1 Göteborg Pediatric Growth Research Center, Institute for the Health of Women and Children and Departments of 2 Heart and Lung Diseases, 3 Histology, and 4 Pharmacology, and the 5 Wallenberg Laboratory, University of Göteborg, S-416 85 Goteborg, Sweden
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ABSTRACT |
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Prenatal events appear to program hormonal
homeostasis, contributing to the development of somatic disorders at an
adult age. The aim of this study was to examine whether maternal
exposure to cytokines or to dexamethasone (Dxm) would be followed by
hormonal consequences in the offspring at adult age. Pregnant rats were injected on days 8, 10, and 12 of gestation with
either human interleukin-6 (IL-6) or tumor necrosis factor-
(TNF-
) or with Dxm. Control dams were injected with vehicle. All
exposed offspring developed increased body weight (P < 0.05-0.001), apparently due to an increase of 30-40% in
adipose tissue weight (P < 0.05-0.01). Corticosterone response to stress was increased in the IL-6 group (P < 0.05-0.01). Dxm-treated male rats exhibited
blunted Dexamethasone suppression test results. In male rats, insulin
sensitivity was decreased after IL-6 exposure (P < 0.01), whereas basal insulin was elevated in the TNF-
group
(P < 0.01). In female rats, plasma testosterone levels
were higher in all exposed groups compared with controls
(P < 0.01-0.001), with the exception of
Dxm-exposed offspring. Males in the TNF-
group showed decreased
locomotor activity (P < 0.05), and females in the IL-6
group showed increased locomotor activity (P < 0.05).
These results indicate that prenatal exposure to cytokines or Dxm leads
to increased fat depots in both genders. In females, cytokine exposure
was followed by a state of hyperandrogenicity. The results suggest that
prenatal exposure to cytokines or Dxm can induce gender-specific
programming of neuroendocrine regulation with consequences in adult life.
glucocorticoids; intrauterine exposure; hypothalamic-pituitary-adrenal axis; hypothalamic-pituitary-gonadal axis
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INTRODUCTION |
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SEVERAL STUDIES HAVE SUGGESTED that events that occur prenatally and early in life may play an important role in the pathogenesis of diseases at adult age in both animals (5, 29, 40) and humans (4, 40). Different kinds of stressors during a defined developmental stage, or "window," result in persisting changes in the behavioral (43) and hormonal (18, 26) responses to stress in adulthood, and in male rats may induce hormonal feminization, with low testosterone levels as well as feminine sexual behavior (15, 46).
There seem to be gender differences, although conflicting results have been reported in this regard (14, 15, 26). Examples include an altered stress response in females but not in males (26), decreased testosterone levels in males and elevated androstenedione in females (15), and both decreased adrenal weight and more pronounced histological abnormalities, such as cellular degeneration in the zona fasciculata, in female than in male rats (14).
Maternal infection during pregnancy represents one form of
stressful event for the fetus. Lipopolysaccharides (LPSs) from gram-negative bacteria have been shown to induce permanent
neuroendocrine changes (41) via the release of the
cytokines interleukin-1 (IL-1
), IL-6, and TNF-
(15, 21,
44). This has been found after prenatal (15) and
neonatal exposure (41).
Damaged placentas may be permeable to cytokines (11), but little is known about the permeability for cytokines in a healthy placenta (8). In early pregnancy, the placenta appears to be permeable to infective agents (1). IL-6 receptors are widely expressed in human and murine tissues, such as the brain, spinal cord, adrenals, and the trophoblasts of the placenta. In humans, this is already found from 8 days postconception (10).
Cytokines, with the exception of IL-1, are commonly believed not to
penetrate the blood-brain barrier (BBB) but apparently reach the brain
through other pathways, inducing the production of
corticotropin-releasing hormone and prostaglandins (21,
23). Cytokines may also exert an influence at the levels of the
adrenal (44) or the central nervous system by stimulating
peripheral visceral vagal afferent nerves (21). Saturable
transport of IL-6 and TNF-
crossing the BBB has previously been
reported (3).
