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Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221-0006
1To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • protein malnutrition • craniofacial • skeleton • sexual dimorphism • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Malcolm 1979
).
In nature, growing neonates make the greatest demands for food that is
rich in nitrogen for the synthesis of new protein (White 1993
). Numerous adaptations exist that allow consumption of
different species and ages of vegetation; the crucially limiting
resource generating all of these adaptations is food that contains
sufficient protein for successful reproduction. The major factor
limiting the numbers of animals is the search for sufficient protein to
sustain females through pregnancy and lactation, and the young through
growth after weaning (White 1993
). Protein is critical
for growth; levels of 5–10% protein in food are marginal for an
increase in body weight for laboratory rats, and growth accelerates
with increasing dietary protein levels up to 25% (Edozien and Switzer 1978
). Studies using body weight as a measure of growth
show that protein malnutrition results in smaller-sized individuals
(Cabak et al. 1963
, Cameron and Eshelman 1996
, Cotheran et al. 1985
, Edozien and Switzer 1978
, Elias and Samonds 1977
,
Fleagle et al. 1975
, Pucciarelli 1981
,
Samonds and Hegsted 1978
, Stewart et al. 1975
, Yayha and Millward 1994
).
The craniofacial skeleton is one portion of the body that is critically
affected by malnutrition. Understanding how the mammalian skull
develops is necessary for understanding the effect of malnutrition. The
skull is not a single developing unit; rather, it has two distinct
regions, the viscerocranium and the neurocranium (Cheverud 1982
). The viscerocranium is used during feeding and breathing,
and its growth is continuously subject to muscular loading
(Cheverud 1982
, Herring 1993
), whereas
the neurocranium houses the brain, and its growth is influenced
primarily by brain expansion (Young 1959
). The
viscerocranium appears more susceptible to epigenetic factors than the
neurocranium (Fields 1991
, Pucciarelli 1980
and 1981
). Stewart et al. (1975)
found that changes
in the shape of the head were attributable to the size of the facial
bones, but that overall head length was less markedly affected. If the
cranial bones had been restricted to the same extent as other bones,
there would have been substantial pressure on the nearly full-size
brain.
However, one overlooked issue in many of these studies is the dynamics
of growth trajectories, or how malnourishment affects the rates and
timing of developmental events. Much of this experimental work
(Stewart et al. 1975
, Yayha and Millward 1994
) convincingly demonstrates the effect of protein
malnourishment on growth. However, these studies share the problem of
lacking complete growth trajectories of these individuals. Furthermore,
there are no estimates of ultimate body size for malnourished
individuals. It is not known how normal growth patterns are interrupted
to produce variation in sizes and shapes throughout ontogeny as a
result of malnutrition or whether these differences in size and shape
are found in the ultimate body size of the individual.
This paper addresses the effect of protein malnutrition on growth and body size, on the craniofacial skeleton in particular. A longitudinal design permitted measurement and analysis of differences among individual growth trajectories. These data can provide a basis for understanding the specific effect of low protein on growth trajectories, those bones that are most are affected by protein deficiency, and whether males and females react similarly to protein malnutrition.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Breeders of Rattus norvegicus were obtained from a colony of Zivic Miller: Sprague-Dawley strain of rats at the University of Cincinnati. All animals procedures were approved by the University of Cincinnati (IACUC # 91–05-27–01 approval). All rats (n = 37) used were from three litters that had equal amounts of relatedness.
Diets.
The two treatments in this study were a control diet (CT) consisting of
24% protein and an experimental low protein diet (LPT) of 4% protein.
The 24% CT fell within the range of the maximum growth rates
associated with increases in protein intakes up to 25% (Edozien and Switzer 1978
); the 4% LPT was deficient enough for
differences in the rates of growth to be detected but still high enough
to reduce health risks in the LPT rats (Anthony and Edozien 1975
, Cameron and Eshelman 1996
, Edozien and Switzer 1978
, Elias and Samonds 1977
,
Fleagle et al. 1975
, Samonds and Hegsted 1978
, Yayha and Millward 1994
). Both diets were
based on the AIN-93G standard diet recommended to support growth
(Reeves et al. 1993
). The diets (Dyets, Bethlehem, PA)
were isocaloric; thus the only dietary variable altered was protein
(Table 1
). Food consumption and spillage were measured to the nearest 0.1 g
using a Fisher Scientific Model S-400 (Denver Instrument, Denver, CO)
electronic scale.
