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Endocrinology, doi:10.1210/en.2006-1306
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*DEXAMETHASONE
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Endocrinology Vol. 148, No. 4 1813-1822
Copyright © 2007 by The Endocrine Society

Effects of Prenatal Dexamethasone Treatment on Postnatal Physical, Endocrine, and Social Development in the Common Marmoset Monkey

Jonas Hauser, Andrea Dettling-Artho, Sonia Pilloud, Claudia Maier, Alana Knapman, Joram Feldon and Christopher R. Pryce

Behavioural Neurobiology Laboratory, Swiss Federal Institute of Technology Zurich, CH-8603 Schwerzenbach, Switzerland

Address all correspondence and requests for reprints to: Joram Feldon and Christopher Pryce, Behavioural Neurobiology Laboratory, Swiss Federal Institute of Technology-Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland. E-mail: feldon{at}behav.biol.ethz.ch; or christopher.pryce{at}novartis.com.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The prophylactic treatment of diagnosed preterm delivery with synthetic glucocorticoids, such as dexamethasone (DEX), is commonplace. Long-term effects of such treatment are not well understood. In the present study, we exposed pregnant common marmosets (Callithrix jacchus), small-bodied monkeys that are therefore advantageous for long-term primate studies, to daily repeated DEX (5 mg/kg orally) either during early (d 42–48) or late (d 90–96) pregnancy (gestation period of 144 d). Relative to control, we investigated DEX effects in terms of maternal endocrinology (plasma cortisol and estrogen titers) and offspring physical growth, plasma and urinary ACTH and cortisol titers, and social and maintenance behaviors from birth to weaning. Both DEX treatments resulted in markedly reduced maternal plasma cortisol titers during treatment and reduced estimated gestation period. Both treatments were without effects on neonate morphometric measurements and basal hypothalamic-pituitary-adrenal axis activity. Early DEX treatment resulted in increased infant body weight at postnatal d 56 and 84, co-occurring at the behavioral level with increased time spent in eating solid food, a mobile state, solitary play, and exhibiting tail hair piloerection. The constellation of physical and behavioral effects of early DEX suggests interesting parallels with the human metabolic syndrome, providing primate support that the latter is causally associated with the fetal environment, including prenatal programming. This novel primate in vivo evidence for postnatal effects of prenatal synthetic glucocorticoid exposure indicates the importance of improved understanding of this acute clinical treatment in terms of its long-term effects on offspring well-being.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE USE OF prenatal synthetic glucocorticoid (GC) as a prophylactic treatment of at-risk preterm birth (1) has become commonplace and is recommended by the National Institutes of Health (2). The National Institutes of Health has emphasized the importance of increasing knowledge of potentially harmful long-term effects of such treatment (3). The primary synthetic GCs are dexamethasone (DEX) and betamethasone (BETA), and these are used as specific agonists of the glucocorticoid receptor (GR). The GR is a nuclear transcription factor expressed in several organs, including brain, that binds cortisol with low affinity and synthetic GCs with high affinity [reviewed by de Kloet et al. (4)]. Upon binding of a ligand, GR regulates the expression of genes possessing a GR-responsive element in their promoter. The GR has been reported to undergo fetal programming: set-up of adulthood expression levels based on the developmental availability of its ligand (5). This mechanism is proposed to mediate several of the observed long-term effects of experimental prenatal GR activation (reviewed in Ref. 6), including hypertension, hyperglycemia, hyperinsulinemia, and obesity, which were all reported in adult rats after prenatal GC exposure (7, 8, 9, 10). These long-term effects are all components of the metabolic syndrome, a cluster of diseases (11), thereby rendering fetal programming of GR a good candidate for mediation of the metabolic syndrome (6).

Prenatal GR activation resulted in birth weight reduction in rats (12) and sheep (13) but not guinea pigs (14). This treatment led to an increased hypothalamic-pituitary-adrenal (HPA) axis reaction to a stressor in adult rats (15); a sex-specific HPA modulation in adult guinea pigs, with males showing HPA hypoactivity and females having an estrus cycle-dependent modulation of the HPA activity (14); and an age-dependent effect on HPA axis in sheep, with prenatal GR activation resulting in young sheep with increased HPA response (16) and in older sheep with decreased HPA response (17). Relative to the important rodent and ovine evidence, there are few studies of the effects of prenatal GC treatment in primates, and most of those studies focused on fetal rather than postnatal effects. In the rhesus macaque, prenatal GC exposure has been reported to cause delayed parturition (18) and damage to the hippocampus in neonates and adults (19, 20), whereas findings with respect to prenatal organ differentiation are equivocal (18, 21, 22). A study in pig-tail macaques reported no prenatal GC effects on newborn brain weight or hippocampal cytoarchitecture (23). Baboons exposed to prenatal GC had reduced levels of microtubule-associated protein and synaptophysin (24). Prenatal DEX impaired cell proliferation but not differentiation in the dentate gyrus in newborn marmoset monkeys (25). These primate studies have used various designs, thereby making comparison difficult [for review see Coe and Lubach (26)], but there is general agreement in terms of blunted maternal cortisol titers during prenatal GC treatment and reduced offspring birth weight. In humans, randomized clinical trials and studies report no effect of prenatal GR activation on birth weight and HPA axis activity (27). However, behavioral problems have been reported in infants exposed to prenatal DEX, including hyperactivity (28) and social withdrawal (29).