In humans, the amount of cortisol passing the placenta is limited,
because the enzyme 11-hydroxysteroid dehydrogenase, or 11
-HSD, type 2, converts most cortisol to less active cortisone before it reaches the fetus (40). Dxm, however, a potent
synthetic glucocorticoid without mineralocorticoid activity, passes the placenta without being inactivated and affects fetal growth (5, 40). Dxm exposure in late, but not early, pregnancy has been reported to result in reduced birth weight, hyperinsulinemia, increased
hepatic glucocorticoid receptor (GR) expression (29), and
hypertension at adult age (5), illustrating the apparent phenomenon of a "window" of time sensitivity of the fetus to such impacts.
In the present study, IL-6 and TNF- were selected for further
exploration in this regard. To avoid insensitive time periods of fetal
response, repeated injections were given every 2nd day from day
8 to day 12 of gestation, which in rats is a period of early fetal brain development (30, 32). The effects of the cytokines were compared with those of exposure to Dxm to explore whether the effects are similar to those of exposure to glucocorticoids.
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METHODS |
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Animals. Timed-pregnant nulliparous Wistar rats (purchased from B&K Universal, Sollentuna, Sweden), weighing 232 ± 9 g (range 189-298 g), were housed with one animal to a cage under controlled conditions with a temperature of 21 ± 1°C, humidity of 55-65%, and lights on from 0700 to 1900. Animals received a commercial rat chow (containing 18.7% protein, 4.7% fat, and 63% carbohydrates with a sufficient supply of vitamins and minerals, purchased from B&K Universal) and tap water ad libitum. Pups were raised with a lactating mother until 4 wk of age. Thereafter, they lived in cages, with three animals from the same group per cage.
The study was approved by the Animal Ethics Committee of the University of Göteborg, Goteborg, Sweden.Dams and litters.
Dams were randomly divided into groups of three mothers each, with the
exception of the control group, which consisted of four dams. Male
offspring were also brought from five other Dxm-exposed dams and three
more control dams. The dams were injected on days 8, 10, and
12 of gestation, either intraperitoneally with 9 µg/kg human IL-6 (n = 3) or 4.5 µg/kg TNF-
(n = 3) (Boehringer Mannheim Biochemica, Mannheim,
Germany), both dissolved in phosphate-buffered saline (PBS; Roche
Diagnostics, Bromma, Sweden), or intramuscularly with 100 µg/kg
Dxm (n = 8) (Merck Sharp & Dohme, Haarlem, The Netherlands). Control dams (n = 8) were injected
intraperitoneally with 0.8 ml of PBS. Blood samples from the mothers
were collected 4 h after injection to determine levels of ACTH and corticosterone.
Food intake. At 9-10 wk of age, food consumption for each cage (three animals per cage) was recorded every 2nd day for 8 days and calculated as food intake in grams per rat per day. The intake was measured on the following day by subtracting the uneaten food plus spillage from the total food given.
Stress test procedure. At 5 wk of age, the corticosterone stress response was tested between 0730 and 0900 by exposing the animals to novel-environment stress (25). After a 4-wk rest period without injections, tests, or any other manipulations except for the daily animal-keeping routine and weekly weight registration, the rats were singly brought from their home cages within the animal room to a novel environment (new cages, laboratory room, loud background, and bright light). For estimation of the basal plasma levels of corticosterone, great care was taken to keep the rats undisturbed the night before the experiment. A prestress blood sample (30 µl) was taken immediately before the animals were placed in the new cage, less than 25 s after removal from the home cage. Blood tail samples (30 µl) were then taken from the same animals 15, 30, 45, 60, 90, and 120 min after exposure to the novel environment.
