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Respiratory Physiology & Neurobiology 159 (2007) 155–162

Organ growth in chicken embryos during hypoxia:


Implications on organ “sparing” and “catch-up growth”
Milène A. Azzam, Jacopo P. Mortola ∗
Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada
Accepted 11 June 2007

Abstract
The primary aim of this study was to establish whether or not embryonic hypoxia selectively affects the growth of specific organs. Chicken
embryos were incubated either in normoxia (Nx) or in hypoxia (15% O2 from embryonic day E5, Hx). The length of the beak and third toe (as
indexes of skeletal growth) and the weights of internal organs (eyes, brain, heart, lungs, liver, kidneys, stomach, and intestines) were collected at
E14, E17, E19, and E20. Hypoxia reduced embryonic body weight (BW). At any given age, the specific weight (organ weight/BW) of some organs
in Hx was higher, and that of others was lower, than in Nx. However, almost all differences disappeared when organ weights were compared as
function of BW, rather than at fixed chronological ages. The important exception was the chorioallantoic membrane (CAM), the mass of which
in Hx developed out of proportion. In a third group of embryos, hypoxic until E14 and normoxic thereafter, there was no post-hypoxic catch-up
growth, differently from what known to occur postnatally. A possible interpretation is that catch-up growth does not depend on the age of the
embryo but on its BW. In conclusion, at least in the chicken embryo and for the level of hypoxia tested, hypoxia has no selective effects on the
growth of specific organs, except for the CAM. Qualitative differences in the weight response to hypoxia among organs observed at any given age
can be explained largely by the effects of the blunted growth on the growth trajectory of the individual organs.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Embryonic development; Heart; Hypoxia; Lungs; Chorioallantoic membrane; Normalisation

1. Introduction opposite had occurred. Non-homogeneous effects of hypoxia


among internal organs have been observed also in mammals dur-
In mammals, hypoxia during gestation usually results in small ing development (Mortola, 2001, for review). These inter-organ
neonates, although the maternal response to hypoxia can limit differences may reflect differences in metabolic sensitivity to
the blunting of fetal growth (Moore and Price, 1948; Metcalfe hypoxia and the redistribution of O2 delivery, which appears to
et al., 1962; Smith et al., 1969; Robinson et al., 1983; Chang favour key vital organs, at the expense of organs less crucial for
et al., 1984; Faridy et al., 1988; Moore et al., 1982; Monge the immediate survival (Kuwahira et al., 1993; Côté and Porras,
and León-Velarde, 1991; Moore, 2003). In the avian embryo, 1998).
hypoxia during incubation consistently decreases body growth The impression that, during hypoxia, the growth of some
(e.g., Tazawa et al., 1971; Wangensteen et al., 1974; Metcalfe organs may increase at the expense of others is based on the
et al., 1981; McCutcheon et al., 1982; Xu and Mortola, 1989; finding that, at any given developmental age, their specific
Azzam et al., 2007). As one may expect, small embryos also weights are higher than in normoxic controls. However, BW-
have small internal organs. However, upon normalisation by normalisation when comparing same-age animals with different
body weight (BW), some organs have larger specific weights growth rates (as it happens in hypoxia) can lead to misleading
(organ weight/BW) than normoxic controls, meaning that dur- conclusions whenever the growth rate of various organs differ,
ing hypoxia the drop in their weight was not as marked as that which is typically the case during embryonic development. In
of the whole body, at the expense of other organs where the fact, for an organ normally growing at a rate lower than the whole
body (and therefore dropping its specific weight with age), in
the case of stunted body growth, at any given age its specific
∗ Corresponding author. Tel.: +1 514 398 4335; fax: +1 514 398 7452. weight must exceed the control value. The opposite has to occur
E-mail address: jacopo.mortola@mcgill.ca (J.P. Mortola). for any organ normally growing at a rate higher than that of

