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Primates Nutrient Requirements – 2003

Nutrient Requirements of Nonhuman Primates: Second Revised Edition

Committee on Animal Nutrition, Ad Hoc Committee on Nonhuman Primate Nutrition, National Research Council
ISBN: 0-309-51524-6, 308 pages, 8.5 x 11, (2003)

Includes Vitamin D, Vitamin K, Sulfur, Iodine, Magnesium, and many others

Note IU are typically given per kg of FEED not WEIGHT

 Download the PDF from VitaminDWiki.

Vitamin D

For the primate species that have been studied, vitamin D is not an essential component of the diet as long as they have adequate exposure to sunlight (Holick, 1994). But it appears to be essential in the tissues of most primates for maintenance of calcium and phosphorus homeostasis and for normal bone mineralization (Holick, 1996). In the absence of solar exposure, these primates must be exposed to sources of artificial light of appropriate wavelengths or must receive sufficient vitamin D in the diet. In this review we will try to put into perspective what is known about vitamin D in humans and to compare this information with what is known about its role in nonhuman primates and other vertebrates.!

PHOTOBIOLOGY, METABOLISM, AND FUNCTION OF VITAMIN D

Vitamin D is a secosteroid (a split- or open-ringed steroid) that originates from a four-ringed steroid known as provitamin D, with double bonds at carbons 5 and 7. The 5,7-diene of the sterol has maximal ultraviolet (UV) radiation absorption at wavelengths of 265, 272, 281, and 295 nm and does not absorb radiation above 315 nm. Thus, when provitamin D3 (7-dehydrocholesterol, the 5,7-diene counterpart of cholesterol) or provitamin D2 (ergosterol, the 5,7-diene sterol found in fungi and plants) is exposed to solar UV radiation up to 315 nm, the 5,7-diene absorbs it and undergoes a transformation of the double bonds; the result is an opening of the B ring to yield previtamin D. Previtamin D exists in two conformers, the cis, cis and cis, trans forms. Although the cis, trans conformer is thermodynamically stable and therefore favored, only the cis, cis form ultimately can be converted to vitamin D. In nonbiologic systems (such as in organic solvents) at 37°C, it takes about 24 hours for 50% of previtamin D to be converted to vitamin D. However, in biologic systems, the previtamin D is sandwiched between fatty acids of the bilipid layer of the cell membrane. In that location, only the cis, cis conformer exists, and it is rapidly converted to vitamin D. This is evolutionarily important because coldblooded vertebrates would have been unable to make vitamin D3 in their skin efficiently at usual ambient temperatures in light of the slow conversion of previtamin D3 to vitamin D3.

During exposure to sunlight, 7-dehydrocholesterol in the epidermis and dermis of humans absorbs UV radiation between 290 and 315 nm, the shortest wavelengths that regularly penetrate the atmosphere and reach the earth's surface. After UV absorption, 7-dehydrocholesterol is converted to previtamin D3 which undergoes an internal isomerization to form vitamin D3. Vitamin D3 is biologically inert and is exported out of the skin into the plasma, where it is bound to a vitamin D-binding transport protein. It can be stored in the fat for later use or—in most higher vertebrates, including amphibians, reptiles, birds, nonhuman primates, and humans—undergoes hydroxylation in the liver to form 25-hydroxyvitamin D3, 25(OH)D3or calcidiol. This metabolite is the major circulating form used to assess vitamin D status in most terrestrial vertebrates. When vitamin D is ingested, either as vitamin D2 (ergo-calciferol, or ercalciol) or vitamin D3 (cholecalciferol, or calciol), it is incorporated into chylomicra, and about 80% in humans is absorbed into the lymphatic system and directed to the liver (Holick, 1999).

25(OH)D, although the major circulating form of vitamin D, is biologically inert at normal physiologic concentrations and undergoes 1a-hydroxylation in the kidney to form 1,25-dihydroxyvitamin D, 1,25(OH)2D. 1,25(OH)2D iscon-sidered the principal biologically functioning form of vitamin D, responsible for maintaining calcium and phosphorus homeostasis and normal bone metabolism. Specific nuclear receptors for 1,25(OH)2D3, known as vitamin D receptors (VDRs), have been identified in the tissues of rodents, birds, nonhuman primates, and humans. It is suspected that there are also nuclear vitamin D receptors in lower vertebrates, including amphibians and reptiles (Holick, 1996). 1,25(OH)2D interacts with its target-tissue nuclear VDR and in birds, rodents, and humans combines with retinoic acid X receptor to form a heterodimeric complex. This heterodimeric complex then sits on vitamin D-responsive elements in the genomic DNA to alter transcriptional activity and modulate calcium metabolism (Holick, 1989; Darwish et al., 1993). In the small intestine, 1,25(OH)2D enhances intestinal calcium transport along its entire length. However, the region of highest efficiency for vitamin D-mediated calcium transport is the duodenum. In bone, 1,25(OH)2D interacts with osteoblasts to induce production of osteocalcin, osteonectin, osteopontin, and alkaline phosphatase (Lian et al., 1987; Darwish et al., 1993). It also stimulates the expression of the osteoclast differentiation factor in osteoblasts that, in turn, signals preosteo-clasts to become mature (Holick, 1999). Thus, 1,25(OH)2D3 indirectly increases the number of mature osteoclasts, which increase mobilization of calcium stores from the bone.