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Data collection.
For data collection, the rats were lightly anesthetized in a small
induction chamber using an Ohio 4000 Compact Anesthesia Machine with
isoflurane gas (Anaquest, Liberty Corner, NJ) at 2–3.5% per liter of
oxygen for ~5 min. Once the rats were sedated, they were hand
positioned on a film cassette for radiographing. Two radiographs were
taken of each rat, one in a dorsal-ventral plane and another in a
lateral plane. We used Kodak MRM-film and low amounts of radiation
from a Bennett Mammography Machine (Bennett X-Ray, Copiague, NY)
set for 0.25 s at 75 mA and 44–47 kV, depending on the size of
the rat. The rats awoke within minutes and suffered no ill effects.
Rats were radiographed three times per week starting at 22 d of
age, when growth was occurring at its fastest rate. The frequency of
the radiography sessions decreased ultimately to once every 2 wk as the
rate of growth slowed down and continued until an accurate estimate of
the final size of the individual rat was determined. Previous studies
indicated that there are no adverse growth effects from the radiography
(Fiorello and German 1997
).
The data on craniofacial dimensions were taken from radiographs using a
Numonics AccuGrid Digitizing Tablet (Numonics, Montgomeryville, PA;
accuracy of 0.127 mm). Radiographs were assessed for misalignment or
poor resolution. In >1400 radiographs, only eight were removed because
of bad resolution. Cartesian coordinates were obtained from landmarks
on the skull bones that were both homologous and repeatable in all rats
in the study. A total of 31 points on each radiograph were digitized,
19 points from each dorsoventral view and 12 points from each lateral
view. The points were used to measure two-dimensional distances in
millimeters in the different regions of the skull (Figs. 1
and
2). Points were identified (Table 2
) from descriptions given by Lightfoot and German (1998)
and Popesko et al. (1990)
.
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Statistical analysis.
Mammalian growth is usually nonlinear, and we used the nonlinear
Gompertz equation to model growth (Gille et al. 1996
).
This equation is recommended for modeling mammalian ontogeny because it
provides one of the best empirical fits for the sigmoidal nature of
mammalian growth (German et al. 1994
, Lightfoot and German 1998
, Laird 1965
and 1966
,
Laird et al. 1965
, Maunz and German 1996
). Furthermore, the Gompertz equation has biological
meanings associated with the parameters of the equation (Gille et al. 1996
). To analyze the data we used the NONLIN module of
SYSTAT (Wilkinson 1997
) with two algebraically
equivalent forms of the Gompertz equation as follows:
 | (1) |
 | (2) |
where y is the variable being measured, t
is time and was measured in days, e is the base of the natural
logarithm, and b is a parameter of limited biological
importance describing initial growth (Laird et al. 1965
). Parameter w is the value of y at
t = 0 and is an estimate of the initial size,
I is the initial slope of the line at t = 0
and is an estimate of the instantaneous initial rate of growth,
k measures growth decay and is an estimate of how fast
growth slows down, and A is the asymptote or an estimate of
the final size of the measurement y. A,
b, and k were obtained from nonlinear
regressions, whereas values for w and I were
calculated from the following relationships:
 | (3) |
 | (4) |
These equations can also provide an estimate for the time at
which growth stops. The first derivative of the Gompertz equation gives
the rate of growth over time. From the first derivative, we have the
following:
 | (5) |
We calculated the maximum rate (Rm) of growth and the time at which each measurement was increasing at 5% of its maximum rate Tf, and used this as an estimate for the duration of growth.