Dexamethasone suppression test. At 6 wk, the Dexamethasone suppression test, modified according to Oxenkrug et al. (31), was performed in all females and a subgroup of males. Pilot tests with 7-wk-old Wistar control rats from another batch of rats had previously been performed to determine an optimal dose for partial suppression of endogenous corticosterone levels, which would enable us to distinguish individuals with resistant suppression from those with normal response. The dose (0.15 µg Dxm/100 g body wt im) was decided on for this purpose. Tests were started randomly on nonfasting rats between 0900 and 1000. Tail blood was collected before the test for determination of basal levels of corticosterone, and then 2, 4, and 6 h after injection of Dxm.
Vaginal smear. Vaginal smears were obtained daily during 8-11 wk of age to determine the estrous cycle (42). A cycle is divided into four stages; estrus, diestrus 1, diestrus 2, and proestrus. The usual duration of a cycle in rats is ~4 days. In this study, cycles of 4 or 5 days, with clear ovulation (measured as a characteristic, rich amount of epithelial cells without leukocytes in the smears), were considered normal.
Baseline hormone levels.
At 8-11 wk of age, blood samples were collected from a nick in the
tail, after fasting the rats overnight, to determine levels of glucose
and insulin (both weeks 8 and 10) and leptin
(week 9). In males, testosterone and progesterone levels
were measured at 10 wk of age, whereas in females, testosterone,
17-estradiol, and progesterone levels were analyzed at 11 wk of age,
the day after estrus, in other words at the beginning of diestrus 1 (when these hormone levels are known to be still low compared with
levels during the proestrus phase) (36). All samples were
taken between 0800 and 0900 on the same day.
Locomotion test. Locomotor activity was assessed at 9 (males) and 10 (females) wk of age with photocell animal motility meters in eight soundproof, ventilated boxes connected to a computer (Kungsbacka mät-och reglerteknik, Fjärås, Sweden). The activity boxes, with a floor area of 700 × 700 mm, were equipped with two rows of eight photocells each. Locomotor activity during 60 min was registered, in dim light, as the breaking of a sequence of beams, representing movement in a single direction (12). The order in which the rats were placed in the boxes was randomized. The time of day (between 1200 and 1500) and time of feeding were standardized for all groups.
Euglycemic hyperinsulinemic clamp.
Rats were subjected to a euglycemic hyperinsulinemic clamp, as
described previously (20), at 10-11 wk of age in
males and 12-13 wk of age in females. The animals were
anesthetized with 125 mg/kg body weight of thiobutabarbital sodium
(Inactin, RBI, Natick, MA). Thereafter, catheters were inserted into
the left carotid artery for blood sampling and into the right jugular
vein for infusion of glucose and insulin. The body temperature was maintained at 37°C with a heating blanket. After a bolus injection, insulin (Human Actrapid, 100 U/ml, Novo, Copenhagen, Denmark) was
continuously infused at a rate of 8 mU · kg1 · min
1. A 15%
glucose solution in physiological saline was administered to maintain
the plasma glucose concentration at 7 mM. Glucose was infused at a rate
guided by glucose concentration measurements in 30 µl of blood at
regular intervals (every 5 min during the first 40 min then every 10 min). Steady state for plasma glucose and insulin concentrations was
reached at ~50 min and was maintained to the end of clamp, in this
study until 170 min. At 0, 40, 80, 120, and 160 min of infusion,
250-µl blood samples were taken for determination of the insulin
concentration. Erythrocytes were given back continuously during sample
collection. A total of <2 ml of blood was used for the measurements
and was compensated for by the infusion volumes. Two male rats (one
control and one TNF-
rat) and four female rats (one control, one
IL-6, and two TNF-
rats) died during the clamp procedure.
Tissues. At the completion of the clamp, the rats were decapitated. The adrenals, thymus, heart, spleen, gonads, and extensor digitorum longus, tibialis anterior, and soleus muscles of the hindlimb, as well as the epididymal, mesenteric, and retroperitoneal adipose tissues, were dissected out and weighed immediately.