MEASURES OF VITAMIN D ACTIVITY

The World Health Organization has defined an international unit (IU) of vitamin D activity as that provided by 0.025 |j,g (65.0 pmol) of crystalline cholecalciferol (Norman, 1998). The US Pharmacopeia (USP; Rockville, MD) makes available a USP Reference Standard which provides 1 IU of vitamin D activity per 0.025 |j,g (or 40 IU-/ g).

VITAMIN D DEFICIENCY

A deficiency of vitamin D in humans, rodents, birds, and nonhuman primates results in a decrease in intestinal calcium absorption. The decrease leads to a decline in plasma ionized calcium (detected by the calcium sensor in the parathyroid glands), which results in an increase in the production of parathyroid hormone (PTH) (Darwish et al., 1993). PTH has several effects on calcium and phosphorus metabolism. It interacts with osteoblasts to induce osteoclast differentiation factor, which stimulates preosteoclasts to become mature (Holick, 1999); this ultimately results in an increased number of osteoclasts and increased bone mineral mobilization. PTH enhances reabsorption ofmobi-lized calcium in the distal renal convoluted tubules and increases loss of mobilized phosphate into the ultrafiltrate; this loss results in phosphaturia. PTH also stimulates the renal production of 1,25(OH)2D, which, in turn, enhances intestinal calcium absorption (Darwish et al., 1993).

Chronic vitamin D deficiency results in mineralization defects in the skeleton. During growth, before skeletal epiphyseal plates have closed, vitamin D deficiency can lead to marked epiphyseal plate hypertrophy, producing bulges at the ends of the long bones and at the costachon-dral junctions in the rib cage. In adults, after the epiphyseal plates have closed, vitamin D deficiency results in a more subtle defect known as osteomalacia. Although the osteo-blasts function normally and lay down collagenous bone matrix, the deficiency of vitamin D results in an inadequate calcium x phosphate product, preventing normal mineralization of the soft osteoid and leading to an increased risk of bone fracture. Vitamin D deficiency and consequent secondary hyperparathyroidism also result in increased mobilization of precious calcium stores from the adult skeleton, thereby inducing and exacerbating osteoporosis. Chronic vitamin D deficiency with low calcium intake ultimately results in hypocalcemia; this can lead to severe spasms of skeletal muscle, with tetany, laryngospasms, and death.

There are numerous reports of rickets or osteomalacia in captive nonhuman primates (Vickers, 1968; Miller, 1973;Fiennes, 1974; Ullrey, 1986; Allen et al., 1995; Morrisey et al., 1995; Meehan et al., 1996). The syndrome has been called simian bone disease, woolly monkey disease, and cage paralysis. Signs of deficiency have been reported more frequently in young than in mature primates and in platyr-rhines (New World monkeys) than in catarrhines (Old World monkeys and apes). Some have proposed that the difference is a result of higher vitamin D requirements in New World monkeys or a limited ability to use vitamin D2 (Hunt et al., 1966). The suggestion by Freedman et al. (1976) that it is a failure to convert vitamin D2 to vitamin D3 is not consistent with known metabolic pathways (Norman and Collins, 1994; Holick, 1999)

Signs of vitamin D deficiency were seen in a nursing red howler (Alouatta seniculus) infant (Ullrey, 1986) and in three juvenile colobus monkeys (Colobus guereza kikuy-uensis) (Morrisey et al., 1995) housed with their mothers in zoo exhibits without sunlight exposure or an artificial UVB source. The infants ate little solid food and depended heavily on mother's milk for their nutrient intake. Gradually, their activity declined, and they had difficulty in walking, climbing, and grasping their mothers. Physical examination revealed bone pain, bowed long bones, and limb joints that were lax and swollen. Changes visualized with radiography included cupping of the metaphyses, widening of the epiphyseal plates, and thinning of the cortices. Some bones exhibited fibrous osteodystrophy, and fractures were seen in the distal femoral epiphyses. Serum calcium, inorganic phosphorus, and alkaline phosphatase in a severely affected 10-month-old female colobus were 8.1 mg-dl-1, 2.7 mg-dl-1, and 1,293 IU-L-1, respectively. The serum 25(OH)D concentration was less than 10 ng-ml-1.A 2-month-old colobus monkey showed mild widening of epi-physeal plates radiographically and had increased serum alkaline phosphatase activity (2,268 IU-L-1) and low 25(OH)D concentration (10 ng-ml-1). After intramuscular injection of ergocalciferol and solar exposure, the radio-graphic appearance of the skeleton returned to normal, and serum 25(OH)D rose to 19 ng-ml- 1. Although milk vitamin D concentrations were not measured, the authors proposed that nonhuman primate milk was low in vitamin D, as is human and cow's milk, and nursing infants that do not eat substantial amounts of other vitamin D-containing foods are at risk if not exposed to UVB. It is noteworthy that rickets has not been seen after installation of UVB-transparent skylights in the red howler and the colobus zoo exhibits.