A Gompertz curve was fit to each rat's individual growth trajectory for all measurements; thus the individual rat was the unit of analysis. A three-way ANOVA was used to test for significant differences among diet, sex and litter for each of the seven Gompertz growth parameters. Litter was included in the ANOVA as a random factor so that the model was complete. This allowed us to partition any variation due to litter effect, although it reduced both the degrees of freedom and the amount of variation seen in the model due to error. In no case was the litter factor significant. By including litter as a factor, however, any variation in the data due to differences in litter would be excluded from our analysis of differences in diet and sex.
The full model also tested for an interaction between sex and diet.
Corrected R2 values were used to
determine how much of the variation could be explained by the model. It
is important to use the same model for both treatments to be able to
compare differences in growth (Klingenberg 1998
). Given
the large number of comparisons and dependent or response variables,
groups were considered significantly different if the
P-value was < 0.001 and marginally different if the
P-value was < 0.01. These values are in line with
standard Bonferroni corrections for the calculation of multiple ANOVA
(Neter et al. 1996
).
Additional tests were computed using initial and final sizes. The data used were the measured weights at the earliest time (weaning), 0 d, or at the time of final measurement, which varied for different treatments. Thus, the raw values for weight were tested for treatment differences at the start of data collection with a three-way ANOVA, using litter, sex and diet as factors. The two measures of final size, the A parameter and the actual values for each measurement at the end of the study quantified slightly different things. The A parameter was a prediction, based on the growth trajectory, of ultimate final size. If the model predicted further growth, then A would be higher than the final measurements from the radiographs.
Linear regressions were used to determine the relative proportions of
the different areas of the skull and to test for scaling or allometric
differences between the diets (Klingenberg 1998
). This
method allowed determination of the change in relative shape over time,
and provided information in addition to examining the individual
measurements. It allowed testing of the hypothesis that variation in
shape as a function of growth differed as a result of diet. These
allometric tests measured proportionate shape change, beyond how each
individual measure changed with time. Regressions were fit to the data
for each individual rat for seven different relationships; thus the
unit of analysis was again the individual. A linear slope was
calculated for all of the following measurements: mandible length vs.
distance between mandibular angles; mandible length vs. mandible
height; nasal bone length vs. nasal width; lateral neurocranial length
vs. neurocranial width; lateral neurocranial length vs. neurocranial
height; lateral skull length vs. skull width; and lateral skull length
vs. skull height. Each of the seven sets of slopes was tested for
significant differences among the diets and sexes using a
mixed-model three-way ANOVA, with sex and diet as fixed factors,
and litter as a random factor. Finally, we tested for differences in
food consumption by rats consuming the two diets using a
repeated-measures ANOVA model with factors for sex, diet and
litter.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The amount of protein in the diet was a fixed factor for all rats in the study, but because they were allowed to eat and drink ad libitum, variation occurred in the amount of protein but not in the percentage of protein relative to total daily energy intake. CT rats consumed significantly more food than LPT rats at any given age (P < 0.001). At any given body mass, absolute consumption was greater in the LPT than in the CT group (P < 0.001). However, when corrected for body weight, total protein consumed relative to body weight was always greater in the CT group (P < 0.001)
Body weight.
Initial body weight did not differ between the two groups (P
= 0.850), although it did differ between sexes (P
< 0.001). The patterns of growth in body weight were different
between the two treatment groups (Fig. 3
). Final body weight differed between diet groups and between sexes
(P < 0.001). There was also a significant interaction
between sex and diet, with the diet effect greater in males than in
females. These results differed from the predictions of the Gompertz
model in which there was no significant diet effect or interaction for
final body weight predicted by the A parameter. All other
Gompertz parameters that measured rates and duration of growth were
overwhelmingly significant for differences due to diet and sex.
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The Gompertz model fit the skeletal data well (Fig. 4
). The mean corrected R2 was 0.966 over
all models. The minimum corrected R2
for any single measurement was 0.873 for frontal length, and the
maximum R2 was 0.996 for skull width.
