Vol. 88, Issue 1, 47-53, January 2000
Effect of delivery temperature on endocrine stimulation of
thermoregulation in lambs born by cesarean section
M. E.
Symonds,
J. A.
Bird,
C.
Sullivan,
V.
Wilson,
L.
Clarke, and
T.
Stephenson
Academic Division of Child Health, School of Human Development,
University Hospital, Queen's Medical Centre, Nottingham NG7 2UH,
United Kingdom
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ABSTRACT |
We examined the hypothesis that exogenous
stimulation with physiological doses of 3,5,3'-triiodothyronine
(T3) and/or norepinephrine at birth can improve
thermoregulation in near-term lambs delivered by cesarean
section. This was achieved by investigating the effect of
delivery temperature [i.e., warm (30°C) vs. cool
(15°C) ambient temperatures] on hormonal
stimulation on uncoupling protein-1 (UCP1) abundance in brown adipose
tissue. In vivo measurements of temperature control (i.e., colonic
temperature, oxygen consumption, and incidence of shivering) were made
over the first 2.5 h after birth. Each lamb was injected with saline
with or without T3, norepinephrine, or T3 plus
norepinephrine. Irrespective of delivery temperature, abundance of UCP1
increased and incidence of shivering decreased by all hormonal
treatments, but this only reduced the rate of decline in colonic
temperature of cool-delivered lambs. Oxygen consumption was higher in
cool-delivered lambs that were able to fully restore body temperature,
an adaptation not observed in controls or any warm-delivered groups.
Exogenous administration of endocrine stimulatory factors can enhance
the abundance of UCP1 in cesarean-section-delivered lambs with the
magnitude of thermoregulatory response being greater at cool than warm
delivery temperatures.
birth; brown adipose tissue; norepinephrine; thyroid hormones
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INTRODUCTION |
THE METABOLIC RESPONSES that occur during the
transition from fetal to neonatal life represent a change from a
thermoregulatory quiescent state in which inhibitory stimuli dominate
(3, 13) to one of near maximal rates of heat production that are rarely matched again during postnatal or adult life. The route of delivery is
known to have a critical role in determining thermoregulatory adaptation after birth in both infants and lambs (8, 11). Lambs born
vaginally at term are able to maintain a normal body temperature (i.e.,
39°C) even when maintained at a cool ambient temperature of
15°C (5, 11). In contrast, near-term lambs delivered by cesarean
section rapidly become hypothermic (25). It has been proposed that
cesarean section delivery compromises thermoregulation because of an
impairment of heat production by nonshivering thermogenesis in brown
adipose tissue (BAT) (8, 11). Lambs and infants born near term by
cesarean section are characterized as having a lower postpartum surge
in plasma thyroid hormone concentrations and reduced sympathetic
activity over the first 30 min of life (11, 31). The rate of decline in
body temperature after cesarean section birth is reduced after delivery into a warm ambient temperature of 30°C because of a
lower thermal stimulus to the lamb. This does not appear to be the case
for lambs born per vaginum, which exhibit rapid activation of heat
production of a unique uncoupling protein-1 (UCP1) (6, 12) within BAT
(10).
Thyroid hormones are known to have a critical role in thermoregulatory
adaptation after birth (5, 26), and plasma concentrations remain well
above adult values for several weeks of postnatal life (29).
Thermoregulation is compromised in lambs delivered by cesarean section
1 wk premature even though plasma 3,5,3'-triiodothyronine (T3) concentrations would be considered normal in
comparison to adults (i.e., 2-3 nmol/l; Ref. 9), but these are
appreciably lower than those recorded immediately after vaginal birth
at term (i.e., 6 nmol/l; Ref. 31). We have proposed that impaired
thermoregulation after cesarean section delivery is due in part to a
delay in the rate of appearance of endocrine stimulatory factors,
including T3 and norepinephrine. The extent to which the
absence of these stimulatory factors act to maintain low levels of mRNA
for UCP1 and its thermogenic activity throughout fetal life (7, 10) remains to be fully established. The present study was, therefore, designed to examine the hypothesis that exogenous stimulation with
T3 and/or norepinephrine at the time of birth has the
potential to improve thermoregulation in near-term lambs delivered by
cesarean section. It is established that newborn lambs born vaginally
exhibit an almost immediate thermogenic response to exogenous
T3 or norepinephrine injection (1, 18), but it is not known
whether lambs delivered by cesarean section respond in a similar
manner. The present study was undertaken to determine whether the
control of thermoregulation can be manipulated hormonally in near-term
lambs delivered into warm (30°C) or cool
(15°C) ambient temperatures. These temperatures were
adopted as they have been shown to have significant effects on
thermoregulation in newborn lambs (10). A combination of in vivo
recordings, measurement of UCP1 abundance and the catecholamine content
of BAT, and circulating levels of thyroid hormones and nonesterified fatty acids (NEFA) was made during the first 2.5 h of neonatal life.
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METHODS |
Animals and diet.
Twenty-five Bluefaced Leicester cross Swaledale ewes of similar age
(i.e., 5 yr) and of known mating date, and diagnosed as being pregnant
with twins with the use of a real-time ultrasound echograph, were
entered into the study. All ewes had experienced at least two previous
successful pregnancies. Six weeks before the predicted lambing date,
each ewe was individually housed and fed 0.4-0.6 kg of concentrate
and 1.2 kg of hay per day, the combination of which contained
sufficient energy and nitrogen to fully meet requirements for
maintenance and pregnancy over this final period of gestation (1). The
mean ewe body weight was 80.1 ± 8.9 (SE) kg (n = 28). All
ewes (n = 28) had adequate body fat stores as assessed by the
body condition score, which was 3.5 ± 0.2 arbitrary units
(an index of body energy reserves as assessed by the distribution of
fat in the lumbar region on and around the backbone in the loin area
immediately behind the first rib).
Experimental design.
Each twin was randomly preassigned a treatment and delivery temperature
before the experiment commenced by using random-number tables. Cesarean
section delivery was performed as described by Clarke et al. (10)
between 144 and 146 days of gestation (term = 147 days), while ewes
were maintained in a purpose-built constant-temperature control room at
15 ± 1°C. Paravertebral anesthesia was administered by inserting
spinal needles to allow blockage of the T13,
L1, and L2 spinal nerves by surrounding them
with 2% Xylocaine, as the dorsal and ventral branches of these nerves
pass above and below the transverse processes of the vertebrae. This
was followed by jugular venous injection of 4-6 ml of ketamine
(100 mg/ml in saline) into the ewe. A flank incision was made, and the
first fetus was delivered and placed onto the ewe's flank. A bolus
injection of 0.5 ml of saline with or without hormone treatment was
then injected into the umbilical vein at a site ~5 cm from its entry into the fetus. Five seconds later the cord was clamped, sutured, and
cut, and the lamb was immediately placed into its allocated delivery
temperature. This process was then immediately repeated for its twin. A
5-s interval was adopted, because pilot studies, in which an air bubble
was injected into the umbilical vein after saline injection,
demonstrated that the time taken for all the remaining blood in the
vein as well as the air bubble to enter fetal circulation was always
<5 s.
The number of lambs in each treatment group is given in Table
1. The dose of T3 (i.e., 2 nmol) was calculated on the basis that plasma volume was 6% of body
weight (33). This dose is in accord with the low dose used in newborn
lambs by Lynch et al. (17), for which a more rapid thermogenic response
was observed compared with a dose three times higher. We aimed to
obtain an immediate increase in neonatal plasma T3
concentration at the time of delivery that was sufficient to achieve a
plasma concentration of ~6 nmol/l, which is the value recorded in
vaginally delivered lambs (33). The norepinephrine dose was based on
the priming dose described by Alexander and Williams (2), i.e., 50 µg
norepinephrine bitartrate salt dissolved in 0.5 ml saline, including
0.3% ascorbic acid as a preservative. For lambs receiving a
combination of T3 plus norepinephrine, the doses were the
same as when given separately.
All lambs were monitored to ensure that continuous breathing was
established, which normally occurred within 2-4 min of birth. Colonic temperature was continuously monitored by using an electronic thermometer (type 3GID, Light Laboratories, Brighton, UK), and the
lambs were dried with a towel. At 25-30 min after birth, a jugular
vein catheter was inserted to allow blood sampling, and a 5-ml sample
was taken. Three skin surface electrodes were also inserted to enable
electrocardiogram recordings for heart rate measurement. Local
anesthetic (10% Xylocaine spray) was applied to each site a few
minutes before any needles were inserted into the lamb. Each lamb was
subsequently placed in an indirect calorimeter maintained at the same
ambient temperature into which it was delivered. Continuous
measurements of colonic temperature and breathing frequency and pattern
with the use of inductance plethysmography (30) were made until lambs
were 2-2.5 h old. Sleep state was determined from these
respiratory pattern measurements, and the occurrence of shivering was
assessed from observations of interference on the respiratory pattern
(29). Blood samples were taken every 30 min. Oxygen consumption was
measured continuously by using indirect open-circuit calorimetry
commencing from 50-60 min after birth. The mean values presented
represent values obtained during 10- to 15-min periods of
non-rapid-eye-movement sleep, to minimize variations due to animal
movement, and were recorded by using two identical indirect-calorimetry
systems based on that described by Symonds et al. (30), with the
modification that air flow was measured by using a differential flow
indicator (Perflow Instruments, Willesdon, UK). Lambs were then
humanely killed 2.5 h after birth by intravenous administration of
barbiturate (100 mg/kg pentobarbital sodium; Euthatal, RMB Animal
Health). Both perirenal adipose tissue depots were rapidly removed,
placed in liquid nitrogen, and stored at 
70°C
for measurement of UCP1 abundance, protein, lipid, and DNA contents as
described by Symonds et al. (30). All operative procedures and
experimental protocols had the required Home Office approval as
designated by the Animals (Scientific Procedures) Act of 1986.
Laboratory procedures.
Mitochondria were prepared from frozen perirenal adipose tissue as
described by Symonds et al. (30). The protein contents of homogenates
and mitochondria were measured by the method of Lowry et al. (16). UCP1
was detected in mitochondria after separation by SDS-PAGE followed by
immunoblotting and enhanced chemiluminesence (Amersham) with antibodies
raised against purified ovine UCP1 (26). Densitometric analysis was
then performed on each membrane after image detection by using a Fuji
film LAS-1000 cooled charge-coupled-device camera (Fuji Photo Film,
Tokyo, Japan), and all values were then expressed as a percentage of a
reference sample run in duplicate on all gels (i.e., from a 4-h-old
vaginally delivered lamb). The total catecholamine content of BAT was
determined as described by Clarke et al. (9), whereas lipid content was
determined by ether extraction (30) and DNA content was measured
fluorometrically (15). Plasma concentrations of NEFA and glucose were
measured enzymatically, whereas total T3 and thyroxine
(T4) were measured by radioimmunoassay (11). All chemicals
used in the study were purchased from Sigma Chemical, unless otherwise stated.
Statistical analysis.
This experiment was of nonorthogonal factorial design with temperature
at two levels and treatment at four levels. Statistical analysis of
treatment (3 degrees of freedom) and delivery temperature (1 degree of
freedom) effects and their interactive effect were assessed with 42 residual degrees of freedom by using a general linear model procedure
for two-way ANOVA. The SAS program accounted for missing values with
appropriate alterations in residual degrees of freedom. In the case of
in vivo or plasma measurements, ANOVA with correction for repeated
measures was used. For plasma thyroid hormone and glucose
concentrations, there were no significant changes with time after
birth; therefore, a mean value was used for each animal. Significant
differences among the number of lambs that shivered in each group were
assessed by using a 
2 test.
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RESULTS |
Thermoregulation after birth.
Five minutes after birth, colonic temperature was not influenced by
T3 and/or norepinephrine treatment but was higher
(P < 0.05) in warm- than in cool-delivered lambs (Fig.
1). In all lambs delivered into a cool
ambient temperature, colonic temperature decreased significantly
(P < 0.05) with time after birth. This response was lower
(P < 0.05) in all hormone-treated compared with
saline-treated groups. For warm-delivered lambs, however, although
colonic temperature decreased (P < 0.05) after birth in all
groups, this response was greater in hormone-treated compared with
saline-treated lambs. Saline-treated lambs delivered into a warm or
cool ambient temperature were subsequently unable to restore colonic
temperature to values close to those recorded immediately after birth
(Fig. 1; Table 1). In contrast, hormone-treated groups delivered into a
cool but not a warm environment were able to fully restore colonic
temperature by 120 min after birth. Irrespective of delivery
temperature, the majority of control lambs continued to shiver after
restoration of body temperature, which contrasted with T3-
and/or norepinephrine-treated lambs, the majority of which had ceased
shivering (Table 2).
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Fig. 1.
Mean colonic temperature in near-term lambs delivered by cesarean
section into cool (15°C) (A) or warm (30°C) (B)
ambient temperatures and treated with saline,
3,5,3'-triiodothyronine (T3), norepinephrine (NE), or
a combination of both (T3+NE). Values are means ± SE;
n = 5-7 animals/group.
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UCP1 abundance and perirenal adipose tissue composition.
All hormonal treatments resulted in a significantly higher abundance of
UCP1 with the exception of T3 treatment of cool-delivered lambs (Fig. 2). The greatest effect on UCP1
was observed in cool-delivered lambs treated with T3 plus
norepinephrine. There was no influence of hormone treatment or ambient
temperature on BAT weight, protein, mitochondrial protein, or lipid
(results not given). Ambient temperature had no effect on the amount of
DNA in BAT, which was significantly (P < 0.05) higher in
T3- and norepinephrine-treated groups compared with
controls (Fig. 3). Ambient temperature and
hormone treatment had no effect on norepinephrine content of BAT (Table
3). Two hours after delivery, perirenal
adipose tissue content of epinephrine was higher (P < 0.05)
in warm- than in cool-delivered lambs treated with saline. In cool- but
not warm-delivered lambs, treatment at birth with T3,
norepinephrine, or a combination of both reduced the epinephrine
content of adipose tissue.
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Fig. 2.
Mean uncoupling protein-1 (UCP1) abundance in perirenal adipose tissue
mitochondria sampled from near-term lambs delivered by cesarean section
into warm (30°C) or cool (15°C) ambient temperatures and
treated with saline, T3, NE, or T3+NE. Values
are means ± SE; n = 5-7 animals/group. Significant
differences between saline- and hormone-treated groups: * P < 0.05, ** P < 0.01.
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Fig. 3.
Mean DNA content of perirenal adipose tissue sampled from near-term
lambs delivered by cesarean section into warm (30°C) or cool
(15°C) ambient temperatures and treated with saline,
T3, NE, or T3+NE. Values are means ± SE;
n = 5-7 animals/group. Significant differences between
saline- and hormone-treated groups: * P < 0.05.
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Oxygen consumption and heart rate.
In saline- treated lambs, increased delivery temperature resulted in a
lower (P < 0.05) rate of oxygen consumption between 95 and
135 min after birth (Table 4). Oxygen
consumption was similar for cool-delivered groups and remained
unchanged with time after birth, with the exception of
T3-treated lambs in which a significant decrease (P
< 0.01) occurred between 65-75 and 125-135 min. For
warm-delivered lambs, oxygen consumption declined (P < 0.05)
between 65-75 and 95-105 min after birth in saline- and norepinephrine-treated groups. Oxygen consumption was lower (P < 0.05) in T3- and T3 plus
norepinephrine-treated groups delivered into a warm compared with a
cool ambient temperature between 65-75 min and 95-105 min
after birth. By 125-135 min after birth, oxygen consumption was
only lower (P < 0.05) in saline- and
norepinephrine-treated lambs delivered into a warm compared with a cool
ambient temperature.
Delivery temperature only influenced heart rate in saline-treated lambs
35 min after birth when it was higher (P < 0.01) in the
warm-delivered group (Fig. 4). Heart rate
was higher (P < 0.05) in cool-delivered lambs treated with
T3 and/or norepinephrine compared with controls at 35 min,
after which time heart rate declined and was only higher (P < 0.05) in T3- compared with saline-treated groups at 100 min. In warm-delivered lambs, heart rate was lower (P < 0.01)
in norepinephrine-treated lambs compared with other groups at 35 min.
There was a decrease (P < 0.05) in heart rate between 35 and
130 min in saline- and T3- but not T3 plus
norepinephrine-treated groups, which had higher (P < 0.05)
heart rates at 100 and 130 min. At 100 min after birth, heart rate was
higher (P < 0.01) in warm- compared with cool-delivered lambs
treated with T3 plus norepinephrine. In contrast, mean
heart rates were lower (P < 0.05) in warm- compared with
cool-delivered lambs and in lambs treated with norepinephrine at 35 min
and with T3 at 100 and 130 min.
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Fig. 4.
Mean heart rate in near-term lambs delivered by cesarean section into
cool (15°C) (A) or warm (30°C) (B) ambient
temperatures and treated with saline, T3, NE, or
T3+NE. Values are means ± SE; n = 5-7
animals/group.
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Plasma hormone and metabolite concentrations.
Ambient temperature had no effect on plasma T3 [cool
delivered: saline 3.94 ± 0.49 nmol/l (n = 6), T3
4.01 ± 0.49 nmol/l (n = 7); warm delivered: saline 4.09 ± 0.49 nmol/l (n = 6)] or T4 concentrations
[cool delivered: saline 129 ± 13 nmol/l (n = 6); warm
delivered: saline 141 ± 10 nmol/l (n = 6)]. Thyroid hormone concentrations were also
uninfluenced by hormone treatment (results not given). Plasma NEFA
concentrations were not influenced by hormone treatment or time after
birth in cool-delivered lambs (Fig. 5) but
were consistently lower (P < 0.05) in T3-
compared with saline-treated groups delivered warm. NEFA levels
remained lower (P < 0.05) in T3- or
T3 plus norepinephrine-treated groups delivered into a warm
compared with a cool ambient temperature. Hormone-treated lambs
delivered into a cool ambient temperature had higher mean plasma
glucose concentrations compared with controls [cool delivered:
saline 2.4 ± 0.4 nmol/l (n = 6); T3 4.4 ± 0.3 nmol/l (n = 7, P < 0.01); norepinephrine 3.8 ± 0.4 nmol/l (n = 6, P < 0.01); T3
plus norepinephrine 4.0 ± 0.3 nmol/l (n = 7, P < 0.01)], an effect not observed in warm-delivered groups
[warm delivered: saline 3.2 ± 0.6 nmol/l (n = 6);
T3 2.5 ± 0.7 nmol/l (n = 7); norepinephrine 2.9 ± 0.5 nmol/l (n = 6); T3 plus norepinephrine 2.8 ± 0.7 nmol/l (n = 7)].
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Fig. 5.
Mean plasma nonesterified free fatty acid (NEFA) concentrations in
near-term lambs delivered by cesarean section into cool (15°C)
(A) or warm (30°C) (B) ambient temperatures and
treated with saline, T3, NE, or T3+NE. Values
are means ± SE; n = 5-7 animals/group.
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DISCUSSION |
The present study's major finding is that the significant effects of
an umbilical vein injection of T3 and/or norepinephrine at
the time of cesarean section delivery, with respect to changes in
colonic temperature after birth, are dependent on delivery temperature.
By 120 min after birth, hormonally treated lambs delivered into a cool
ambient temperature were able to fully restore colonic temperature to
values similar to those recorded at the time of birth. Warm-delivered
lambs were unable to achieve a similar response. By comparing the
different effects of delivery temperature on UCP1 abundance, incidence
of shivering and metabolic rate (i.e., oxygen consumption) provides an
explanation for the divergence in thermoregulatory response to hormonal
stimulation. An increase in UCP1 abundance after hormone treatment was
accompanied by a decrease in the recruitment of shivering, irrespective
of delivery temperature. The net effect of a reduction in the incidence
of shivering, which is an inefficient method of thermoregulation as a
result of disruption of the boundary layer of air around the sleeping
lamb, thereby acting to increase heat loss, will be to improve thermal
efficiency. Furthermore, hormone-treated lambs delivered into a cool
ambient temperature maintained a greater rate of oxygen consumption
than those delivered into the warm temperature at the same time as they
benefited from a lower rate of heat loss because of an improvement in
thermal efficiency. Critically, for cool-delivered lambs, not only was
heat production within BAT likely to be increased by treatment with
norepinephrine or T3 plus norepinephrine but also an
enhancement of peripheral vasoconstriction in conjunction with a
redistribution of blood flow to the body's core (14) may have promoted
colonic temperature. Epinephrine in perirenal adipose tissue is derived
from the adrenal medulla via the circulation in response to stress
(27). The finding of a reduced epinephrine content of adipose tissue of hormone-treated cool-delivered lambs compared with controls suggests that adrenal stimulation was lower in these lambs. Importantly, this
was not associated with any decline in plasma glucose concentration, which was actually highest in hormone-treated cool-delivered lambs.
By 2.5 h after birth, with the exception of T3-treated
cool-delivered lambs, all mean UCP1 values were significantly greater in hormonally treated lambs than in controls and were similar to those
recorded in vaginally delivered lambs (11). Our findings are in accord
with in vitro studies in rodent BAT that have shown that norepinephrine
is necessary for UCP1 synthesis (19) and in vivo studies in BAT from
fetal rat pups indicating that T3 may regulate basal UCP1
mRNA expression (20). UCP1 content was greatest in cool-delivered lambs
treated with T3 plus norepinephrine, suggesting that these
hormones may have an additive effect on UCP1 expression in vivo. It is
likely that norepinephrine and T3 are acting through
different mechanisms, with T3 forming a complex heterodimer
unit within the nucleus involving the binding of T3 and
retinoid X receptors (22), whereas norepinephrine promotes UCP1
synthesis by binding to 
3-adrenergic receptors located
on the plasma membrane (24).
Irrespective of hormone administration, all treated lambs exhibited the
expected decline in colonic temperature after cesarean section delivery
(11, 25). This may be due to a delay in hormonal treatment overcoming
inhibitory influences of placental factors, such as adenosine and
prostaglandin E2, which inhibit lipolysis during late
gestation (3, 13). The finding that norepinephrine treatment of
warm-delivered lambs actually increased the rate of decline in colonic
temperature immediately after birth is surprising and could be linked
to a lower rate of heat production compared with that in controls. This
meant that, although the incidence of shivering was reduced in each
hormone-treated warm-delivered group, no benefit was observed in terms
of maintenance or restoration of colonic temperature because of a lower
rate of heat production. Any interaction between peripheral thermal
inputs and hormonal effects may be mediated by changes in hypothalamic
stimulation, which is known to have a primary role in temperature
control (32). Divergence in response to hormonal stimulation between
cool- and warm-delivered groups was not confined to thermoregulation
but also included heart rate and plasma NEFA concentrations. In this respect, heart rate acutely increased in hormone-treated cool-delivered lambs, but not in those warm delivered. Plasma NEFA concentrations were
also lower in hormone-treated warm-delivered lambs compared with those
delivered cool, and this is indicative of a reduced rate of lipolysis.
Further evidence that hormone treatment was having cellular effects on
BAT is provided by the greater amount of DNA in BAT from lambs treated
with T3 or norepinephrine compared with that from controls,
irrespective of delivery temperature. We have previously observed a
decline in DNA content in BAT over the first 24 h of life in normally
delivered lambs (4) and, therefore, speculate that, in the present
study, hormonal treatment delayed this process. A decline in DNA
content was not accompanied by similar changes in lipid and protein,
resulting in these lambs containing more lipid per cell compared with
hormone-treated lambs. One explanation for a lower DNA content in
control lambs is that the rate of apoptosis in their adipocytes was
enhanced. Apoptosis has been observed in human adipocytes in vitro
after growth factor deprivation or mild heat injury (21). The rate of
apoptosis in some tissues is significantly influenced by both body
temperature (18) and T3 (28), but it is not known whether
this can also determine the rate of cell resorption.
The potential benefits resulting from using a physiological dose of
T3 and/or norepinephrine are emphasized in the finding that
no adverse consequences were observed with respect to plasma thyroid
hormone concentrations, which remained within the normal range for
cesarean-section-delivered lambs (11). This point is emphasized in rat
studies in which combined thyrotrophin-releasing hormone and
glucocorticoid treatment prenatally actually lessened the survival of
newborn rats during prolonged high-oxygen exposure, a response that may
be linked to inappropriately high plasma thyroid hormone concentrations
(23).
In conclusion, exogenous administration of endocrine stimulatory
factors can enhance the abundance of UCP1 in cesarean-section-delivered lambs with the magnitude of thermoregulatory response being greater at
cool than at warm delivery temperatures.
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ACKNOWLEDGEMENTS |
This work was funded in part by the Wellcome Trust. J. A. Bird was
supported by a Biotechnology and Biological Research Council Studentship, and C. Sullivan by a Rank Prize Vacation Scholarship.
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FOOTNOTES |
Present addresses: J. A. Bird, The Nightingale Institute, Division of
Nursing and Midwifery, School of Life, Basic and Medical Health
Sciences, Kings College, London SE1 9RT, UK; L. Clarke, Department of
Agriculture and Horticulture, Wye College, University of London, Wye
Ashford TN25 5AH, UK.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. E. Symonds,
Academic Division of Child Health, School of Human Development,
University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, UK
(E-mail: Michael.Symonds{at}nottingham.ac.uk).
Received 9 February 1999; accepted in final form 7 September 1999.
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