DISCRIMINATION BETWEEN VITAMIN D2 AND VITAMIN D3

The major structural difference between vitamin D2 and vitamin D3 is that vitamin D2, which originates from the fungal and plant sterol ergosterol, has a methyl group on carbon 24 and a double bond between carbons 22 and 23.
In the 1930s, it was shown that chickens fed vitamin D2 developed rickets (Holick, 1996), and ultimately vitamin D3 was found about 10 times more effective than vitamin D2 in preventing rickets in poultry (Hurwitz et al., 1967).
For years, the biologic activities of the two vitamins were assumed equal in domestic mammals.
However, studies showed that vitamin D2 is also less active than vitamin D3 in the pig, cow, and horse, but the difference is not as great as in the chicken.
The vitamin D-binding and vitamin D-metabolite-binding transport proteins appear to vary among species (Edelstein, 1974; Hay and Watson, 1976a, 1976b, 1977), and Edelstein et al. (1973) speculated that the apparent dissimilarity between New World and Old World monkeys in the biologic activity of vitamins D2 and D3 (Hunt et al., 1967; Lehner et al., 1968) might be due to these differences.
The mechanism of discrimination is not entirely understood, but Horst et al. (1988) published data suggesting that there is less absorption of vitamin D2 from the gut and enhanced clearance of 25(OH)D2 and 1,25(OH)2D2 from the blood than is the case for vitamin D3 and its metabolites. Furthermore, there is some evidence that tissue vitamin D receptors do not recognize 1,25(OH)2D2 as well as 1,25(OH)2D3 (Holick, 1996).

There are about 100 species of New World monkeys (platyrrhines) and over 100 species of Old World monkeys and apes. Relatively few species in either group have been studied, and published research findings are inadequate to make generalizations about differences between them.
Nevertheless, the evidence that vitamin D2 is less active than vitamin D3 in the New World species that have been studied is convincing.
Well-controlled studies comparing the activities ofthe two vitamin forms in Old World species appear not to have been conducted.

Lehner et al. (1968) fed growing squirrel monkeys (Saimiri sciureus) no vitamin D or vitamin D2 at 1,250, 2,500, 5,000, or 10,000 IU-kg- 1 of diet. They grew poorly and exhibited rickets, regardless of treatment.
In contrast, when squirrel monkeys were fed vitamin D3 at 1,250, 2,500, 5,000 or 10,000 IU-kg- 1 diet, all grew equally well, and no rickets were seen. Hunt et al. (1967) fed adult white-fronted capuchin monkeys (Cebus albifrons) purified diets containing 0.8% calcium, 0.46% phosphorus, vitamin A and D2 at 12,500 and 2,000 IU-kg- 1, respectively, for 2 years. The monkeys developed fibrous osteodystrophy, were thin and inactive, and had distorted limbs, kyphosis, and multiple fractures with no evidence ofcallus formation. When dietary vitamin D2 was replaced by vitamin D3 at 2,000 IU-kg- 1 for 5 months, the appearance ofthe capuchin monkeys improved, and they became more active. Previous fractures became resistant to movement, and callus formation was evident radiographically. Hunt et al. (1967) also fed adult cotton-top tamarins (Saguinus oedipus), white-lipped tamarins (Saguinus nigricollis), and black-chested mustached tamarins (Saguinus mystax) a commercial primate diet containg vitamin D2 at 2,200 IU-kg- 1 for 8-12 months and observed deficiency signs that were similar to but less severe than those seen in the capuchins. Healing was initiated by feeding each animal 500 IU of vitamin D3 per week. The researchers reported anecdotally that they had seen fibrous osteodystrophy in squirrel monkeys fed vitamin D2 but not in squirrel monkeys or woolly monkeys (Lagothrix spp.) fed vitamin D3 or exposed to sunlight. Although no information on dietary nutrient concentrations or husbandry was provided, they also stated that thousands of rhesus and other Macaca species (Old World monkeys) had been fed diets containing only vitamin D2 without evidence of metabolic bone disease. Vickers (1968) observed osteomalacia and rickets in capuchins fed a commercial primate diet containing vitamin D2 and noted that injections ofvitamin D (form unspecified) or vitamin D3 at 2,200 IU-kg-1 diet would reverse the disease. Lehner et al. (1968) observed bone lesions in squirrel monkeys that could not be prevented by vitamin D2at 10,000 IU-kg- 1 diet, but the lowest concentration of vitamin D3 tested, 1,250 IU-kg-1 of diet, was effective.

METABOLIC RESISTANCE TO VITAMIN D3 IN CALLITRICHIDS

In 1983, Shinki et al. reported blood concentrations of 25(OH)D3,1,25(OH)2D3, and 24,25(OH)2D3 in seven adult (five males and two females) marmosets (Callithrix jac-chus) that weighed about 300 g. They were fed a commercial diet ostensibly containing vitamin D3 at 9,100 IU-kg-1 (not analyzed) and fruit. In addition, they were given 500 IU of vitamin D3 orally twice a week. Housing was not described. Daily mean feed intake (± SEM) was reported to be 20 ± 5 g, but there was no indication whether this was the intake of DM, whether fruit was included, or whether the mean was derived from daily food intake for the group or for individual animals. Serum calcium concentrations in these marmosets ranged from 7.9-9.9 mg-dl-1, and serum phosphorus ranged from 2.1-4.7 mg-dl-1. Circulating concentrations of 25(OH)D3 were 12.4-204.1 ng-ml-1, with a mean of 94.5 ng-ml-1, about 5 times that in six volunteer men from whom blood samples were taken. The mean 1,25(OH)2D3 concentration of 418.8 pg-ml- 1, with a range of 196.1-642.4 pg-ml- 1, was about 10 times that in the volunteers. Two marmosets that had serum calcium concentrations of 8.8 and 9.9 mg-dl-1 with serum phosphorus concentrations of 2.1 mg-dl- 1 and serum 25(OH)D3 concentrations of 16.5 and 12.4 ng-ml- 1 had somewhat increased alkaline phosphatase values, were osteomalacic, and had bone fractures. Serum 24,25(OH)2D3 concentrations ranged from less than 0.2 ng-ml- 1 (in the marmosets with fractures) to 8.23 ng-ml- 1, but the mean, although numerically higher than the mean in the volunteers, did not differ significantly from it. It should be noted that a later report from the same research group (Yamaguchi et al., 1986) stated that marmosets were housed in pairs in cages and that the very low serum levels of 25(OH)D3 in osteomalacic marmosets were probably due to insufficient intake of food (and of vitamin D) because of interference in food selection by cagemates.

In the same study, six young adult female rhesus monkeys (Macaca mulatta) weighing 4-6 kg were fed a commercial diet containing vitamin D3 at 2,400 IU-kg-1 of diet (not analyzed). The mean serum concentration of 25(OH)D3 (estimated by measuring column heights in Shinki et al. 1983, Figure 1) was 50 ng-ml-1 and of 1,25(OH)2D3 was 96 pg-ml- 1. Those were not significantly different from the concentrations in the volunteers, who had a mean 25(OH)D3 concentration (estimated as above) of 17 ng-ml-1 and a mean 1,25(OH)2D3 concentration of 44 pg-ml- 1. The mean 24,25(OH)2D3 concentration in the serum of rhesus monkeys was essentially identical with that in the marmosets.

The finding of extremely high serum concentrations of 1,25(OH)2D3 without hypercalcemia in common marmosets was duplicated in emperor tamarins (Saguinus imperator) by Adams et al. (1984). Another study of the common marmoset (Callithrix jac-chus) as an animal model for vitamin D-dependent rickets, type II, was published by Suda et al. (1986). (Apparently this study was republished by Yamaguchi et al. 1986 with slightly different marmoset data.) Seventeen adult marmosets weighing about 300 g were fed a diet containing vitamin D3 at 1,480 IU-kg-1 and were given an additional 1,000 IU of vitamin D3 orally twice a week. On the basis of a mean daily intake of 20 g of diet, vitamin D3 intakes were estimated to be 110 IU-BW100g-1-day-1. Five rhesus monkeys (Macaca mulatta) weighing about 5 kg were fed a diet containing vitamin D3 at 2,400 IU-kg- 1. On the basis of a daily diet intake of about 100 g, vitamin D3 intake was estimated to be 5 IU-BW100g-1-day-1. Two of the 17 marmosets were found to have bone fractures and radio-graphic evidence consistent with osteomalacic changes in their bones despite the high vitamin D intake, whereas none of the five rhesus monkeys showed any signs of osteomalacia. The mean (± SEM) serum 25(OH)D3 concentration in the rhesus monkeys was 50 ± 4 ng-ml- 1; in the 15 marmosets showing no osteomalacia, it was 478 ± 108 ng-ml- 1. The serum level of 1,25(OH)2D3 in the rhesus monkeys was 95 ± 17 pg-ml- 1; in the marmosets, it was 491 ± 93 pg-ml- 1. The two osteomalacic marmosets had serum calcium concentrations of 8.8 and 9.9 mg-dl- 1 and serum inorganic phosphorus concentrations of 2.2 mg-dl- 1 compared with means of8.4 ± 0.2 and 4.5 ± 0.2 mg-dl- 1, respectively, in the normal marmosets. Serum 25(OH)D3 and 1,25(OH)2D3 concentrations in the osteomalacic marmosets were 17 and 12 ng-ml- 1 and 642 and 524 pg-ml-1, respectively. Two rhesus monkeys were given vitamin D3 at 900 IU-BW100g-1-day- 1 for 1 month; it resulted in serum 25(OH)D3 concentrations of 1,352 and 1,651 ng-ml- 1 and serum 1,25(OH)2D3 concentrations of 73 and 74 pg-ml- 1. In vitro studies with kidney homogenates and intestinal cytosols led these researchers to conclude that 1a-hydroxy-lase activity is higher in the kidney of the marmoset and 24-hydroxylase activity is higher in the kidney of the rhesus monkey. In addition, there appeared to be fewer 1,25(OH)2D3 receptors and lower activity of the receptor-binding complex in the intestine of the marmoset than in that of the rhesus monkey (see also Takahashi et al., 1985). Whether the differing dietary history of the tissues used in the in vitro tests might have influenced the results was not explored.

To put the above observations on vitamin D metabolite concentrations in the serum of captive primates in perspective, it should be noted that 18 free-ranging, wild cotton-top tamarins (Saguinus oedipus) in Colombia had serum 25(OH)D concentrations of 25.5-120 ng-ml-1 with a mean of 76.4 ng-ml-1 (Power et al., 1997). Serum 25(OH)D concentrations in six normal captive cotton-top tamarins consuming diets containing vitamin D3 at 2,500 IU-kg-1 of dry matter were 48-236 ng-ml- 1 with a mean of 143.5 ng-ml- 1. Serum 25(OH)D concentrations in 24 captive cotton-top tamarins consuming diets containing vitamin D3 at 26,000 IU-kg- 1 of dry matter were 11-560 ng-ml-1; two were 11 and 12 ng-ml-1, five ranged from 46 to 60 ng-ml-1, three were between 126 and 176 ng-ml-1, and the remaining 14 were over 224 ng-ml-1. None of the tamarins exhibited bone disease (Ullrey et al., 1999). Analyses of 1,25(OH)2D and 24,25(OH)2D were not performed in the studies of either Power et al. (1997) or Ullrey et al. (1999).

Liberman et al. (1985), using soluble extracts of Epstein-Barr virus-transformed B lymphocytes, found that extracts from a single common marmoset (Callithrix jacchus) had a lower binding affinity for 1,25(OH)2D3 (Kd, 2.2 nM) than did extracts from three normal humans (Kd, 0.27 nM). 1,25(OH)2D3 binding capacity for extracts from the marmoset lymphocytes also were lower (6.9 fmol-mg-1 of protein) than those from human lymphocytes (15.4 fmol-mg-1 of protein). Soluble extracts from herpesvirus papio-transformed B lymphocytes from a stump-tailed macaque (Macaca arctoides) had a 1,25(OH)2D3 binding affinity of 0.40nM and a 1,25(OH)2D3 bindingcapacityof14 fmol-mg-1 of protein. The researchers speculated that a defective receptor for 1,25(OH)2D3 could account for target-tissue resistance to this hormone in the common marmoset, but they acknowledged that the type of defect (binding affinity versus capacity) appeared to vary with the cell system analyzed. For example, Chandler et al. (1984) found that LLC-MK2 cells isolated from renal tissue of rhesus monkeys (M. mulatta) had a 1,25(OH)2D3 binding affinity lower by a factor of 30 than LLC-MK2 renal cells from humans.

Gacad and Adams (1992) studied the specificity of steroid binding in B95-8 B-lymphoblastoid cell lines established by Epstein-Barr virus transformation of peripheral blood mononuclear cells from the common marmoset (Cal-lithrix jacchus). The binding of 1,25(OH)2D 3 and 25(OH)D3 in extracts ofthe lymphoblastoid cells was studied in the presence and absence of potentially competitive ligands, including 1,25(OH)2D3, 25(OH)D3,17(3-estradiol, testosterone, and progesterone. Compared with extracts containing the authentic nuclear 1,25(OH)2D3 receptor, extracts of B95-8 cells bound 180% more 1,25(OH)2D3 and 12 times more 25(OH)D3 by weight. The rank order of steroid binding by this intracellular competitive binding component was 25(OH)D3 > 1,25(OH)2D3 > estradiol = progesterone = testosterone. The investigators suggested that the higher concentrations of 25(OH)D3 in the serum of some New World primates result from the relative lack of 25(OH)D3-24-hydroxylase activity and are necessary to ensure that there is adequate substrate for maintenance of the increased 1,25(OH)2D3 concentrations that these primates require. Furthermore, they speculated that the elevated 1,25(OH)2D3 concentrations represented an evolutionary adaptation to ancestral diets that included hyper-calcemic plants similar to Solanumglaucophyllum, containing high concentrations of 1,25(OH)2D3 glycosides. One means of avoiding life-threatening hypercalcemia would be for the authentic nuclear 1,25(OH)2D3 receptor to coex-press or overexpress an intracellular steroid-binding protein that would intercept such glycosides. Alternatively, the intracellular binding protein might have evolved to protect against non-vitamin D steroid-like compounds. Because the nocturnal Aotus trivirgatus also expresses this protein, but at a much lower level, these workers suggested that the vitamin D so readily supplied via cutaneous photosynthesis during daytime in an equatorial environment also might have contributed to the development of vitamin D-resistant primate phenotypes.

ANIMALS NOT EXPOSED TO NATURAL SUNLIGHT OR UNABLE TO MAKE VITAMIN D IN THEIR SKIN

Diverse terrestrial vertebrate species are never exposed to sunlight, these including some species of bats and some rodents. The rodent species Rattus rattus has 7-dehydro-cholesterol in the skin, providing the substrate required for cutaneous photosynthesis of vitamin D; considering this rat's nocturnal behavior, it is uncertain whether vitamin D requirements are met mostly by photosynthesis or by the diet. Intense skin pigmentation and minimal exposure to sunlight might put some species at substantial risk for vitamin D deficiency. Some nonhuman primate species are nocturnal, and solar UVB exposure is slight. It has not been established how such species obtain their vitamin D supply or, in some cases, whether they require vitamin D.

Naked mole rats spend their entire lives underground and are never exposed to sunlight. Furthermore, vitamin D has not been found in the roots and other foods that they eat (Skinner et al., 1991). There is evidence that naked mole rats have extremely low circulating concentrations of 25(OH)D and 1,25(OH)2D (Buffenstein et al., 1993). Little is known about parathyroid function in these animals, but it appears that their intestine is able to transport calcium adequately in the absence of vitamin D (Pitcher et al.,1992).

A remarkable observation is that cats have extremely low concentrations of 7-dehydrocholesterol in their skin for which Morris (1999) provide convincing evidence of an ineffectiveness in photosynthesizing vitamin D. As a result, vitamin D must be present in their diet to maintain circulating concentrations of 25(OH)D and 1,25(OH)2D in the physiologic ranges needed to satisfy requirements for normal calcium homeostasis and bone metabolism. However, cats are carnivorous, in contrast with most primate species; because tissues of carnivore prey usually contain sufficient vitamin D, there presumably would be little need for cutaneous vitamin D photosynthesis. Whether any nonhuman primate species resembles cats in that regard has not been established.

(Note: Cats may get vitamin D from their fur, not their skin)

VITAMIN D REQUIREMENTS

Presumably, if nonhuman primates have little or no exposure to UVB radiation, either from the sun or from artificial sources, they require vitamin D in their diet. Few studies have been conducted to define requirements quantitatively. Lehner et al. (1968) made it clear that the form of vitamin D used in setting the requirement is important when they found that vitamin D3 at 1,250 IU-kg-1 of diet (the lowest concentration studied) was adequate for growing squirrel monkeys (Saimiri sciureus) but that vitamin D2 at 10,000 IU-kg-1 was not. Because the difference in biologic activity between vitamins D2 and D3 has been observed in so many species, estimates of vitamin D requirements will be given here only in terms of vitamin D3.

(Note: Primates need D3, not D2)

In a study of vitamin E deficiency, Ausman and Hayes (1974) fed a purified diet for 2 years that furnished vitamin D3 at 1,000 IU-kg-1 to juvenile crab-eating macaques (Macaca fascicularis) and capuchins (Cebus albifrons, apella), Old World and New World monkeys, respectively. Growth was normal, and no bone lesions were observed in any of the monkeys. Hunt et al. (1967) induced fibrous osteodystrophy in adult white-fronted capuchins (Cebus albifrons) by feeding a purified diet containing vitamin D2at 2,000 IU-kg- 1 for 2 years. When vitamin D3 at 2,000 IU-kg- 1 (lowest concentration studied) replaced the vitamin D2 for 5 months, callus formation began and the fractures were stabilized. The previous National Research Council (1978) recommendation for nonhuman primates was vitamin D3 at 2,000 IU-kg-1 of diet (presumably 90% DM), and Flurer and Zucker (1987) reported that this concentration supported serum 25(OH)D concentrations of 30-300 nmol-L-1 (12-120 ng-ml- 1) in saddle-back tamarins (Saguinus fuscicollis) and was sufficient to meet their needs.

To establish baseline serum 25(OH)D concentrations for assessing vitamin D status of captive callitrichids, Power et al. (1997) collected blood samples from 18 wild, free-ranging cotton-top tamarins (Saguinus oedipus) in Colombia. They found serum 25(OH)D concentrations of 25.5120 ng-ml- 1 with a mean of 76.4 ng-ml-1. Assuming that cotton-top tamarins that have serum 25(OH)D concentrations in or near that range are adequately nourished with respect to vitamin D, the minimal dietary concentration of vitamin D3 supporting such concentrations in captive cotton-top tamarins with no UVB exposure could be used as an estimate of the minimal dietary requirement. Ullrey et al. (1999) found that a diet containing vitamin D3 at 2,500 IU-kg-1 of DM, fed to six captive cotton-top tamarins with no UVB exposure for 2 years, supported growth, reproduction, and serum 25(OH)D concentrations of 48236 ng-ml-1 with a mean of 143.5 ng-ml-1, with no evidence of pathologic changes. Lower dietary concentrations of vitamin D3 were not tested.

The growth of common marmosets (Callithrix jacchus) fed purified diets was studied by Tardiff et al. (1998). Power et al. (1999) then tested the ability of adult marmosets on these diets (males and nulliparous and pregnant or lactating multiparous females) to distinguish between water and calcium lactate solutions. According to Power (2000, personal communication), those and related studies involved feeding the purified diets to marmosets for 5 years. The initial dietary vitamin D3 concentration was 3,000 IU-kg-1, and it was used for about 21/2 years. Because of concern about suspected vitamin D deficiency in some animals, the dietary vitamin D3 was increased to 9,000 IU-kg-1, although there was no evidence of pathologic changes in most of the marmosets at the lower concentration. No other dietary vitamin D3 concentrations were tested, and no explanation for the variation in response has been provided.

Barnard and Knapka (1993) discussed callitrichid nutrition and summarized much of the research related to callitrichid nutrient requirements and dietary husbandry. They noted that when commercial primate diets were supplemented with fruit, preferences for fruit often reduced the intake of more nutritious food and resulted in nutrient imbalances and deficiencies. Ultimately, a highly palatable pelleted diet was formulated that, when fed alone, maintained normal weight in adult Saguinus mystax (Barnard et al., 1988). It was designated the NIH 48 Open Formula Pelleted Diet, and Barnard and Knapka (1993) presented details of its composition. The vitamin premix supplied vitamin D3 at 2,145 IU-kg-1 of diet. The diet contained 10.3% moisture, so the premix added vitamin D3 at about 2,400 IU-kg- 1 of dietary DM. Information on vitamin D supplied by the other ingredients was not provided, but on the basis of published analyses, amounts of vitamin D supplied by ingredients other than the vitamin premix would be negligible.

Because few studies were designed to define vitamin D requirements and there are disparate findings, it is not possible to identify a minimal dietary requirement with certainty. For the species that have been studied, it appears that in the absence of solar or artificial UVB exposure, dietary vitamin D3 concentrations of 1,000-3,000 IU-kg- 1 DM meet the needs of most. However, considering our present degree of uncertainty about minimal requirements and safe upper limits of vitamin D3 in the diet, it might be prudent to provide some exposure to natural or artificial UVB radiation. That requires either unimpeded exposure to solar radiation, careful selection of UVB-transparent plastics for windows or skylights, or use of artificial light sources that emit substantial UVB energy at appropriate wavelengths. Ullrey and Bernard (1999) have published information on UVB-transmitting plastics and UVB-emitting artificial lights.

HYPERVITAMINOSIS D

Daily oral doses of 50,000-100,000 IU of Vitamin D3 produced hypervitaminosis D in squirrel monkeys and white-fronted capuchins, whereas similar amounts of vitamin D2 did not (Hunt et al., 1969). The syndrome in squirrel monkeys included hypercalcemia, hyperphospha-temia, uremia, and death in 20-35 days, with no substantial metastatic calcification and minimal nephrocalcinosis. The capuchins died in 52-89 days and exhibited widespread metastatic calcification, including mineralization in the kidneys, aorta, lungs, myocardium, stomach, and various tissue arteries and arterioles. Bone lesions were not seen in either species.
Daily oral doses of 50,000-200,000 IU of vitamin D2 produced hypercalcemia in rhesus monkeys, but no soft-tissue calcification or deaths (Hunt et al., 1972). However, comparable oral doses of vitamin D3 produced marked hypercalcemia, death in 16-160 days, and evidence of nephrocalcinosis at necropsy.