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). The initial size, w, at the time of weaning was larger for
male than for female rats for all but five measurements. There were few
differences found for the instantaneous growth rate, I, for
which the growth curves of female rats were initially steeper. Female
rats reached a significantly higher maximum rate of growth for 16
measurements, but after reaching that maximum rate, their growth slowed
more quickly than that of male rats, as reflected by their higher
k values for 19 measurements.
Tf was significantly larger in male
rats for 16 measurements. This indicated that male rats grew for a
longer period of time, except in the neurocranium in which four of the
six measurements were nonsignificant.
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Normal growth for craniofacial dimensions was markedly sigmoidal and
nonlinear. The LPT rats had a more linear appearance to their growth
trajectory; therefore it is more difficult to find a good empirical fit
using the Gompertz model for this group (Fig. 5)
. The corrected
R2 were slightly lower for the LPT
fits (R2 = 0.962) compared with the CT
(R2 = 0.968). Furthermore, the initial
size of the individual, w, was significantly different for
some measurements. Statistical tests of the actual measurements at the
beginning of the study showed no significant difference among diet
groups (P > 0.350). The differences in the initial
size of the rats suggested that the Gompertz equation was not providing
an accurate measure of initial size. This is probably attributable to
the linear appearance of the LPT curves compared with the more
sigmoidal growth curves for CT rats.
The LPT rats had a lower initial instantaneous growth rate, a lower
maximum rate of growth, a lower rate of decay of growth and a longer
duration of growth; k, I,
Tf, and
Rm were significantly different
between diet groups (P < 0.001) in all 22 skeletal
measurements and body weight. The graphical interpretation of these
patterns was evident in Figure 5
. The first derivative plot clearly
showed a lower initial absolute rate of growth for the LPT rats. The
rate of growth in the CT rats slowed drastically as growth continued
(k parameter); thus the LPT rats were at a higher rate of
growth by ~80 d of age, and this continued until 300 d or
longer.
Final size measured by the A parameter was different from
the final values measured for most skeletal variables. For
A, the final size was not significantly different between
the CT and LPT rats for 12 of 22 skeletal measurements (Table 3
). In four measurements of lengths, the CT rats had a marginally or
significantly larger value of A. The LPT rats had a larger
A for five of the measurements for widths and heights.
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). The average difference in final size of the measurements between the
two diet groups was relatively small, 2.7% for female and 6.9% for
male rats.
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. For areas in which CT rats
were larger than LPT rats, we expected a relatively shorter duration of
growth for the latter group and a relatively higher rate of growth for
the former. However, the maximum rates of growth,
Rm, were higher than in other
measurements for both CT and LPT rats. The ratio of CT
Rm to LPT
Rm was 2.7, whereas in measurements in
which the CT and LPT were of equal size, the ratio of CT
Rm to LPT
Rm was 3.1. This suggested that the
LPT rats had a relatively higher than expected maximum rate for the
measurements in which they were smaller. The important difference,
then, was that for variables in which the CT rats were larger, the
duration of growth for the LPT rats was significantly shorter than that
for LPT rats in variables in which the two treatment groups were the
same size. In those cases in which the LPT rats were ultimately larger, with a higher A value than the CT rats, a somewhat more complex pattern existed. First, the duration of growth in the LPT rats was significantly longer and included the five longest durations, all of which were at least 40 d longer than the other measurements. The duration of growth in the CT rats, however, did not differ from the duration for all other measurements. The maximum rate of growth, Rm, was lower in this group of measurements than for the other measurements for both CT and LPT rats. The CT Rm was almost 30% lower, but the LPT group was at less than half the rate it achieved in other measurements.
Interaction.
There were few interactions between sex and diet in any of the measurements. Thus, variation in the data were attributable to the main factors, i.e., sex and diet. The parameter with the greatest number of interactions was Tf, the duration of growth, with three significant and six marginal differences, equally in the neurocranium and viscerocranium. In these cases, there was a higher degree of sexual dimorphism between the LPT rats than between the CT rats.
Allometry and scaling.
Differences among growth variables suggested that some scaling
differences over time existed among the four groups. There were no
significant interactions between sex and diet for any of the seven
comparisons. For the scaling in the skull, the slopes of length vs.
width for both the mandible and nasal measurements, along with total
skull length vs. total skull width, had significantly different scaling
relationships between the CT and LPT groups, and the mandible length
vs. height was marginally different (Table 5
). In all of these relationships, the CT rats had a larger slope,
indicating that as width or height increased, y increased in
length at the higher rate (Fig. 6
). The mandible and skull length vs. width scaling were the only
significant differences between males and females. There were no
significant rate differences between the diet groups or sexes for
neurocranium length vs. neurocranium width or neurocranium height,
although the LPT rats had a smaller length at any given width (Fig. 6)
.
The intercepts of the two diet group lines for neurocranium and skull
scaling relationships were not significantly different, implying that
the slopes were not different and that there were no shape differences
between the rats fed the two diets in this area of the skull.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Edozien and Switzer 1978
). The rats fed the low protein diet consumed significantly
more food per gram of body weight than did the CT group. Cameron and Eshelman (1996)
showed a similar increase in ingestion by
hispid cotton rats to attempt to compensate for low levels of protein.
The increased consumption had the effect of increasing energy intake,
given that the two diets are isocaloric. However, the additional
consumption did not fully compensate for the amount of protein in the
diet. Edozien and Switzer (1978)
found that rats fed a
low protein diet are less energy efficient because they grew less,
despite consuming more energy.
All of the measurements in this study showed ultimate body size sexual
dimorphism. Three or more significant or marginal differences in
Gompertz parameters led to the ultimate body size sexual dimorphism in
18 of the 23 measurements. In the significant differences between males
and females, all six Gompertz parameters followed consistent trends.
The smaller initial size, faster deceleration of growth and shorter
duration of growth contributed to the smaller size of females, as is
true in other species (Lightfoot and German 1998
,
Maunz and German 1996
). The most surprising result was
that females had a higher maximum rate of growth in 16 variables. In
mammalian growth, the rate of growth slows with the age of an animal
until it approaches adult size (Laird et al. 1965
), with
the maximum rate of growth often occurring perinatally in some aspects
of growth, particularly these skeletal measurements (Fig. 4)
.
As an individual moves along its growth trajectory, the potential
increases for processes outside of genetic control to act on growth
(Edozien and Switzer 1978
, Elias and Samonds 1977
, Fleagle et al. 1975
, Helm and German 1996
, Laird et al. 1965
, Samonds and Hegsted 1978
). Helm and German (1996)
suggested that early growth in miniature pigs is less susceptible to
nongenetic perturbations, but as growth continues, so does the
potential for the effect of epigenetic factors on body size. Their
change in diet with weaning had less effect on early growth than on
later growth. Edozien and Switzer (1978)
found
significant differences in growth rates of rats. These differences
increased progressively with increasing levels of dietary protein.
However, their study was not long enough to determine whether the
differences in growth rate would be reflected in the ultimate body
size.
The differences in final size between rats fed the two diets were either nonexistent (using the A parameter to predict final size) or small (using the final measurements). This suggested that low amounts of dietary protein in the diet did not necessarily result in smaller skulls. In every measurement, the CT rats had a higher decay of growth, a higher instantaneous initial rate of growth, a higher maximum rate of growth, and the LPT rats had a much longer duration of growth. The average duration of growth of all of the measurements for the LPT rats was four times the duration of growth of the CT rats (CT = 91.4 d, LPT = 365.1 d).
These results differed dramatically from those in the literature, which
suggest a much larger effect of protein malnutrition on size. Previous
studies did not include a sufficient duration of growth for accurate
measurement of ultimate adult size (Edozien and Switzer 1978
, Elias and Samonds 1977
, Pucciarelli 1980
and 1981
, Samonds and Hegsted 1978
,
Stewart et al. 1975
, Yayha and Millward 1994
). When we followed growth over time, final size was not
significantly different, whereas the paths by which that size was
achieved were significantly different.