Histological examination. After the ovaries and adrenals were weighed, they were fixed in 4% buffered formaldehyde. They were then rinsed in PBS containing 7.5% sucrose and frozen in liquid nitrogen. Cryostat sections, 5 µm thick, were prepared and stained with hematoxylin and eosin, dehydrated, and mounted.
Analytical methods.
Blood was collected in heparinized microtubes and centrifuged
immediately in a microcentrifuge at 4°C. Blood for ACTH determination in the pregnant mothers was collected in chilled EDTA microtubes and
centrifuged. Plasma glucose was determined enzymatically in 15-µl
samples on a YSI 2700 SELECT biochemical analyzer (Yellow Springs
Instruments, Yellow Springs, OH). Plasma insulin was analyzed with a
rat insulin RIA kit (Linco Research, St. Charles, MO) and human
insulin, administered during the clamp, with a double-antibody radioimmunoassay (Pharmacia, Uppsala, Sweden). Testosterone was measured with a solid-phase radioimmunoassay (Coat-A-Count Total Testosterone, Diagnostic Products, Los Angeles, CA). Both
17-estradiol and progesterone were assayed with commercially
available enzyme immunoassays (ELISA; Biomar Diagnostic Systems,
Marburg, Germany). ACTH levels were determined with an
immunoradiometric assay (IDS, Boldon, UK) and corticosterone by a
radioimmunoassay (RSL 125I corticosterone RIA; ICN
Biomedicals, Costa Mesa, CA), with a detection level above 25 ng/ml.
Leptin was determined by a radioimmunoassay (rat leptin RIA kit); Linco
Research, St. Louis, MO.
Statistical methods.
Distribution of variables is given as means ± SE. A Mann-Whitney
nonparametric U-test was used for a comparison between the treatment groups and the control group. A Wilcoxon signed-rank test was
performed for paired comparison between basal corticosterone and
response to the Dexamethasone suppression test. A two-way ANOVA was
performed for comparison of locomotion activity between treatment and
control groups. A two-tailed P value of <0.05 was considered statistically significant. A 2-test was
performed to compare statistical differences between vaginal smears in
treated animals and controls.
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RESULTS |
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Dams and litters.
TNF--injected dams showed significantly elevated corticosterone
levels 4 h after the injection (i.e., on days 8 and
10 of gestation) compared with controls (TNF-
dams had
mean corticosterone levels of 640 ± 45 ng/ml, P < 0.05; IL-6-treated dams, of 592 ± 51 ng/ml, P = 0.09; and controls, of 432 ± 50 ng/ml). IL-6-injected dams
showed significantly elevated ACTH levels 4 h postinjection (IL-6
dams had levels of 194 ± 24 pmol/l, P < 0.05;
the TNF-
group, of 156 ± 24 pmol/l, P = 0.16;
and controls, of 99 ± 26 pmol/l). Dxm-injected dams showed
suppressed corticosterone and ACTH secretion (below detection levels).
Body weight development and body composition.
Table 1 shows total body weight
development for male (3-10 wk of age) and female rats (3-12
wk of age). Until 8 wk of age, prenatal exposure to cytokines and Dxm
resulted in significantly elevated body weight (P < 0.05-0.001) in both genders and all treated groups except for the
TNF- males.
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Food intake.
At 9-10 wk of age, the average food intake for male rats was
24.8 ± 1.3 g per rat and day for the IL-6 group, 21.5 ± 1.2 g for TNF--exposed rats, 25.2 ± 0.9 g for the
Dxm group, and 25.0 ± 0.5 g for the controls. Female rats
showed an average food intake at 9-10 wk of age of 18.8 ± 3.8 g for the IL-6 group, 20.4 ± 0.9 g for the TNF-
group, 20.2 ± 0.9 g for Dxm-exposed rats, and 21.0 ± 0.8 g for controls. None of these differences was significant compared with controls.
Stress-induced corticosterone secretion.
Table 3 shows the basal plasma
corticosterone and plasma corticosterone response to the
novel-environment stress test, expressed as the difference between
plasma corticosterone values at 15, 30, 45, 60, 90, and 120 min and the
basal plasma corticosterone at 5 wk of age.
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Dexamethasone suppression test.
Table 4 shows the basal plasma
corticosterone and plasma corticosterone response to Dexamethasone
suppression expressed as the difference between plasma corticosterone
values at 2, 4, and 6 h after the Dxm injection and the basal
plasma corticosterone level.
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Baseline hormone levels.
Table 5 shows fasting plasma
concentrations of insulin, glucose, leptin, and testosterone in male
and female rats.
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Locomotion test. ANOVA results for all groups indicate that the exploratory locomotion was dependent on time (P < 0.001).
Figure 1A shows locomotor activity (counts/5 min) in male rats. The TNF-
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Euglycemic hyperinsulinemic clamp.
Figure 2 depicts the glucose infusion
rate for each individual during the euglycemic hyperinsulinemic clamp
in male rats. IL-6-treated rats showed a significantly lower glucose
uptake (18.9 ± 1.1 mg · kg1 · min
1;
P < 0.01) during steady state (50-170 min) than
did control rats (22.9 ± 0.8 mg · kg
1 · min
1). The
glucose infusion rate in the TNF-
(20.7 ± 1.2 mg · kg
1 · min
1) and Dxm
(22.1 ± 0.9 mg · kg
1 · min
1) male rats
did not differ from that of the control group. During steady state,
neither plasma insulin (levels in the IL-6 group were 190 ± 10 mU/l; in the TNF-
group, 217 ± 30 mU/l; in the Dxm group,
211 ± 5.1 mU/l; and in controls, 194 ± 15 mU/l) nor plasma
glucose (levels in the IL-6 group were 6.9 ± 0.0 mmol/l; in the
TNF
group, 6.8 ± 0.1 mmol/l; in the Dxm group, 6.9 ± 0.1 mmol/l; and in the controls, 6.9 ± 0.1 mmol/l) differed among the
groups.
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Vaginal smear.
Estrous cycles were counted during a period of 18 days (4 completed
cycles). Normal estrous cycles were found in 50, 75, 75, and 80% of
TNF-, IL-6, Dxm, and control females, respectively. These
differences were not statistically different when analyzed with the
2-test.
Histological examination. The ovaries of the cytokine and Dxm-treated offspring showed a normal histology. They had a similar relative proportion of stroma and gamete-producing structures in the cortex to that seen in ovaries from control animals. Furthermore, all stages of developing follicles, as well as corpora lutea, could be identified.
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DISCUSSION |
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In both humans and rats, perinatal exposure to various factors has been shown to be followed by permanent, disease-generating consequences during adulthood. LPSs (35, 41), cytokines (15), and glucocorticoids (5, 14, 29) are believed to be involved, programming the regulation of both the neuroendocrine and the autonomic nervous systems. The present study was therefore performed to focus on the metabolic and endocrine effects of cytokines on prenatally exposed offspring at adult age. The aim was also to try to sort out whether or not the effects are related to glucocorticoids, because both LPSs and cytokines are powerful stimulators of glucocorticoid secretion (35, 44).
In this study, multiple injections were used to cover the sensitive period when brain development is most pronounced in the rat fetus (32). The doses chosen were in accord with those used on adult rats in previous studies (6, 16, 19, 29, 38). The synthetic glucocorticoid Dxm was used to separate out the effects of glucocorticoids, because it is known to pass the placental barrier (29). Administration of Dxm during pregnancy will therefore expose the fetus to a powerful glucocorticoid.
The injection of pregnant dams with cytokines caused either elevated ACTH or corticosterone levels. The injection of Dxm, on the other hand, caused a significant inhibition of both ACTH and corticosterone secretion, which was expected because of feedback regulation (9).
