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,**
Departments of
*
Internal Medicine and
Nutrition and
**
California Regional Primate Research Center, University of California, Davis, CA 95616
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONREFERENCES |
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KEY WORDS: • activity • behavior • monkeys • diet
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONREFERENCES |
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). In primates, a period of rapid growth
commences in utero after embryogenesis and is completed postnatally,
corresponding to the end of lactation. Growth continues at a slower
pace through a prolonged juvenile phase (childhood) that is
infrequently encountered in nonprimate species. Then, before puberty, a
striking growth spurt occurs, reproductive maturity is gradually
established and linear growth ceases as a result of epiphyseal closure
at the end of adolescence. This discontinuous pattern of growth is not
present in common laboratory animals used to study the effects of
malnutrition. However, it is important to note that there are also
further differences within primate species in growth and maturational
staging.
We have been studying the effects of developmental zinc deprivation for
a number of years in rhesus monkeys. Purified diets were used in these
studies to allow precise control of trace element composition, and the
zinc deprivation was characterized as marginal or moderate (Keen et al. 1993
) depending on whether the diet contained 2 or 4
µg Zn/g. During these studies, we noted that clinically
detectable zinc deficiencies appeared only toward the end of periods of
rapid growth, i.e., the third trimester, late infancy and early
adolescence. Behavioral measures were included in a number of our
studies, as well as in other studies of zinc deficiency in rodents and
monkeys (Golub et al. 1995
).
More recently, we have turned from infancy to adolescence in our
studies of developmental zinc deprivation (Golub et al. 1995
). The adolescent growth spurt in rhesus monkeys is
a convenient and valuable model system for studying effects of
malnutrition on growth and behavior. Monkeys are seasonal breeders;
puberty is timed to the breeding season, with menarche occurring in the
breeding season of y 3 of life (30 mo of age) and the growth spurt
occurring just before this. Growth is approximately twice as fast
during the 5-mo peak in growth rate (age 28–33 mo) than in the
previous or succeeding months (Blackwelder and Golub 1996
). Seasonal breeding also means that monkeys are born
within a few months of each other each spring and will go through the
growth spurt in synchrony.
With this information, it was possible to plan dietary interventions
during the growth spurt in female monkeys; our most recent experiment
combined iron and zinc deprivation in female rhesus (Golub et al. 1999
). Iron and zinc co-occur in high protein food
items frequently missing from poor quality diets, and these nutritional
deficiencies are often seen together in malnourished children. In the
U.S., studies indicate that 83% of adolescent girls consume less than
the RDA for iron and 81% consume less than the RDA for zinc
(Johnson et al. 1994
). Thus, an isolated zinc deficiency
is not likely during this time. Also, in girls, the onset of
menstruation at the peak of the growth exacerbates dietary deficiencies
of iron.
The effect of diet on the rapid growth of adolescents is of concern,
but it is also appropriate to consider the effect of nutrient
deficiency on brain function during development (Beard 1995
, Sandstead et al. 1998
). Adolescent brain
development has several distinct characteristics. Cognitive development
is marked by onset of the ability to manipulate symbols and conceptual
representations. Brain electrical activity demonstrates increased
coherence and speed, with less energy use. Anatomically, myelination in
brain commissures is completed, allowing faster transmission of
information. There is a decrease in gray matter in some cortical areas,
presumably due to completion of synaptic "pruning." In the
hypothalamus, intricate networks of growth factors, neurotransmitters
and hormone releasing factors are established for controlling
reproductive cycles. Changes in neurotransmitter receptor expression
and sensitivity to agonists and antagonists appear throughout the
brain.
In addition to studying iron-zinc deprivation, a component of the
study examined the effect of meat as a common dietary source of zinc
and iron. At the end of the anticipated period of most rapid growth, we
introduced a supplemental food in the form of 4-g tablets of baked,
lyophilized beef. The zinc contents of the control diet (35
µg/g) and deprived diet (2 µg/g) were
based on our previous experience with marginal and moderate zinc
deprivation. The iron deprivation content (10 µg/g)
was adopted from a study of developmental iron deficiency in rhesus
infants (Munro 1987
); controls were fed 20
µg Fe/g diet. We intended the supplement to be
equivalent to a 100-g serving of beef for an 11- to 14-year-old girl in
terms of the percentage of daily protein intake, and to restore zinc
and iron intake to near normal levels. However, it should be noted
that, by using beef, rather than adding zinc and iron to the basal
diet, we cannot be sure whether the additional zinc and iron were
responsible for the effects of the beef tablets.
Figure 1
shows that the short-term zinc-iron deprivation did not decrease
growth rate during the growth spurt or later during the supplement
period. Group differences in plasma zinc and iron were seen by the end
of the growth spurt, although the deprived group could not be said to
be in a state of clinical zinc or iron deficiency. (Plasma zinc and
iron may not be good indicators of zinc and iron status in cross
sections of children, but they are more reliable with the controlled
environments and well-defined diets and ages of the monkeys in this
experiment.) Further indication of the effect of the deprived diet was
seen in hematological parameters at the end of the study. Half of the
continuously deprived group (4 of 8) met the criteria for
iron-deficiency anemia [hematocrit < 30%; hemoglobin
< 10 gm/dL; mean cell volume (MCV) < 70 fL; ferritin
< 10 ng/mL] by the end of the experiment, but only 1 of 8 in the
beef-supplement group and 0 of the 8 controls met these criteria.
Thus, a detectable but mild deficiency was suggested in plasma trace
element and hematological parameters.
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, Roberts and Sahakian 1993
, Rutschman et al. 1986
) were conducted four
times weekly throughout the growth spurt and supplement period. The
Continuous Performance Test assesses the vigilance aspect of attention;
the Delayed Nonmatch to Sample Test assesses visual discrimination and
short-term memory. For testing, a video screen displayed colored
stimuli and monkeys responded by touching the screen. Selection of the
correct stimulus resulted in a reward, a small fruit-flavored sugar
pellet. The monkeys were not food deprived for testing. In addition to
assessing performance in terms of the percentage of correct responses,
we also assessed the time taken to respond, i.e., the response latency.
A third type of measure was termed participation and was measured as
the number of sessions that the monkey started, or during which it
completed at least 25% of the possible responses.
Figure 2
shows the influence of the deprived diet and the supplement on
performance of these tasks. In the Continuous Performance test, colored
squares flashed on the video screen, and the monkey had to touch the
white square when it appeared (a correct "hit") and avoid touching
the red and green squares (correct rejection). The percentage of
correct "hits" was lower for the deprived group than controls
(middle left panel). However, the percentage of correct
rejections (bottom left panel) was
higher, indicating that the monkeys were generally responding less to
the stimuli. Diet did not influence performance on the Delayed Nonmatch
to Sample Test (middle right panel). The data also
indicated that the monkeys were less willing to participate in the
behavioral testing (top panel) and were slower to
respond to the stimuli (bottom right panel). The
performance of the beef-supplement group tended to return toward
that of the control group, with the exception of response latencies.
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). The continuously deprived
group was generally less active after the onset of the experiment and
significantly less active by the end of the study. The activity of the
beef-supplement group stabilized after introduction of the
supplement. There was considerable individual variability in these
data, especially in controls, but the general pattern agrees with the
performance measures from the behavioral tasks.
In this study, no effects on growth and only marginal effects on iron
and zinc status were recorded along with a behavioral syndrome of
lethargy and apathy. Interindividual variability was seen throughout
the data base, so that many of the patterns of changes were not
significant group differences. Table 1
shows correlations between growth rate, activity level and hematocrit
in zinc-iron–deprived adolescent monkeys. The positive correlations
suggest that the monkeys whose behavior was most affected also had the
lowest growth rates and hematocrit values. The finding that only
behavioral variables were significantly different from controls,
whereas growth and hematological parameters were not, suggests that
behavior was the most sensitive measure.
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, Waterlow 1986
). Interestingly, energy restriction (undernutrition)
without changes in diet quality (malnutrition) has not been found to
lead to reduced activity in nonhuman primate and rodent studies; in
fact, increased activity levels are reported (Weed et al. 1997
). Thus, micronutrients such as zinc and iron may be the
determiners of the behavioral lethargy/apathy syndrome. During
adolescence, reduced activity could help conserve these nutrients for
continued growth before the onset of growth retardation, as has been
previously suggested in preschoolers (Spurr 1990
).
Subsequently, stunting of growth could be considered an adaptation that
allows continued supply of micronutrients needed for behavioral
adaptation. Certainly under conditions of severe deprivation, both
types of endpoints could be affected. But under mild or moderate
deprivations, there may be a dissociation of effects on growth and
behavior. In the case of iron deficiency, studies in girls have
demonstrated effects on behavior in the absence of anemia
(Bruner et al. 1996
). Understanding of these
relationships could contribute to identification and remediation of
diet-induced growth and behavioral function deficits in
malnourished teenagers.
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FOOTNOTES |
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2 Supported by the National Cattlemen’s Beef Association and RR00169.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONREFERENCES |
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1.
Beard J. One person’s view of iron deficiency, development, and cognitive function. Am. J. Clin. Nutr. 1995;62:709-710
2. Blackwelder T., Golub M. S. Premenarchial weight gain in rhesus macaques. Am. J. Phys. Anthropol. 1996;99:449-454[Medline]
3. Bruner A., Joffe A., Duggan A., Casella J., Brandt J. Randomized study of cognitive effects of iron supplementation in non-anemic iron-deficient adolescent girls. Lancet 1996;348:992-996[Medline]
4.
Golub M., Keen C., Gershwin M. Behavioral and hematological consequences of marginal iron-zinc nutrition in adolescent monkeys and the effect of a powdered beef supplement. Am. J. Clin. Nutr. 1999;70:1059-1068
5. Golub M. S., Keen C. L., Gershwin M. E., Hendrickx A. G. Developmental zinc deficiency and behavior. J. Nutr. 1995;125:2263S-2271S
6. Johnson R. K., Johnson D. G., Wang M. Q., Smiciklas-Wright H., Guthrie H. A. Characterizing nutrient intakes of adolescents by sociodemographic factors. J. Adolesc. Health 1994;15:149-154[Medline]
7. Keen C. L., Lonnerdal B., Golub M. S., Olin K., Graham T., Uriu-Hare J., Hendrickx A., Gershwin M. Effect of the severity of maternal zinc deficiency on pregnancy outcome and infant zinc status in rhesus monkeys. Pediatr. Res. 1993;33:233-241[Medline]
8. Munro N. A three year study of iron deficiency and behavior in rhesus monkeys. Int. J. Biosocial Res. 1987;9:35-62
9. Overman W. H. Performance on traditional matching to sample, non-matching to sample and object discrimination tasks by 12- to 32- month old children. Diamond A. eds. The Development and Neural Bases of Higher Cognitive Functions 1990:1192-1202 New York Academy of Sciences New York, NY.
10. Roberts A., Sahakian B. Comparable tests of cognitive function in monkey and man. Sahgal A. eds. Behavioural Neuroscience: A Practical Approach 1993;vol. 1:165-184 Oxford University Press New York, NY.
11. Rutschman J., Cornblatt B., Erlenmeyer-Kimling L. Sustained attention in children at risk for schizophrenia: findings with two visual continuous performance tests in a new sample. J. Abnorm. Child Psychol. 1986;14:365-385[Medline]
12. Sandstead H., Penland J., Alcock N., Dayal H., Chen X., Li J., Zhao F., Yang J. Effects of repletion with zinc and other micronutrients on neuropsychologic performance and growth of Chinese children. Am. J. Clin. Nutr. 1998;68:470S-475S[Abstract]
13. Spurr G. Physical activity and energy expenditure in undernutrition. Prog. Food Nutr. Sci. 1990;14:139-192[Medline]
14. Waterlow J. Metabolic adaptation to low intakes of energy and protein. Annu. Rev. Nutr. 1986;6:495-526[Medline]
15. Watts E. Evolution of the human growth curve. Falkner F. Tanner J. eds. Human Growth 1986:153-166 Plenum Press New York, NY.
16. Weed J., Lane M., Roth G., Speer D., Ingram D. Activity measures in rhesus monkeys on long-term calorie restriction. Physiol. Behav. 1997;62:97-103[Medline]
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