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Departments of 1 Pediatrics, 2 Pharmacology and Toxicology, and 4 Medicine, Medical College of Wisconsin, Milwaukee 53226; and 3 Endocrine Research Laboratory, St. Luke's Medical Center, Milwaukee, Wisconsin 53215
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Increases in plasma lipids occur during hypoxia in suckling but not in weaned rats and may result from altered hepatic enzyme activity. We exposed rats to 7 days of hypoxia from birth to 7 days of age (suckling) or from 28 to 35 days of age (weaned at day 21). Hypoxia led to an increase in hepatic lipid content in the suckling rat only. Hepatic lipase was decreased to ~45% of control in 7-day-old rats exposed to hypoxia but not in hypoxic 35-day-old rats. Hypoxic suckling rats also had a 50% reduction in lactate dehydrogenase activity, whereas transaminase activity and CYP1A and CYP3A protein content were not different between hypoxic and normoxic groups. Additional rats were studied 7 and 14 days after recovery from hypoxic exposure from birth to 7 days of age; hepatic lipase activity had recovered to 85% by 7 days and to 100% by 14 days in the rats previously exposed to hypoxia. Administration of dexamethasone to neonatal rats to simulate the hyperglucocorticoid state found in hypoxic 7-day-old rats led to a moderate decrease (~75% of control) in hepatic lipases. Developmentally, in the normoxic state, hepatic lipases increased rapidly after birth and reached levels more than twofold that of the newborn by 7 days of age. Hypoxia delays the maturation of hepatic lipases. We suggest that the decrease in hepatic lipase activity contributes to hyperlipemia in the hypoxic newborn rats.
liver; lipids; transaminase; cytochrome P-450; dexamethasone
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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NEONATAL HYPOXIA IS A COMMON perinatal emergency and is often accompanied by serious morbidity (11, 25). Although considerable efforts have been directed at evaluating alterations in neurological, cardiopulmonary, and renal function (12, 25, 33), the metabolic response to hypoxia in the neonate has not been extensively examined. Neonatal hypoxia results in significant disorders in plasma lipids, particularly in nursing infants. This neonatal hypoxic dyslipidemia, observed over 25 years ago, has been attributed to direct effects of hypoxia on hepatic function (7, 15) although these studies were not definitive or complete.
We recently demonstrated that hypoxia led to marked increases in plasma cholesterol, triglycerides, and nonesterified fatty acids in the suckling neonatal rats but not in weaned 35-day-old rats (26). The liver is known to play an important role in lipid metabolism. Hepatic lipases modulate the uptake of cholesterol (31, 32) and the metabolism of many types of lipoproteins (9, 14 17). In humans, hepatic lipase deficiency results in elevated plasma triglycerides and/or phospholipids (4, 6, 8, 24). Mice carrying the combined lipase deficiency mutations that affect the translation of lipoprotein lipase and hepatic lipase develop massive hypertriglyceridemia and die (30). In hepatic lipase knockout mice, increases in total circulating cholesterol, phospholipids, and high-density lipoprotein (HDL) cholesterol (but not triglyceride) are observed (16). Infusion of vectors expressing hepatic lipase into these knockout mice normalizes the plasma levels of these components (1).
The aims of the present study were to 1) analyze changes in hepatic lipid content and lipase activity in neonatal suckling rats exposed to hypoxia for 7 days from birth compared with juvenile, weaned rats exposed to hypoxia for 7 days (from 28 to 35 days of age); 2) analyze the time course of recovery of neonatal rat from hypoxic exposure; and 3) determine whether the hypoxic effect on hepatic lipase can be mimicked by glucocorticoid administration.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal Treatment
The animal protocol was approved by the Institutional Animal Care and Use Committees of the Medical College of Wisconsin and St. Luke's/Sinai Samaritan Medical Center. Timed pregnant Sprague-Dawley rats (Harlan Sprague Dawley) were obtained at 14 days gestation and maintained on a standard sodium diet (Richmond Standard #5001) and water ad libitum in a controlled environment (0600-1800 lights on). Parturition usually occurred on the afternoon of gestational day 21 during which time rats were kept under observation.Hypoxia from 0 to 7 days of age.
As soon as a litter was completely delivered, the dam and her pups were
immediately moved to an environment chamber and exposed to normobaric
normoxia (21% O2; room air) or hypoxia (12%
O2) as described previously (26, 27, 29, 33).
We have previously shown that this exposure leads to arterial
PO2 levels in adults of ~50-55 Torr with
sustained hypocapnia and alkalosis (27, 29). Lactating
dams were maintained with their litters for 7 days in a normoxic or
hypoxic environment (28, 33). Chambers were briefly opened
on day 4 to clean the cages. The experimental day was at the
end of 7 days of exposure of dams and their litters to either normoxia
or hypoxia. At 0800 of day 7, eight rat pups randomly
selected from four different litters each from the normoxic and hypoxic
groups were decapitated, and trunk blood was collected. Then, their
livers were removed, cut into pieces, frozen immediately on dry ice,
and stored at 
80°C until analyzed.
Hypoxia from 28 to 35 days of age. Male and female rats (n = 16) from randomly assigned litters raised under normoxic conditions were weaned at 21 days of age. At 28 days of age, they were placed in chambers, exposed to normoxia or hypoxia for 7 days, killed, and livers were collected as described above.
Treatment with dexamethasone. Female and male normoxic newborn rats (n = 18) were given single dose of dexamethasone daily (from days 0 to 6 by intraperitoneal injection at a dose of 13 ng/g body wt) or vehicle (same volume of dimethyl sulfoxide, the solvent for dexamethasone). This dose of dexamethasone was chosen to mimic the hypercorticosteroid condition observed in the hypoxic 7-day olds (28). A noninjected group was also included as controls. All animals were killed at 7 days of age.
Development of hepatic lipase.
Four litters of normoxic rats were used for this experiment. The day of
birth was designated as age 0. Pups were allowed to suckle
freely until the time of death. At 0, 1, 4, 5, 7, 21, and ~180
(adult) days of age, rats (4-8/age) were killed and livers were
removed and stored at 80°C as described until analyzed.
Measurements
Tissue homogenization.
For the determination of lipase activity, a weighed amount of hepatic
tissue was thawed and homogenized in ice-cold water with a Polytron for
30 s with the container immersed in ice. Triton X-100 was added to
a final concentration of 0.08% and mixed. The homogenate was left on
ice for 1 h with occasional stirring. Homogenate was then
centrifuged for 6 min at 1,500 g at 4°C. The supernatant fraction was collected and either analyzed immediately for enzyme assays or immediately frozen and stored at 80°C for later assays.
Hepatic lipid and protein measurement. Liver lipid contents were determined by the gravimetric method according to Folch et al. (10) with slight modifications. Briefly, 100- to 150-mg portions of liver fragments were homogenized in a 3.0-ml mixture of chloroform and methanol (2:1) using a motor-driven Teflon pestle homogenizer. The liquid portion was decanted, and the residual was rehomogenized in another 3 ml of chloroform-methanol mixture and allowed to sit at room temperature for 10 min with occasional stirring. Combined organic phases were filtered through glass wool, and 12 ml of distilled water were added to the filtrate. The mixture was stirred for 30 s and centrifuged at 500 g for 4 min at room temperature. The aqueous layer, up to the interphase, was discarded, and 3 ml of chloroform-methanol mixture were added to the remaining liquid and mixed for 30 s. The mixture was centrifuged at 500 g for 4 min. The bottom organic phase was carefully collected and transferred to preweighed vials. Evaporation of the organic solvent was carried out under a stream of N2, and the vials were reweighed. The results are expressed as milligrams of lipid per gram of liver.
Protein concentration was determined by the method of Bradford (3) using Bio-Rad reagents (Bio-Rad Laboratories).Biochemical measurements. Hepatic lipase was measured according to Ledford and Alaupovic (20) with some modifications. Briefly, the lipolytic activity was determined by potentiometric titration (at a constant pH of 8.0) of ionized free fatty acids (FFAs) liberated from tributyrin (20 mM) in a citrate-phosphate buffer (l mM) with 0.01% Triton X-100. Lipase activity was measured in the presence of 0.075 M and again in 2.4 M NaCl to distinguish between lipoprotein lipase and hepatic lipase, because the presence of a high-ionic strength environment inhibits lipoprotein lipase but not hepatic lipase (5). Units are expressed as micromoles of NaOH required to neutralize FFAs liberated per minute per gram of tissue or per gram of protein.
Lactate dehydrogenase (LDH) was determined by the "reverse" reaction in the presence of NADH using pyruvate as the substrate as previously described (34) and expressed as units per minute per gram of tissue or per gram of protein. Alanine aminotransferase/glutamate pyruvate transaminase (ALT/GPT) was determined by the sample-start procedure with the ALT/GPT kit from Sigma (St. Louis, MO) and expressed as units per minute per gram of tissue or per gram of protein. Total plasma cholesterol and triglyceride were measured as previously described (26).Cytochrome P-450 Westerns. Microsomes from the livers of hypoxic and normoxic 7-day-old rats were prepared by differential centrifugation as described previously (21). Western blots for the determination of cytochrome P-450 (CYP) 1A and CYP3A proteins were carried out as described previously (21, 23) using antibodies that react specifically with rat CYP1A or CYP3A proteins (from Xenotech). Protein concentration was determined by the method of Bradford (3) using Bio-Rad reagents (Bio-Rad Laboratories).
Statistics.
Results are reported as means ± SD. Student's t-test
was used to compare the means between two groups with P 
0.05 considered significant. Two-way ANOVA and Duncan's multiple-range
test were used for comparisons with more than two means.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Figure 1 shows the hepatic lipid and
protein content from rat pups exposed to hypoxia from birth to 7 days
of age and from juvenile rats weaned at 21 days of age and subsequently
exposed to hypoxia from 28 to 35 days of age. Hypoxia from birth to 7 days of age resulted in a significant increase in lipid content and a
decrease in hepatic protein content. There was no effect of hypoxia on
hepatic lipid or protein content in 35-day-old rats that had been
exposed to hypoxia for the prior 7 days.
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Table 1 summarizes the hepatic enzyme levels from rat pups exposed to
hyposia from birth to 7 days of age and from juvenile rats weaned at 21 days of age and subsequently exposed to hypoxia from 28 to 35 days of
age. Hypoxia from birth to 7 days of age resulted in significant
decreases in total hepatic and lipoprotein lipase activity (assayed in
the presence of 0.075 M NaCl) and hepatic lipase (assayed in the
presence of 2.4 M NaCl). Hepatic LDH activity was also
significantly decreased but not ALT/GPT activities. There was no
effect of hypoxia on hepatic lipases, LDH, and ALT/GPT in juvenile rats
weaned at 21 days of age and subsequently exposed to hypoxia from 28 to
35 days of age (Table 1). Liver microsomal CYP1A and 3A contents were
similar in hypoxic and control 7-day olds (Fig.
2).
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Table 2 shows the hepatic lipase activity
of 7-day-old hypoxic rats and rats 7 and 14 days after return to
normoxic environment. At 7 days of hypoxia, total hepatic lipase was
decreased compared with age-matched normoxic controls. When the hypoxic
7-day-old rats were returned to normoxic conditions for 7 days (14 days of age), their hepatic lipases had recovered to ~85% of control age-matched normoxic groups. At this stage, the hepatic protein concentration was also lower than the corresponding control level. At
14 days after the return of the 7-day-old hypoxic animals to normoxic
condition (21 days of age), there were no differences in either the
hepatic lipase level or protein concentration between the previously
hypoxic group and the age-matched control normoxic group.
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Figure 3 shows total plasma cholesterol
and triglycerides. Increases in total plasma cholesterol and
triglyceride levels were evident in the 7-day-old hypoxic rats. After
hypoxic animals were returned to normoxic condition, their total plasma
cholesterol and triglyceride levels had returned to normal by 7 days
after the termination of hypoxia.
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Table 3 summarizes the effect of a daily
treatment of newborn rats from birth to 7 days of age with a low dose
of dexamethasone (simulating the hypercorticosteroid condition in the
hypoxic 7-day olds) (28) on hepatic lipase levels and
protein concentrations. Treatment with the vehicle (dimethyl sulfoxide)
alone did not result in a change in hepatic lipase (both total and
hepatic lipase) and protein concentrations. Treatment with
dexamethasone for the same duration resulted in a moderate decrease in
hepatic lipase (both total and hepatic lipase) to ~75% of control.
Protein concentration, however, increased slightly but not
significantly.
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Figure 4 shows the developmental profile
of hepatic lipase activity (total and hepatic lipase) from newborn to
adult under normoxic conditions. At birth, hepatic lipase (assayed in
2.4 M NaCl) was relatively low and showed rapid increase during the first week of life. Thereafter, it plateaued at ~14-21 days of age and gradually declined to the adult level. Total lipase (assayed in
0.075 M NaCl) showed a similar pattern of rise from newborn to 7 days
of age, leveled off, and declined to the adult level after weaning.
Thus, by 7 days of age, most of the postnatal development of hepatic
lipase had already occurred. There was no observable difference in the
development profile between female and male rats (data not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have shown previously that hypoxia resulted in increases in plasma cholesterol, triglycerides, and nonesterified fatty acids in the suckling neonatal rats but not in weaned 35-day-old rats (26). Hepatic lipases play a critical role in lipid metabolism and modulate the plasma levels of many lipid metabolites (14, 17, 24). Hepatic lipase deficiency in humans results in the accumulation of serum HDL particles with elevated levels of triglycerides and/or phospholipids (4, 6, 8, 24). In animals, hepatic lipase enhances the uptake of cholesterol by hepatocytes in vitro (31). In vivo inhibition of hepatic lipase by antibodies to hepatic lipase decreases the rate of cholesterol uptake by the liver from chylomicron remnants (32). The same in vivo treatment with antihepatic lipase serum also resulted in increases in circulating triglycerides, phospholipids, and cholesterol content of lipoproteins (9, 18).
The present study evaluated the effects of 7 days of hypoxia on hepatic lipid contents and hepatic lipases in neonatal (suckling) and juvenile (weaned) rats. Hypoxia induced significant increases in liver fat content with concomitant decreases in hepatic lipases in the 7-day-old hypoxic rats but not in the 35-day-old (weaned) rats. Both total (assayed in the presence of low ionic strength) and hepatic lipases (assayed in the presence of high ionic strength) were affected. These results coupled with the observed increases in plasma total cholesterol, triglycerides, and FFAs in the 7- but not 35-day-old hypoxic rats (26) and the reported involvement of hepatic lipases in the formation of dyslipidemia (16, 30) suggested a correlation between the decrease of hepatic lipase levels and the hyperlipidemia in the 7-day-old hypoxic rats. The decrease in hepatic and lipoprotein lipase may also contribute to the increase in lipid content in the liver of 7-day-old hypoxic rats.
Hypoxia also resulted in a slight but significant decrease in hepatic protein concentration in the 7- but not 35-day-old rats. This might reflect the decrease in enzyme proteins and, therefore, reduced lipase activities in the 7-day-old hypoxic animals. Other hepatic marker enzymes were evaluated to see whether this was the case. LDH activity showed >50% reduction in the 7-day-old hypoxic group but a slight increase (+15%) in the 35-day-old hypoxic group. Liver level of transaminase activity (ALT/GPT) showed no difference between the hypoxic and normoxic 7-day-old rats but a slight increase in the hypoxic 35-day olds. Microsomal CYP1A and 3A content were not different between control and hypoxic 7-day olds. Thus not all hepatic enzymes were reduced in the 7-day-old hypoxic group, and, therefore, the lower hepatic lipase found was relatively selective. The observed lowering of hepatic LDH activity might be partly responsible for the increase in plasma lactate level in the 7-day-old pups (unpublished results).
Developmentally, there is a rapid increase in hepatic lipase immediately after birth. Hepatic lipase activity reached a level more than twice that of the newborns by 7 days of age. It is feasible that hypoxia during this critical stage of ontogeny interferes with the normal development of hepatic lipases and results in abnormally low level of these enzymes. If this hypothesis is correct, then returning the hypoxic 7-day-old rats to normoxic conditions should free them from the physiological impairment (hypoxia) and allow them to develop normally and subsequently acquire the normal levels of lipase. This was indeed the case as hypoxic 7-day olds, when returned to normoxic environment, regained a large portion of their hepatic lipase activity (85% of control) by 7 days and were completely recovered by 14 days posthypoxia. Interestingly, the plasma levels of total cholesterol and triglycerides were already normalized by 7 days posthypoxia. It is likely that the levels of hepatic lipases in these once hypoxic animals, although not reaching the levels found in age-matched controls, had reached a level that was sufficient for the maintenance of normal levels of plasma lipids. Furthermore, there are other factors, such as milk lipid contents from the dam, besides hepatic lipases that also play a role in modulating the plasma level of these lipid compounds. These factors might be affected by neonatal hypoxia but take less time than hepatic lipases to recover.
Although the exact mechanism for the effects of hypoxia on hepatic lipase development is not known, we speculated that hypoxia might act, at least in part, through modulation of the endocrine system. One of the observations that is more relevant to the present study is that of a marked increase in plasma corticosterone during neonatal hypoxia (28). Glucocorticoids are known to have important functions in modulating the ontogeny of many enzyme systems, notably in the exocrine pancreas and the gastrointestinal tract (19), the liver (13), and the lung (2). In addition, we have shown previously that glucocorticoids inhibit the development of lipases in the rat lingual gland (22). In the present study, we attempted to simulate the increase in plasma glucocorticoid as observed in hypoxia by daily administration of a low dose of dexamethasone (a synthetic glucocorticoid with a longer biological half-life and higher potency than corticosterone) for the same duration as the hypoxic treatment in newborn rats from birth to 7 days of age. The dexamethasone-injected animals showed a decrease in hepatic lipases (75% of control) but to a lesser degree than in hypoxia (<45% of control). Liver protein concentration, unlike that of a reduction in the hypoxic rats, was not affected with dexamethasone. Thus the increase in glucocorticoid that resulted from hypoxic treatment might have contributed, in part, to the decrease in hepatic lipases but could not account for the entire action of hypoxia. A more definitive experiment is, however, required to establish a link between hypoxia, steroid hormones, and hepatic lipase activities.
In conclusion, the present study demonstrated that hypoxia in neonates causes dyslipidemia due, at least in part, to disturbance of lipid metabolism in the liver. Hypoxic conditions lead to lowering of hepatic lipases whose activities are important in maintaining the normal levels of plasma lipid components. Hypoxia might, in part, act through increases in plasma glucocorticoids in its effects on hepatic lipases.
Perspectives
Hypoxia is recognized as one of the most common neonatal syndromes. Conditions that result in hypoxia frequently occurred in the pre- and postnatal period. Fetal distress is the most common cause of prenatal hypoxia. Asphyxia at birth due to prematurity, trauma, blood loss, or obstruction of airway accounts for varying duration of hypoxia in infants. Hypoxia causes considerable morbidity and mortality in the neonate. Although the primary concerns of neonatal hypoxia are the detrimental effects on neurological, cardiopulmonary, and renal changes, the observed dysfunction in lipid metabolism might play an important role in the nutritional adaptation of the hypoxic infants, particularly during the recovery phase. Infants have a high rate of metabolism to provide for rapid growth (and repair if necessary). Lipid is a major source providing the necessary fuels for metabolism and building blocks for essential metabolites in growth and repair. Dysfunction of lipid metabolism in neonatal hypoxia will compromise the tissue uptake and utilization of nutrients. This might have a more profound effect on the health of the infant than previously appreciated.| |
ACKNOWLEDGEMENTS |
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This study was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-54685 (to H. Raff) and by St. Luke's Medical Center/Aurora Health Care.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. C. Lee, Gastroenterology Div., Dept. of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226 (E-mail:pclee{at}mcw.edu).
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. Section 1734 solely to indicate this fact.
Received 3 January 2000; accepted in final form 19 June 2000.
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METHODS
RESULTS
DISCUSSION
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 E. D. Bruder, P. C. Lee, and H. Raff Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids J Appl Physiol, March 1, 2005; 98(3): 981 - 990. [Abstract] [Full Text] [PDF]
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 E. D. Bruder, P. C. Lee, and H. Raff Lipid and fatty acid profiles in the brain, liver, and stomach contents of neonatal rats: effects of hypoxia Am J Physiol Endocrinol Metab, February 1, 2005; 288(2): E314 - E320. [Abstract] [Full Text] [PDF]
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E. D. Bruder, P. C. Lee, and H. Raff Metabolomic analysis of adrenal lipids during hypoxia in the neonatal rat: implications in steroidogenesis Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E697 - E703. [Abstract] [Full Text] [PDF]
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 H. Raff, L. Jacobson, and W. E. Cullinan Elevated corticosterone and inhibition of ACTH responses to CRH and ether in the neonatal rat: effect of hypoxia from birth Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1224 - R1230. [Abstract] [Full Text] [PDF]
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 P. C. Lee, M. Struve, and H. Raff Effects of Hypoxia on the Development of Intestinal Enzymes in Neonatal and Juvenile Rats Experimental Biology and Medicine, June 1, 2003; 228(6): 717 - 723. [Abstract] [Full Text] [PDF]
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H. Scholz The adrenal response of neonates to hypoxia Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R76 - R77. [Full Text] [PDF]
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H. Raff, J. J. Hong, M. K. Oaks, and E. P. Widmaier Adrenocortical responses to ACTH in neonatal rats: effect of hypoxia from birth on corticosterone, StAR, and PBR Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R78 - R85. [Abstract] [Full Text] [PDF]
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