85. Canolty, N. L., and L. J. Koong. 1976. Utilization of energy for maintenance and for fat and lean gains by mice selected for rapid postweaning growth rate. J. Nutr. 106:1202–1208. Cerecedo, L. R., and L. J. Vinson. 1944. Growth, reproduction and lactation in mice on highly purified diets, and the effect of folic acid on lactation. Arch. Biochem. 5:157–161. Cercedo, L. R., F. P. Panzarella, A. B. 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Representative terms from entire chapter: