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Integrated Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706
3To whom correspondence should be addressed. E-mail: sherry{at}nutrisci.wisc.edu.
ABSTRACT
Although the rhesus monkey (Macaca mulatta) is a widely used experimental animal, its exact vitamin A requirement is unknown. An amount of 430-3600 IU/d [129–1080 retinol equivalents (RE)] is recommended, largely on the basis of depletion studies. Normal hepatic vitamin A appears to be 1 µmol/g liver. Our goal was to determine hepatic vitamin A concentrations of captive monkeys. Liver autopsy samples from rhesus and marmoset (Callithrix jacchus) monkeys were obtained from the Wisconsin Regional Primate Research Center. The rhesus monkeys consumed a diet with 40 IU (12 RE) retinyl acetate/g. Male and female monkeys consumed an estimated 250 and 175 g diet/d, respectively. Marmosets were fed a powder-based diet consisting of 20 IU (6 RE) retinyl acetate/g. The marmosets consumed an estimated 25 g of the diet/d. Liver samples were extracted and analyzed by HPLC. The vitamin A concentration of the rhesus monkey livers was very high at 17.0 ± 6.3 µmol/g. The hepatic vitamin A of the marmosets was 1.25 ± 0.58 µmol/g liver. Histologic examination of the livers revealed Ito cell hypertrophy and hyperplasia in the rhesus monkeys compared with the marmosets. Considering that the natural diet of the rhesus monkey (fruits, seeds, roots and insects) is not high in preformed vitamin A, the vitamin A content of the diet appears excessive, supplying four times the NRC recommendation and resulting in high liver stores.
KEY WORDS: • rhesus monkeys • marmoset monkeys • vitamin A intake • liver storage • subtoxicity • vitamin A status
The rhesus monkey (Macaca mulatta) is a widely used
experimental animal. Detailed knowledge of its specific nutritional
needs is important to ensure that data obtained are not confounded by
unintended nutrient deficiency or excess (1
). However, the
systematic study of the nutrient requirements of animals, particularly
of vitamins, has largely passed, predating the extensive use of
nonhuman primates for clinical investigation (2
). Thus,
estimated nutrient requirements for nonhuman primate species are based
largely on the experimental production of deficiencies and on nutrient
levels that produce adequate health, growth and reproduction
(1
, 3
). Additionally, information has been obtained from
results of nutrition studies whose primary design was not necessarily
to establish nutrient requirements (1
). Extensive
extrapolation from the nutritional needs of other species, including
humans, has also contributed to the estimation of nutrient requirements
for nonhuman primates. In formulating the diets for nonhuman primates
held in captivity, general practice appears to be to provide some
excess of most nutrients to allow for losses during manufacturing and
storage (3
, 4
).
The vitamin A requirement for the rhesus monkey has not been adequately
determined experimentally (1
, 2
, 4
–6
). Although vitamin A
depletion in the rhesus monkey has been studied (7
–11
),
especially regarding ocular and reproductive health, the effects of
toxicity other than its teratogenicity and of subtoxicity via chronic
ingestion of high physiologic doses have been studied by few
investigators. In light of the extensive use of the monkey in research,
the recent decrease in dietary vitamin A recommendations for humans
(12
) and the observation that vitamin A requirements
appear to vary with the stages of the life cycle (1
), it
is of considerable interest to examine the vitamin A status of monkeys
used in biomedical research.
Dietary vitamin A is obtained from animal products as preformed retinol
(retinyl esters) or as provitamin A carotenoids (e.g., ß-carotene,
-carotene, ß-cryptoxanthin). Retinyl esters are hydrolyzed to
retinol in the intestinal lumen. Retinol is absorbed in the intestine,
bound to a specific cellular retinol-binding protein (CRBP
II)4
, and esterified to retinyl esters. The retinyl esters are transported
by chylomicrons through the lymph and then as chylomicron remnants to
the liver (13
). Once in the liver, retinyl esters are
hydrolyzed into retinol and either bound to retinol binding protein
(RBP) or reesterified for storage, preferentially as palmitate
(14
). The retinyl esters in these stores remain there
unless needed to maintain vitamin A balance, in which case they are
again hydrolyzed to retinol, bound to RBP and transported in the
bloodstream to the tissues. Carotenoids are cleaved in the intestine to
retinal, reduced to retinol and then converted to retinyl esters for
incorporation into chylomicrons. In humans, the absorption rate of the
preformed vitamin A is much higher than that of carotenoids, 70–90%
vs. 20–50% (13
).