A few exceptions to this pattern existed in which the CT and LPT rats did not reach the same final asymptote as predicted by A. Duration of growth was the parameter that best explained these differences in size. For variables in which the LPT rats were smaller than the CT rats, the LPT rats had a duration of growth marginally shorter than they did for other measurements. When the LPT rats were larger, they had durations of growth significantly longer than their average. For both the variables in which either the CT rats were larger or those in which they were smaller, the duration of growth for the CT rats was not different from that of measurements in which the CT and LPT rats were of equal size. However, the patterns of maximum rate of growth for variables with either the LPT rats larger or the CT rats larger were not as expected. When LPT rats were smaller, the maximum rates of growth for both groups were high, and the LPT rats had a proportionately higher maximum rate of growth. When the LPT rats were larger, the maximum rates of growth for both groups were low, and the LPT rats had proportionately lower maximum rates of growth. These patterns of maximum rate were the opposite of what was necessary to produce the final size effect for both sets of variables. This implied that the duration differences must have been of sufficient magnitude to offset this variable to produce the end effect of adult size differences between the two diet groups.
The measurements for which the LPT rats were smaller were all lengths
in the viscerocranium and the entire skull. Previous work suggests that
the viscerocranium grows at a faster rate and for a shorter time than
does the neurocranium (Clark and Smith 1993
,
Dressino and Pucciarelli 1997
). The lengths of the
viscerocranium, in particular, are associated with the functional
demands of weaning and tooth eruption (German and Crompton 1996
, Maunz and German 1996
). It is possible
that there was less flexibility in the growth schedules of this region
of the skull, and therefore growth cannot be extended in the LPT rats.
By the time of weaning, the jaw must be functional for mastication and
of sufficient length to accommodate the postcanine dentition. A delay
in jaw development, particularly the length of the jaw, which is the
functional lever arm during mastication (Hylander et al. 1987
), could have a detrimental effect on normal function.
Therefore, the sutures in these bones, and their growth, would be more
resistant to epigenetic perturbations such as an extension of the
duration of growth.
The measurements in which the LPT rats were larger are neurocranial and
viscerocranial measurements of width. Again, the neurocranium grows
more slowly and for a longer period of time (Clark and Smith 1993
, Dressino and Pucciarelli 1997
,
Maunz and German 1996
). Given that the neurocranium
houses the brain and in fact grows in response to brain growth, timing
constraints due to muscular function are not nearly as severe in the
neurocranium as those in the viscerocranium. Thus, extending the growth
of this region may not have had a high developmental or survival cost.
The widths of the viscerocranium that fell into this group were those
portions of the viscerocranium that were growing most slowly. They were
also less important for the biomechanics of mastication.
The only significant interaction between the sex and diet factors that occurred consistently was in the duration of growth in which larger differences existed between the male rats fed the two diets than between the female rats. Either the LPT male rats were biologically more susceptible to the effect of low protein or the female rats had a biological protection against this problem. Our data did not permit a distinction between these two alternatives.
Few significant differences existed in scaling over time. The shape of
the neurocranium was conserved in the two diet groups. These
measurements were in an area of great stability, and they are less
reactive to force in the postnatal skull (Fields 1991
,
Helm and German 1996
, Zelditch et al. 1992
). The significant differences were in the relationship
between lengths and widths of the viscerocranium and of the total
skull. In the mandible, nasal and total skull regions, all LPT rats had
shorter and relatively wider skulls compared with the CT rats. These
results support the work of Clark and Smith (1993)
, who
found that at birth, the neurocranium has already completed the
majority of its growth, and to attain proper adult proportions, the
viscerocranium must grow faster than the neurocranium. This
differential growth rate was due in part to the functional demands of
the viscerocranium and the application of muscular forces on the facial
skull (Lightfoot and German 1998
). Evidence from this
study supported the idea that functional demands of the viscerocranium
are greater after birth and that to reach functional adult proportions,
growth in this area occurred at a higher rate. Therefore, there was an
increased chance of being affected by an epigenetic factor such as
dietary protein.
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REFERENCES |
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|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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