Obesity, food intake, and locomotor activity. In this study, exposed offspring showed no body weight differences at birth; however, enlarged abdominal fat depots were found in both male and female adult rats. Leptin levels were significantly elevated in males from groups exposed to IL-6 and Dxm, in parallel with the increased amount of the abdominal fat depot. In all exposed females, leptin levels were 40-100% higher than in controls, although this difference did not reach statistical significance. Leptin, the adipocyte-derived hormone encoded by the obese gene (47), is an important regulator of energy balance through the various effects it has on food intake and thermogenesis. Leptin inhibits the activation of the hypothalamic-pituitary-adrenal (HPA) axis at hypothalamic (2, 17) and peripheral levels (7). Endotoxin and cytokines are known to increase plasma leptin (13, 24, 39). Interestingly, in a previous study, male rats exposed to early gestational undernutrition also developed obesity (22).
The elevated fat mass indicates a positive energy balance, in other words, an increased energy intake and/or decreased physical activity. Another explanation could be a decreased thermogenesis, which was not measured. No measurable differences in food intake were seen in the male or female groups. Only the TNF-Corticosterone levels and stress sensitivity.
Perturbation in the regulation of the HPA axis was found in the IL-6
group, because they reacted to novel-environment stress with an
elevated response of corticosterone and showed a suppression of
corticosterone secretion by Dxm. The basal corticosterone levels were
elevated in the TNF- groups, with normal elevated corticosterone response to the novel-environment and normal Dexamethasone suppression conditions compared with basal levels. This indicates an increased central facilitation of the activity of the HPA axis, with a remaining feedback control (9). There was no suppression by Dxm in
the prenatally Dxm-exposed male rats. This finding suggests a blunted regulation of the HPA axis, with a diminished feedback control. Such
changes in the regulation of the HPA axis are usually seen after
repeated, severe challenges in adulthood, resulting in a burnout of the
HPA axis (27). The blunted response to the Dexamethasone suppression may have been due to interference with the function of
central GRs.
Androgenization of female rats.
There were consistently elevated testosterone values in the
cytokine-treated females, with an increase of up to 80%. This is in
accordance with previously reported findings of increased androstenedione in female rats after perinatal application of IL-1
(15). The tendency to more abnormal estrous cycles in the
rats treated with TNF-
indicates that the hyperandrogenicity may be
of ovarian origin, although no abnormalities were discovered in either
weight or the histological appearance of ovaries, such as polycystic
changes. TNF-
has been reported to interfere with ovarian steroid
production, suggesting follicular atresia (37), although
this has not been studied after prenatal exposure.
Insulin resistance.
Male IL-6 rats showed insulin resistance in the clamp measurements, and
the TNF- group had elevated basal insulin values. This may have been
due to the increased body fat mass and/or elevated corticosterone
secretion during stress, both well established generators of such
perturbations. In females there were no indications of insulin
resistance despite enlarged fat depots and the tendency to an increased
stress response of corticosterone. The reason for this gender
difference is not known.
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ACKNOWLEDGEMENTS |
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We are grateful to B. M. Larsson for laboratory work and N. G. Pehrsson for statistical support.
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FOOTNOTES |
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This study was supported by grants from the Swedish Medical Research Council (project nos. 7905, 12206, and 12528), the Wilhelm and Martina Lundgren's Foundation, Novo Nordisk Insulinfond, the Swedish Heart Lung Foundation, Pharmacia Corporation, and National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-28997.
Address for reprint requests and other correspondence: J. Dahlgren, Göteborg Pediatric Growth Research Center, Institute for the Health of Women and Children, Univ. of Göteborg, S-416 85 Goteborg, Sweden (E-mail: jovanna.dahlgren{at}vgregion.se).
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 18 September 2000; accepted in final form 29 March 2001.
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