Regular consumption of diets containing vitamin D3 at 6,000-8,200 IU-kg-1 by several New World and Old World primate species has resulted in increased serum 25(OH)D concentrations and speculation about whether such dietary concentrations might be excessive. When rhesus monkeys were fed a commercial primate diet containing vitamin D3 at 6,600 IU-kg- 1, serum concentrations of calcium, inorganic phosphorus, and parathormone were normal, but the mean (± SD) serum 25(OH)D concentration was 188 ± 94 ng-ml- 1 and was considered high (Arnaud et al., 1985).

Free-ranging rhesus monkeys maintained on Cayo Santiago by the Caribbean Primate Research Center (CPRC) in Puerto Rico were fed a commercial high-protein monkey diet containing vitamin D3 at 8,200 IU-kg-1 to complement wild foods (Vieth et al., 1987). However, monkey density was very high, and the commercial diet made up most of the food consumed (Ullrey, personal observation). Serum from 48 monkeys (six samples from each sex in each of four age classes) that were transferred from Cayo Santiago to the CPRC Sabana Seca Field Station was analyzed for 25(OH)D and 1,25(OH)2D. Group means for 25(OH)D were 143-230 ng-ml-1 and were considered high. Serum concentrations of1,25(OH)2D were variable (group means, 59-247 pg-ml-1) but were also considered high, and the authors suggested that, if the higher concentrations of this metabolite were sustained in individual monkeys, subtle changes in calcium and phosphorus metabolism might partially explain the calcium pyrophosphate dihydrate crystal deposition arthropathy that was a problem in the colony.

Marx et al. (1989) studied the differences between four species of nonhuman primates in response to vitamin D2 and vitamin D3, including a comparison ofserum 25(OH)D concentrations. Consumption ofa commercial primate diet containing vitamin D3 at 6,000-6,600 IU-kg-1 resulted in mean 25(OH)D values of 96, 144, 88, and 148 ng-ml- 1 in the serum of crab-eating macaques, rhesus macaques, night monkeys, and squirrel monkeys, respectively. After transfer to a diet containing vitamin D3 at 1,500 IU-kg-1 for5 months, serum 25(OH)D concentrations were 44, 68, 56, and 60 ng-ml- 1. There was no hypercalcemia, parathormone suppression, or azotemia in primates fed the commercial diet, which would be suggestive of hypervitaminosis D; but the lack of biochemical and histologic evidence of vitamin D deficiency in monkeys fed diets containing vitamin D3 at 1,500 IU-kg- 1 suggested to the researchers that the commercial diet with vitamin D3 at 6,000-6,600 IU-kg-1 was providing more of the vitamin than was needed.

Gray et al. (1982) offered brown lemurs (Lemur fulvus) a commercial primate diet containing vitamin D3 at 6,600 IU-kg- 1 plus fresh fruit and a supplement containing oats, soy flour, eggs, wheat germ, evaporated milk, sugar, and bananas. Calcium concentrations in the serum from 20 lemurs were 9.6-12.6 mg-dl- 1. Serum 25(OH)D3 concentrations were 3.4-94.8 ng-ml-1, and serum 1,25(OH)2D3 concentrations were less than 4 to 220 pg-ml- 1. Because the lemurs could make a variety of food choices, it was not possible to relate composition of the diet consumed directly to animals whose biochemical measures appeared to be outside a normal range. Nevertheless, the researchers suggested that some lemurs were hypercalcemic and might have had increased 25(OH)D3 or 1,25(OH)2D3 because of episodic intoxication by vitamin D from the commercial diet. Some animals had low 25(OH)D3 or 1,25(OH)2D3 concentrations, so it is also possible that some lemurs consumed a diet that was low in vitamin D3, although no clinical signs of deficiency were reported.

In some circumstances, hypervitaminosis D might be less ofa threat to nonhuman primates than to other species that are housed with them. Pacas (Cuniculus paca) and agoutis (Dasyprocta aguti) housed in mixed-species exhibits at three zoos died with extensive soft-tissue mineralization, including mineralization of the kidneys, leading to renal failure (Kenny et al., 1993). New World primates shared the exhibits, and zoo personnel reported that dropped primate diets, containing vitamin D3 at 7,000 to 22,000 IU-kg-1, were consumed by the affected animals. Analyses of blood from four moribund pacas revealed reduced packed red-cell volume and increases in serum calcium, inorganic phosphorus, urea nitrogen, and creati-nine. Histologic examination of affected paca tissues confirmed extensive mineralization ofthe kidneys, heart, major blood vessels, stomach, intestinal tract, liver, spleen, and skeletal muscle. Serum vitamin D metabolites were not analyzed, but a provisional diagnosis of vitamin D toxicity was made.


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