Vitamin A is a necessary nutrient for the rhesus monkey and is
efficiently obtained by cleavage of ß-carotene (15
) or
by ingestion of preformed vitamin A. The vitamin is essential for
vision, growth and cellular differentiation (16
). As in
humans, vitamin A status in monkeys appears to be influenced by many
factors, including fat composition of the diet, protein-energy
deficiency, physical activity, stress, infection and parasites
(1
). The concentration and source of micronutrients in the
diet also appear to influence vitamin A status, e.g., carotenoids
(16
), zinc (17
) and vitamin E
(18
). Vitamin A status most reliably corresponds to the
size of the liver stores and not to plasma levels because plasma
vitamin A concentration does not begin to decrease until liver reserves
have been depleted (19
), which is usually <0.07
µmol/g in humans (13
). Excess vitamin A, that
which is not required for immediate use by the tissues, is stored in
the liver, mainly in the Ito cells (also known as stellate cells,
lipocytes, lipid- and vitamin A-storing cells) as retinyl esters of
fatty acids (14
, 19
, 20
). Hypervitaminosis A is accompanied
by appetite loss, nausea and vomiting, weakness, dry itchy skin,
alopecia, bone thickening, joint stiffness, enlarged liver and spleen,
and hepatocellular damage (13
, 16
). Liver reserves > 1.05 µmol/g (300 µg/g) are considered
excessive (21
). In human adults, chronic intakes > 30,000 retinol equivalents (RE) (100,000 IU) for 
6 mo can
result in symptoms of hypervitaminosis A but individuals vary, with
hypervitaminosis symptoms occurring in some with lower intakes
(22
, 23
). Hepatic vitamin A concentration is the most
accurate means by which to assess whole-body vitamin A status;
however, an exhaustive review of the literature revealed only one study
in which the hepatic vitamin A concentration of normal (i.e., control)
rhesus monkeys was determined. In their study of vitamin A deficiency
and reproduction, O’Toole et al. (7
) analyzed the livers
of two rhesus monkeys that were not fed a vitamin A–deficient diet and
found hepatic vitamin A concentrations of 1.08 and 1.07
µmol/g, respectively.
The rhesus monkey is naturally frugivorous (3
), subsisting
in the wild mainly on fruits, seeds, roots, leaves, insects and grubs
(4
, 24
). Nonhuman primates can dramatically modify their
nutritional intake to such environmental influences as seasonal
availability and competition from other mammals. Nevertheless, it would
appear that the rhesus monkey naturally derives much of its vitamin A
from plant matter, and thus, from carotenoids. The fact that the rhesus
monkey is not a good carotene absorber (15
) but is very
efficient at cleaving ß-carotene lends weight to this conclusion.
Most commercial primate diet manufacturers, however, provide the
majority of their vitamin A as the preformed vitamin (e.g., as retinyl
acetate) and provide 20–40 IU/g of dry food. Our goal was
to determine the vitamin A status of monkeys held in captivity and fed
these diets.
MATERIALS AND METHODS
Animals and diet.
Fresh frozen liver autopsy samples from rhesus monkeys
(n = 10; 6 male and 4 female; 14.1 ± 10.1 y, range 3.5 to 28.2 y) and from marmoset monkeys
(n = 10; 3 male and 7 female; 5.0 ± 3.9 y, range 1.2 to 12.6 y) were obtained from the Wisconsin Regional
Primate Research Center (WRPRC). Refer to Table 1
for anthropometric data for the monkeys. Research and animal care at
the WRPRC are regulated by University committees and national agencies
to ensure compliance with the Animal Welfare Act. The WRPRC is fully
accredited by the American Association for the Accreditation of
Laboratory Animal Care-International. Rhesus monkeys were fed Lab
Diet #5038 (Purina Mills, St. Louis, MO) consisting of 40
IU vitamin A (as retinyl acetate) per gram dry food and 2.5
µg/g carotene (Table 2
). According to primate center staff, males and females consumed an
estimated 250 and 175 g of the diet/d, accounting for a daily
preformed vitamin A intake of 10,000 and 7000 IU for males
and females, respectively. Marmoset monkeys were fed Mazuri
callitrichid high fiber diet #5M16 (Purina Mills) consisting of 20
IU vitamin A/g, also as retinyl acetate (Table 3
). According to staff, the marmosets consumed an estimated 25 g of
the diet/d, for a daily preformed vitamin A intake of 500
IU.
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Rhesus and marmoset liver (100 and 200 mg portions, respectively) were
ground with mortar and pestle and dried with sodium sulfate. Purified
retinyl acetate (0.5 mL) was added to calculate extraction efficiency.
The material was extracted exhaustively and brought to volume (50 mL)
with dichloromethane. Aliquots (0.100 mL) were dried down with argon
gas and reconstituted with an equal volume of 75:25
methanol/dichloromethane. All analyses were conducted under yellow
lights. A reversed-phase HPLC system was used to determine hepatic
retinol and retinyl esters. The HPLC system included a Beckman 110B
delivery module (Fullerton, CA) set at 1 mL/min, a Shimadzu SPD-10A
UV-Vis detector set at 325 nm, and a Shimadzu C-R7A Chromatopac
data processor (Kyoto, Japan). The stationary phase was a
5-µm C-18 column (3.9 x 300 mm, Waters, Milford,
MA), and the mobile phase was 85:15 acetonitrile/dichloroethane plus
0.1% triethylamine. See Figure 1
for a representative chromatogram of retinyl esters.
|
Hematoxylin and eosin staining of representative livers was done at the histopathology laboratory of the University of Wisconsin School of Veterinary Medicine. A veterinary pathologist assisted in the interpretation of the slides.
Statistical comparisons.
All data were entered into a Microsoft Excel spreadsheet. Means, SD and appropriate t testing to determine differences between species were performed on the data. Linear regression to determine associations among vitamin A concentration and age, liver weight and body weight was performed.
RESULTS
The total vitamin A concentration of the rhesus monkey livers,
represented by retinyl esters, was 17.0 ± 6.3 µmol/g
liver compared with 1.25 ± 0.58 µmol/g liver for the
marmosets (P < 0.0001). The predominant retinyl ester
in both monkeys was retinyl palmitate, accounting for 52.2 ± 2.9% of the total in the rhesus monkeys and 63.7 ± 6.4% of the
total in the marmosets (P < 0.0001). Retinyl oleate,
retinyl stearate, and retinyl myristate plus retinyl palmitoleate
(separation of the myristate and palmitoleate fractions was not
achieved) accounted for the majority of the remainder (see Table 4
for full ester profile). Retinol was detectable in only 1 of the 10
rhesus monkeys and represented 0.2% of total hepatic vitamin A in that
monkey. Retinol was also detected in only one of the marmosets and
represented 1.3% of total hepatic vitamin A in that monkey. The HPLC
system limit of detection for retinol was 0.035 µmol/g
because the system was not optimized for detection of relatively small
amounts of retinol compared with the substantial retinyl esters
present.
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illustrates the Ito cell hypertrophy and hyperplasia of the rhesus
monkey livers compared with the marmoset monkey livers. Although
irregular, the livers showed no fibrosis or overt pathology as
confirmed by the pathologist.
|
DISCUSSION
The rhesus monkey livers had very high concentrations of retinyl
esters, with a mean of 17.0 ± 6.3 µmol/g
(range, 7.2–31; median, 17 µmol/g) or 
16 times more
than expected on the basis of O’Toole’s earlier characterization of
normal rhesus monkeys (7
). The retinyl ester concentration
of the marmoset livers was closer to, yet higher than our expectations
at 1.25 ± 0.58 µmol/g (range, 0.44–2.4; median, 1.2
µmol/g). The rhesus monkey diet provided a greater amount
of vitamin A than the marmoset diet (see Tables 2
and 3
). Specifically,
the rhesus monkey diet provided 40 IU/g of food. According
to primate center staff, male and female rhesus monkeys consumed an
estimated 250 and 175 g diet/d for a daily preformed vitamin A
intake of 10,000 and 7000 IU (3000 and 2100 RE),
respectively, and an average of 1200 IU (360 RE)/(kg body
· d) for the males and 840 IU (250 RE)/(kg body · d)
for the females. The marmoset diet provided 20 IU/g of dry
powder or half the vitamin A of the rhesus diet. The marmosets, whose
daily food intake was an estimated 25 g of dry powder, obtained
500 IU (150 RE) of vitamin A/d for a mean of 1600
IU (480 RE)/(kg body · d) for the males and 1500
IU (450 RE)/(kg body · d) for the females. Although the
marmosets actually consumed more vitamin A/kg body than did the rhesus
monkeys, their hepatic vitamin A concentration was 93% less. This is
explained in part by the marmosets having nearly double the liver
weight of the rhesus monkeys when expressed as a percentage of total
body weight (Table 1)
. Perhaps the vitamin A needs are higher than
those of rhesus monkeys when expressed on a body weight basis. The
marmoset diet also contains a higher fiber content, which may affect
the bioavailability of the vitamin A from the diet. Based upon
the 2001 dietary recommendations for adult humans
(12
), the upper limit of what is considered safe for human
intake has been achieved in these rhesus monkeys, i.e., 3000 RE.
Considering that the mean body weight of the rhesus monkeys in this
study is 8–9 times less than that of the mean healthy human (8.2 vs.
70 kg), this study supports the gradual decrease of vitamin A in the
diet and continued monitoring of rhesus monkey vitamin A status.
Bendich and Langseth (23
) noted that the livers of various
carnivore species may contain > 3.4 µmol/g vitamin A
and those of herbivores (e.g., chickens, cows, lambs) appear to average
0.17 µmol/g. Schweigert (24
) reported similar
hepatic vitamin A concentrations for carnivores and herbivores of
0.35–10.5 µmol/g and 0.17–1.4 µmol/g,
respectively. In the wild, the rhesus monkey is neither a strict
herbivore nor a carnivore. Its diet is based largely on fruits, seeds,
roots, leaves, insects and grubs. Therefore, the hepatic vitamin A
concentration of a rhesus monkey in its natural environment could be
expected to be closer to that reported for herbivores. However, the
rhesus monkeys we analyzed had even higher levels of hepatic vitamin A
than most of the carnivorous arctic mammals whose vitamin A
concentration is known [Table 5
(23
–27
)].
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),
mainly in the stellate cells (also known as Ito cells). Stellate cells
are specialized lipid-storing cells that also synthesize collagen.
With administration of excess vitamin A, the lipid droplets in the
stellate cells increase in size (29
). Analysis of the
lipid droplets in rats by Moriwaki et al. (30
) indicates
that the major component is retinyl esters. The volume of the lipid
droplet can be correlated with the quantity of vitamin A stored in the
stellate cell (29
). Animals with high vitamin A intakes
will thus have a large quantity of vitamin A in stellate cells. Other
components of the lipid droplets are triacylglycerol, unesterified
retinol, cholesterol esters, cholesterol, free fatty acids and
phospholipids, but these appear to be less than half the total in
animals with normal vitamin A stores (30
). As the stellate
cells enlarge with greater lipid and retinyl ester concentration, there
is less room for organelles within the cell and compression of nearby
cells (31
). It is unclear whether there are pathological
implications of this compression, at least at subtoxic levels of
vitamin A. Zou et al. (32
) hypothesized that under a
nonpathological (i.e., subtoxic) condition, the enlargement of stellate
cells due to high vitamin A stores may protect the liver from
fibrogenetic insults by preventing the development of the intracellular
organelles that synthesize collagen. This would explain the absence of
fibrotic pathology in the rhesus monkey livers we analyzed. We
therefore conclude that although the vitamin A liver stores of the
rhesus monkeys were high, placing them in a subtoxic-toxic range,
their livers showed no fibrosis and no overt pathology. It appears that
the natural physiologic defenses against vitamin A toxicity, including
the conversion of dietary vitamin A to retinyl esters, the significant
storage capacity of the liver and the controlled release of retinol
from the liver (33
), were sufficient in these monkeys to
prevent observable hepatic symptoms of hypervitaminosis A.
Recent research in humans and rats suggests that vitamin A needs may
change with age. Specifically, the elderly may have a decreased need
for vitamin A due to higher circulating levels. It is unclear whether
this is due to increased absorption of vitamin A (34
) or
decreased clearance of vitamin A from chylomicrons
(35
, 36
). Epidemiologic studies have linked excess vitamin
A in the elderly with a high incidence of osteoporosis in northern
Europe (36
). In light of this and other data, the Dietary
Reference Intakes for humans for vitamin A were recently lowered to 900
and 700 RE for men and women, respectively (12
). Given
that monkeys in experimental conditions may live longer than 30 y
and that they are used in a variety of research initiatives involving
multiple human disease conditions, investigation into their vitamin A
needs throughout the life cycle is immediately necessary.
In addition to providing a source for the preformed vitamin A,
carotenoids appear to provide other health benefits that are
increasingly appreciated. It is widely accepted that ß-carotene and
other carotenoids are potent antioxidants. Cell culture and human
nutrition studies have shown that ß-carotene offers protection
against some types of cancer and cardiovascular disease and that it
stimulates the immune system (13
, 37
). Studies among
nonhuman primates suggest that diets high in carotenoids may be
important not only for protection against cancer but for longevity as
well (38
). To maintain healthy colonies of experimental
monkeys and to protect against disease processes that may confound
research aims, a reformulation of their diets to include more
carotenoids may be of value to researchers and monkeys alike.
It is accepted practice for diet manufacturers to include higher
micronutrient levels than are deemed necessary to maintain healthy
animals. The preformed vitamin A concentration of various commercially
available monkey diets ranges from 20 to 40 IU/g. To
allow for losses during manufacturing and storage, manufacturers may
actually add even more vitamin A to their products. We conclude that
the preformed vitamin A content of the standard monkey diets
commercially available today is excessively high for the following
reasons: 1) data suggest that the daily vitamin A
requirement of the monkeys is in the range of 430-3600 IU/d
(130–1100 RE) or 10 IU/g diet; 2) the rhesus
monkey is physiologically well-suited to obtaining its vitamin A
needs from carotenoids; 3) the risk of hypervitaminosis from
preformed vitamin A is higher than that from other vitamins;
4) there appear to be age-related changes in vitamin A
metabolism, at least in humans, that are currently underappreciated in
monkeys and may warrant modification of nutrient levels in the diet;
5) carotenoids may provide benefits to the monkeys (e.g.,
antioxidant protection, protection against the development of certain
diseases) above and beyond supplying vitamin A; and 6)
observation of monkeys in natural settings suggests that the majority
of the monkey’s vitamin A needs may be met through the ingestion of
carotenoids. The subtoxic-toxic hepatic concentrations of vitamin A
in the rhesus monkeys we analyzed shows that the diet contains too much
preformed vitamin A, substantially more than is required to meet their
physiologic needs. A review of the dietary formulations fed to captive
monkeys with regard to vitamin A is immediately warranted with a
gradual decrease of vitamin A content and continued monitoring of the
vitamin A status of the captive monkeys.
ACKNOWLEDGMENTS
The authors thank Amanda Goudy Trainor at the UW Regional Primate Research Center for assistance with tissue distribution. Lynette A. Phillips of the Pathobiological Sciences department at the UW School of Veterinary Medicine assisted in interpreting the histological samples. Assistance in photographing the slides was provided by George Flentke of the Environmental Health Sciences Center at the UW-Madison.
FOOTNOTES
1 Presented in part at Experimental Biology 2001,
April 2001, Orlando, FL [Penniston, K., & Tanumihardjo, S. A.
(2001) High hepatic vitamin A in rhesus monkeys fed
standard diet. FASEB J. 15: A603 (abs.)]. 
2 Supported by Hatch-Wisconsin Agricultural
Experiment station, number WIS04389; the University of Wisconsin
Graduate School; and the Wisconsin Regional Primate Research Center,
grant number RR00167, publication 41-004.
4 Abbreviations used: CRBP II, cellular
retinol-binding protein; RBP, retinol binding protein; RE, retinol
equivalents; WRPRC, Wisconsin Regional Primate Research Center.
Manuscript received 27 July 2001. Initial review completed 16 August 2001. Revision accepted 27 August 2001.
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  K. L Penniston and S. A Tanumihardjo The acute and chronic toxic effects of vitamin A Am. J. Clinical Nutrition, February 1, 2006; 83(2): 191 - 201. [Abstract] [Full Text] [PDF]
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 K. L. Penniston, J. C. Thayer, and S. A. Tanumihardjo Serum Vitamin A Esters Are High in Captive Rhesus (Macaca mulatta) and Marmoset (Callithrix jacchus) Monkeys J. Nutr., December 1, 2003; 133(12): 4202 - 4206. [Abstract] [Full Text] [PDF]
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