1569-9048/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.resp.2007.06.003
156 M.A. Azzam, J.P. Mortola / Respiratory Physiology & Neurobiology 159 (2007) 155–162

the whole embryo. Therefore, whenever comparisons are made weighed and placed in incubators (Hova-Bator, Savannah, GA)
at fixed chronological ages, one cannot sort out to what extent around midday (embryonic day E0). The incubators maintained
differences in organ specific weights result from the effects of a steady temperature (T) of about 38 ◦ C and 60% relative humid-
hypoxia on that organ or from the generalised blunting in body ity, and provided a 45◦ egg rotation four times a day. For the first
growth. In this study, organ weights of hypoxic and normoxic 4 days all eggs were incubated in normoxic conditions. Then, at
embryos were compared not only at predetermined chronolog- embryonic day E5, they were separated into two groups. Some
ical ages, but also at comparable BWs, reasoning that a unique continued in normoxia (21% O2 , normoxic, Nx, N = 52), others
BW–organ weight relationship between normoxic and hypoxic were transferred into a hypoxic incubator kept at 15–16% O2
embryos would indicate no selective effects of hypoxia on the (on average, 15.5% ± 0.01, including the periods of incubator
growth of the organ. opening for egg transfer and cleaning) (hypoxic, Hx, N = 52).
The primary aim of this study was to establish whether or A third group of eggs was treated as the Hx eggs until day
not embryonic hypoxia affects the growth of specific organs, E14, when they were returned to normoxia, and maintained in
apart from its general effects on body growth. Measurements normoxia thereafter. This group will be referred to as the “post-
were conducted on chicken embryos, rather than on a mam- hypoxic normoxic” group (Hx–Nx, N = 41). The desired level
malian animal model, to eliminate the possibilities of maternal of hypoxia was obtained by leaking a small stream of warmed
and placental contributions to the fetal outcome. Second, we and humidified N2 into the incubator from a pressurised tank,
asked whether or not, during the post-hypoxic return to nor- under the control of a flowmeter. The O2 concentration within
moxia, the “catch-up” growth of some organs might prevail over the incubator was continuously sampled by a calibrated fuel cell
that of others. gas analyser (Foxbox, Sable Systems Int., Las Vegas, NV), dis-
played on a computer monitor, and stored for later averaging. A
2. Methods T-data logger and a hygrometer were inside each incubator; the
former collected the T value every 10 min, while humidity was
Freshly laid chicken eggs of the Leghorn variety were pur- read daily.
chased from a local supplier. Eggs were stored at 15 ◦ C until the Data collection for the Nx and Hx groups was conducted
start of incubation, and for no longer than 7 days. The eggs were on days E14, E17, E19, and E20, with 13 embryos per group

Fig. 1. (Top) Schematic representation of the growth of an organ occurring at a rate slower than that of the whole body (left panel), so that the specific organ
weight declines with age (middle panel). The curves represent the conditions of normoxia (continuous line) and hypoxia (dashed line), the latter with a growth rate
equal to half the normoxic rate. In these conditions, at any given age the organ specific weight in hypoxia exceeds the normoxic value (middle panel). However,
when represented as function of embryo’s weight, the data fall on a unique relationship (right panel). (Bottom) Body and head weights of embryos incubated in
normoxia (open circles) or in hypoxia (filled triangles). At any given age, the head absolute and specific weights were greater in hypoxia than in normoxia (left and
middle panels). However, when plotted against embryo’s weight, the head weights of hypoxic and normoxic embryos fell on the same relationship. Values are group
means ± 1 S.E.M. *Statistically significant difference between the two groups.
M.A. Azzam, J.P. Mortola / Respiratory Physiology & Neurobiology 159 (2007) 155–162 157

and per age, while that for the Hx–Nx group was at days E17 the normoxic value (middle panel). When examined as function
(N = 13), E19 (N = 15), and E20 (N = 13). After weighing the egg, of the embryo’s BW (right panel) the normoxic and hypoxic
the embryo was killed by exposure to CO2 and cold. The egg curves overlapped, meaning that in hypoxia the organ weight
was opened, the embryo was freed from the allantois and yolk, was appropriate for body size.
and its weight and that of the chorioallantoic membrane (CAM) The bottom panels of the figure present the experimental val-
were noted. At day E20, in a few embryos, after opening the ues of head weights in normoxia (open symbols) and hypoxia
thorax, blood was sampled by inserting a heparin-treated micro- (filled symbols). The head was chosen because it is a section
hematocrit tube through the wall of the ventricle, and hematocrit of the body renowned for decreasing its specific weight during
was determined by microcentrifugation. The length of the third development in many species. At any given age, both head and
toe (from phalanx one to four inclusive) and that of the beak BW in Hx were less than in Nx (left panel), and the head specific
(from its tip to the beginning of the eye socket), taken as rep- weight significantly exceeded that of Nx (middle panel). On the
resentative of skeletal growth (Lillie, 1952), were measured by other hand, when the data were presented as function of embry-
use of a fine caliper. Internal organs (eyes, brain, heart, lungs, onic BW (right panels), the curves overlapped. Hence, like in
liver, kidneys, stomach, and intestines) were dissected, lightly the model presented at top, in the Hx embryos the larger specific
blotted and drained of blood or any fluid contents, and weighed weight of the head can be attributed solely to their blunted body
with a digital scale accurate to 10−4 g. The weight of the head growth.
in toto was also collected, for the purpose illustrated in Section
3.1. All organs and the CAM were placed in an oven at 70 ◦ C for 3.3. W-specific organ weights at fixed postnatal ages
1 week; separate measurements had indicated that this period of
time was appropriate for dry weight to stabilise. Although the During the last week of the chicken embryonic development,
eyes, lungs, and kidneys of right and left sides were isolated and most BW-specific weights either decreased (e.g., heart, eyes, and
weighed separately, for the analysis their weights were com- brain) or increased (third toe, stomach, and intestines) (Fig. 2).
bined; the values presented, therefore, represent the sum of the For those organs decreasing specific weights, the values in Hx
right and left organs. tended to be similar to, or most often significantly above, those of
All group data are presented as means ± 1 S.E.M. Statistical
comparisons between two sets of data were done by two-tailed
t-test, and those between the three sets (Nx, Hx and Hx–Nx
embryos) were performed by ANOVA with post hoc Bon-
ferroni’s limitations for the three comparisons. In all cases a
difference was considered statistically significant at P < 0.05.

3. Results

3.1. General effects of hypoxia

At the start of incubation the size of the eggs used for the
measurements averaged 61 g ± 0.3 for the Nx embryos and
59.4 g ± 0.6 for the Hx embryos, with no significant difference
between the two sets for any of the subgroups used at the various
ages. At each of the four ages the Hx embryos were significantly
smaller than controls, on average 87% ± 3 (P < 0.005 from
Nx), 76% ± 3 (P < 0.0001), 85% ± 3 (P < 0.0005) and 75% ± 4
(P < 0.0002) at E14, E17, E19, and E20, respectively. Hemat-
ocrit, measured only in a few embryos at E20, did not differ
significantly between the Hx (28.8% ± 2, N = 5) and Nx embryos
(26.7% ± 1.1, N = 7).

3.2. Expected effects of stunted body growth on W-specific


organ weights

The top panels of Fig. 1 present the hypothetical case of an


embryonic organ growing at a rate lower than that of the whole Fig. 2. Specific organ length (beak and toe, cm/g1/3 ) and specific organ weight
embryo, in normoxia (continuous lines) and in hypoxia (dashed (organ weight/embryo’s weight, %) for embryos incubated in normoxia (open
circles) or hypoxia (filled triangles), at embryonic days E14, E17 and E20.
lines). In this example, hypoxic growth rate was set at 50% of the
Length (beak and toe) was normalised to the one-third power of body weight,
normoxic rate. Because of this combination (stunted embryonic assuming geometric similarity. Percentages refer to the hypoxic/normoxic aver-
growth and specific weight decreasing with development), at any age of the 3 days. Values are group means ± 1 S.E.M. *Statistically significant
given age the organ specific weight during hypoxia exceeded difference between the two groups.
158 M.A. Azzam, J.P. Mortola / Respiratory Physiology & Neurobiology 159 (2007) 155–162

Table 1
Dry–wet weight ratio (%)
Age Organs Normoxia Hypoxia Hypoxia–normoxia

E14 N = 13 N = 13
Eyes 4.7 ± 0.1 4.6 ± 0.04
Brain 10.5 ± 0.1 10.6 ± 0.2
Heart 12.6 ± 0.1 12.3 ± 0.2
Lungs 9.6 ± 0.3 8.7 ± 0.2 (a)
Liver 21.8 ± 0.3 20.7 ± 0.6
Kidneys 13.1 ± 0.5 11.8 ± 0.5
Stomach 13.5 ± 0.6 11.2 ± 0.4 (a)
Intestines 11.0 ± 0.4 10.2 ± 0.4
E17 N = 13 N = 13 N = 13
Eyes 5.6 ± 0.1 5.3 ± 0.1 5.4 ± 0.1
Brain 12.2 ± 0.1 11.7 ± 0.1 11.7 ± 0.1
Heart 12.8 ± 0.2 13.0 ± 0.1 13.1 ± 0.1
Lungs 13.1 ± 0.2 13.1 ± 0.1 12.8 ± 0.3
Liver 25.2 ± 0.4 24.5 ± 0.4 24.5 ± 0.3
Kidneys 15.7 ± 0.3 14.8 ± 0.1 15.2 ± 0.2
Stomach 14.3 ± 0.4 14.5 ± 0.3 14.5 ± 0.5
Intestines 12.0 ± 0.3 12.2 ± 0.2 12.2 ± 0.3
E19 N = 13 N = 13 N = 15
Eyes 5.8 ± 0.1 5.9 ± 0.1 5.8 ± 0.04
Brain 13.3 ± 0.1 13.2 ± 0.1 13.1 ± 0.1
Heart 14.5 ± 0.3 14.8 ± 0.2 14.1 ± 0.3
Lungs 13.6 ± 0.3 13.3 ± 0.3 14.2 ± 0.2 (b)
Liver 29.1 ± 0.4 29.0 ± 0.3 27.8 ± 0.3 (a,b)
Kidneys 15.5 ± 0.1 15.2 ± 0.2 15.3 ± 0.2
Stomach 13.6 ± 0.3 12.5 ± 0.4 (a) 13.8 ± 0.4 (b)
Intestines 10.9 ± 0.2 11.1 ± 0.3 11.6 ± 0.3
E20 N = 13 N = 13 N = 13
Eyes 6.1 ± 0.1 5.9 ± 0.2 6.0 ± 0.1
Brain 13.9 ± 0.3 13.6 ± 0.3 14.0 ± 0.3
Heart 15.1 ± 0.2 15.2 ± 0.2 15.7 ± 0.3
Lungs 15.9 ± 0.5 15.0 ± 0.4 15.9 ± 0.4
Liver 31.6 ± 0.5 29.3 ± 0.8 (a) 31.1 ± 0.7 (b)
Kidneys 16.7 ± 0.2 15.9 ± 0.3 16.6 ± 0.3
Stomach 13.9 ± 0.3 13.4 ± 0.5 14.8 ± 0.7
Intestines 12.7 ± 0.8 11.8 ± 0.7 13.8 ± 0.8 (b)

Values are means ± 1 S.E.M. Hypoxia was for the period embryonic days E5–E20 included. Normoxia after hypoxia started on embryonic day E15. (a) Significant
difference from normoxia. (b) Significant difference from hypoxia.

the Nx embryos; the average percentage of the Nx value is indi- triangles). A visual inspection reveals a substantial overlapping
cated within each panel. Differently, for those organs increasing between normoxia and hypoxia for all organs. For a statistical
their specific weights with development, the values of Hx were comparison of the two groups the data were binned into four
similar (intestines) or significantly lower than in Nx (third toe ranges of embryo weights (Fig. 4). Out of a total of 40 pairs of
and stomach). values (10 organs, each compared over 4 weight ranges), only
The same pattern emerged when the organ dry weights, rather three pairs differed significantly between Nx and Hx, the heart
than the wet weights, were considered because, for the most at the embryonic BW of 15 g, and the lungs and brain at 25 g.
part, the dry–wet ratios were not significantly different between
Nx and Hx embryos (Table 1). In the few cases of a differ- 3.5. The chorioallantoic membrane (CAM)
ence, the dry–wet ratios in Hx were consistently lower than
in Nx, indicating slightly larger water content in the hypoxic At E14 the CAM absolute and specific weights of Hx did not
organs. differ from Nx, while they were significantly higher at embry-
onic days E17, E19, and E20 (Fig. 5, left and middle panels).
3.4. Organ–body weight relationships Unlike any of the embryonic organs considered (Section 3.4.),
the differences in CAM weight from Nx were large and statisti-
Fig. 3 presents the data of organ weight as function of cally significant also when the values were compared as function
embryo’s BW for all Nx (open circles) and Hx embryos (filled of embryo’s weight (Fig. 5, panels at right).
M.A. Azzam, J.P. Mortola / Respiratory Physiology & Neurobiology 159 (2007) 155–162 159

Fig. 3. Length (beak and toe, mm) and weight (g) of various organs for embryos Fig. 4. Length (beak and toe, mm) and weight (g) of various organs for embryos
incubated in normoxia (open circles) or hypoxia (filled triangles), represented incubated in normoxia (open circles) or hypoxia (filled triangles), binned in
as function of the corresponding embryo’s body weight. Data refer to incubation four groups of body weight ranges. The data refer to incubation days E14, E17,
days E14, E17, E19, and E20. E19, and E20 and are those represented individually in Fig. 3. Values are group
means ± 1 S.E.M. *Statistically significant difference between the two groups.

3.6. Post-hypoxic normoxia days E17, E19, and E20. At each age, the BW and the wet weight
of most organs were below the average Nx values (100%, dashed
These embryos (Hx–Nx) were exposed to hypoxia until day lines in Fig. 6), and for the most part did not differ significantly
E14 and to normoxia thereafter; their organs were measured at from the corresponding values of the Hx embryos. The very few

Fig. 5. Absolute (left) and specific (middle) weights of the chorioallantoic membrane (CAM) for embryos incubated in normoxia (open circles) or hypoxia (filled
triangles). At right, the data are plotted against the corresponding embryo’s body weight, either individually (top right) or binned in four groups of body weights
(bottom right). Values are group means ± 1 S.E.M. *Statistically significant difference between the two groups.
160 M.A. Azzam, J.P. Mortola / Respiratory Physiology & Neurobiology 159 (2007) 155–162

example, McCutcheon et al. (1982) found that the three internal


organs that they examined, brain, heart and liver, were smaller
in hypoxic than in normoxic embryos; the decreases in heart and
brain were less than that of the whole embryo, while the liver
had the opposite response. Hence, they concluded that heart and
brain were spared by hypoxia, at the expense of the liver. Similar
results and conclusions were reached by other studies exam-
ining these or other organs at predetermined embryonic ages
in avian (Stock and Metcalfe, 1987; Xu and Mortola, 1989;
Asson-Batres et al., 1989; Dzialowski et al., 2002; Chan and
Burggren, 2005) and non-avian embryonic models (Crossley
and Altimiras, 2006). Also the current data, when analysed
at fixed chronological ages (Fig. 2), would give the impres-
sion that some organs may be protected (e.g., brain, heart, and
eyes) possibly at the expense of skeletal growth (as exemplified
by the toe) or of the abdominal viscera (intestines and stom-
ach). However, we believe that such interpretation of the data is
incorrect.
As mentioned in Section 1 and illustrated in Fig. 1, the
approach of comparing organ-specific weights between animals
at fixed chronological times can lead to misleading conclusions
whenever embryos are growing at different rates and the specific
weights of the organs under consideration change with develop-
ment. Both situations occur in the comparison between hypoxic
and normoxic embryos. When compared as function of BW,
Fig. 6. Average values of embryo’s body weight (at left) and weights of various rather than age, the conclusion was reached that hypoxia had
organs, expressed in percent of the corresponding mean values in normoxia minimal selective effects on the growth of specific organs; there-
(horizontal dashed line), for embryos incubated in hypoxia (filled bars) and
fore, the inter-organ differences in specific weights observed at
for embryos returned to normoxia after hypoxic exposure until day E14 (“post-
hypoxic normoxia”, grey bars). Columns indicate group means at days E17 (top), any given age, for the most part, are attributable to the blunted
E19 (middle), and E20 (bottom), bars are 1 S.E.M. *Statistically significant growth.
difference between the two groups. In young and adult mammals, the most effective responses to
sustained hypoxia are those aiming to save energy and protect O2
exceptions were the toe and, notably, the kidneys at E17, which delivery. However, many of those responses (e.g., drop in ther-
significantly exceeded the Hx values, and the stomach at E19, mogenesis, peripheral vasoconstriction, increased pulmonary
which was significantly smaller. ventilation, cardiac output, and hematocrit) are minimally or
Similar results were obtained with the organ specific dry not functional in the early embryonic phases. The autonomic
weights. In this case, the only significant differences between control of blood flow becomes operational only in the second
Hx–Nx and Hx were the kidneys at E17 (118% ± 7 in Hx–Nx half of incubation (Mulder et al., 1998, 2002). Cardiac hypertro-
and 79% ± 6 in Hx, P < 0.001), the brain at E19 (respectively, phy, which is a characteristic of sustained hypoxia after birth, is
88% ± 2 and 96% ± 2, P < 0.05) and the stomach at E20 (respec- small or absent before hatching (Burton and Smith, 1969; Asson-
tively, 105% ± 11 and 77% ± 7, P < 0.05). Batres et al., 1989), presumably because sustained hypoxia in
the embryo causes vasodilatation and decreases systemic vas-
4. Discussion cular resistance (Adair et al., 1987). Hence, the major survival
strategy against hypoxia is the decrease in body growth. It is
As on many previous occasions (e.g., Smith et al., 1969; interesting to note that the slow rate of body growth not only
Metcalfe et al., 1981; McCutcheon et al., 1982; Adair et al., saves energy but also, by delaying organ growth, achieves some
1987; Stock and Metcalfe, 1987; Xu and Mortola, 1989; Asson- degree of protection for key organs like the heart and the brain.
Batres et al., 1989; Dzialowski et al., 2002; Azzam et al., 2007), In fact, the heart and the brain being among the organs that
also the current measurements indicated that hypoxia during drop their specific weights during development, a slow growth
incubation blunted embryonic growth. The effects on hemat- implies that they will retain a greater proportion of BW for a
ocrit were not significant. Previous data too have shown only longer period of time; the opposite occurs to organs with delayed
small or no increase in hematocrit in hypoxic embryos (Jalavisto development, like the stomach and the guts. Hence, even with
et al., 1965; Burton and Smith, 1969; Tazawa et al., 1971; Xu limited mechanisms to redistribute blood flow, during embry-
and Mortola, 1989; Dzialowski et al., 2002), probably because onic development the inter-organ differences in time trajectories
of the modest erythropoietic response and hemoconcentration (Fig. 2) are such that solely by blunting body growth the relative
at these developmental stages. Several authors had reported on proportion among organs shifts in favour of the heart and the
the effects of hypoxia on the growth of internal organs. For brain.
M.A. Azzam, J.P. Mortola / Respiratory Physiology & Neurobiology 159 (2007) 155–162 161

The CAM is an extra-embryonic organ that becomes fully


formed at E12. After that age, its specific weight declines (Fig. 5,
middle panel). The CAM weight and structural changes in
hypoxia have been reported by several authors (Strick et al.,
1991; Burton and Palmer, 1992; Wagner-Amos and Seymour,
2003; Chan and Burggren, 2005). Differently from all embryonic
organs, the CAM weight increased not only at fixed developmen-
tal ages but also when examined as function of embryo’s BW
(Fig. 5, panels at right). This indicates that hypoxia had a specific
positive effect on the mass of the CAM, most likely providing an
improvement of its O2 diffusion capacity, and reminiscent of the
changes in placenta structure seen in mammals during hypoxic
gestation (Faridy et al., 1988; Monge and León-Velarde, 1991;
Zamudio, 2003).
The second goal of the study was to consider the possibility
that, during post-hypoxic normoxia, some organs may catch-
up at a faster pace than others. However the results, globally
considered, indicated that neither the whole embryo nor its
Fig. 7. Hypothetical growth curves in normoxia (continuous lines), hypoxia
individual organs showed a significant post-hypoxic catch-up (dashed lines), and post-hypoxic normoxia (filled triangles). In (A), the growth
growth. There were very few exceptions to this pattern, and the curves are convex with respect to the time-axis (growth rate increasing with
most notable one was the increase in kidney size at E17, i.e. 3 time); in (B), they are concave toward the time-axis (growth rate declining with
days after termination of hypoxia. This increase, however, was time). In either case, the growth rate of the hypoxic curve is assumed to occur at
only transient, and its basis is not clear; it cannot be ascribed half the normoxic rate. From day 14, the hypoxic growth curve resumes at the rate
that the normoxic curve had at that body weight (filled triangles), mimicking
to a post-hypoxic surge in blood flow, because the increase was the situation of the hypoxic embryos returned to normoxia. Catch-up growth
approximately the same for the wet (121%) and dry kidneys (expressed as percent of normoxia, bottom panels, and filled triangles) in (A) is
(118%). Postnatally, the return to normoxia after several days in virtually non-existent, while in (B) is almost complete by day 24.
hypoxia stimulates an increased speed of growth. For example,
human infants growth-retarded because of cardiogenic cyanotic In conclusion, we confirm previous data that, during embry-
right-to-left shunts recover to the normal, or quasi-normal, W onic hypoxia, at any given age, the specific weight of some
percentile after surgical correction of the disease (Prader and organs may exceed, and that of others may be below, the nor-
Tanner, 1963; Gingell et al., 1981). Catch-up growth has been moxic values. However, at least in the chicken embryo and for the
observed also in numerous animal experiments upon resolution level of hypoxia tested, these differences are largely explained
of the original growth restriction, including the return to nor- by the generalised blunting in body growth, and there is no indi-
moxia after hypoxia (Okubo and Mortola, 1988; Sant’Anna and cation that hypoxia has selective effects on the growth of specific
Mortola, 2003). The current data, on the other hand, show a organs. An important exception is the CAM, the mass of which in
lack of catch-up growth in the hypoxic avian embryo returned hypoxia develops out of proportion. Upon return to normoxia,
to normoxia. The mechanisms behind the phenomenon of catch- differently from the postnatal life, catch-up growth is almost
up growth are still obscure, but it is worth noting that the growth absent, presumably because embryonic growth rate does not
trajectory upon termination of hypoxia can be an important fac- depend on age but on the embryo’s BW. Globally taken, there-
tor in determining the magnitude of catch-up growth. This is fore, these data suggest that during embryonic development the
schematically illustrated in Fig. 7, where the growth curves are mass of the individual organs during hypoxia, and their rate of
depicted as convex (A) or as concave (B) relative to the time- recovery upon return to normoxia, much depend on the effect of
axis. In these examples, the growth curves in hypoxia (dashed hypoxia on embryo’s BW.
lines) are chosen to be half of the normoxic curves. Upon restora-
tion of normoxia (filled triangles), if the growth rate resumed at
the rate pertinent to that body W, catch-up growth will be min- Acknowledgment
imal in condition A and almost complete in condition B. B is
the familiar growth trajectory after birth, while A is the com- This study was supported financially by the Canadian Insti-
mon growth pattern during embryonic development for many tute of Health Research.
species, including the chicken embryo (e.g., Wangensteen et al.,
1974; Vleck et al., 1980; Azzam et al., 2007). Hence, if the References
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