The present study was conducted with the common marmoset monkey (Callithrix jacchus) to investigate the postnatal effects of prenatal DEX in a nonhuman primate in terms of growth, physiology, and behavior. This New World monkey is small bodied (350–450 g) and exhibits primate-typical hemochorial placentation and, relative to body size, prenatal development (gestation period of 144 d), precociality (sensory and motor systems well developed at birth), and postnatal development (weaning at month 3, sexual maturation at month 15–18) (reviewed in Ref. 30). A high dosage of DEX was necessary to achieve mammalian-typical effects due to the relative GC resistance observed in marmosets (31), despite a high homology between the human and marmoset GR genes (32). DEX was administered daily to pregnant marmosets during either wk 7 (first trimester) or wk 13 (late second trimester) of gestation, targeting, respectively, the maturational stage of likely maximal neurogenesis in this primate (33) and the maturational stage similar to that demonstrated by human fetuses at risk for preterm delivery when they are exposed to prenatal DEX. We hypothesized that targeting these two prenatal maturational stages would maximize the likelihood of obtaining effects on biobehavioral phenotypes that would also be of clinical relevance, particularly with respect to the later treatment. Although it is not the typical clinical regimen, which is im weekly injections (34), daily dosing was used because this is the regimen that has often been successfully used in rat, sheep, and monkey studies. Here we report on effects of these DEX treatments, relative to each other and a vehicle-control group on maternal endocrinology and offspring physical growth, HPA peripheral endocrinology, and social and maintenance behavior from birth to weaning.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects and prenatal DEX treatment
This study was conducted under experimental permit in accordance with the Animal Protection Act (1978) Switzerland. Twelve established breeding pairs of common marmosets provided the subjects (Table 1Go). Study family groups consisted of mother, father, and twin offspring. They were each housed in a home cage that measured 3 m3 and was equipped with natural branches, shelves, a removable sleeping box, and a thick sawdust layer on the floor, changed weekly. All groups were kept in the same, dedicated colony room, without visual access to each other; humidity (66 ± 2%) and temperature (23 ± 1 C) were controlled. The room was illuminated by natural sunlight supplemented by artificial lighting on an 11-h light, 13-h dark cycle (lights on at 0800–1900 h); 15 min/d UV light was provided from overhead lamps placed one per cage, and limited infrared light was provided during the dark phase. Animals received a high-protein mash containing vitamin and mineral supplements (Premix; Nafag Animal Nutrition and Feeds, Gossau, Switzerland) in the morning; in the afternoon, twice per week, crickets were scattered in the sawdust and fruits and eggs were fed. Commercial high-protein pellets (Kliba 3450, 4.5 mm; Kliba, Kaiseraugst, Switzerland) and drinking water were available continuously and ad libitum.


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  		TABLE 1. Details of breeding females and study pregnancies and offspring

 
Breeding females were blood sampled, 0.3 ml via the femoral vein, weekly from 3 months before study onset until completion of the study approximately 2 yr later. The prestudy onset of blood sampling was conducted to adjust females to the stressors of capture, restraint, and venepuncture before blood sampling during the study pregnancy. From entering the cage for catching to returning the female to the cage after blood sampling, time required was 3 min maximum. Based on their behavior, females adjusted to the procedure over several experiences of it: thus, at the endocrine level, there was no evidence of stress-related inhibition of ovulation and the cortisol levels obtained across pregnancy were within the basal range and demonstrated the expected pregnancy profile (see Results). EDTA bloods were centrifuged (15 min, 2500 rpm, 4 C) and plasma was stored at –20 C until estrogen and cortisol RIA was performed (see below). Estrogen levels are higher after than before ovulation in the common marmoset (35), and evidence for conception was based on plasma estrone-conjugate titers rising above a threshold value that exceeded follicular and periovulatory titers and being maintained above this threshold for more than 20 d; the date of ovulation/conception was then calculated retrospectively and with an estimated accuracy of within 3 d of the actual day of ovulation (35). Pregnant females were allocated at random but equally, and with counterbalancing for parity and age, to one of the three treatment groups: vehicle (VEH), early DEX (EDEX), or late DEX (LDEX).

DEX tablets (dexamethasone; Jenapharm, Jena, Germany), available at 0.5-, 1.5-, and 4-mg dosages, were crushed and suspended in 3 ml of a palatable fruit syrup to yield an oral dose of 5 mg/kg·d of DEX at 0900 h. This dose has been described to suppress HPA hormones in adult marmosets including pregnant females [(31); Fuchs, E., and C. Schlumbohm, personal communication]. Each breeding female was administered orally at both the estimated periods of gestation d 42–48 inclusive and 90–96 inclusive. Females in the VEH group were given syrup only at each of these periods; EDEX received DEX and syrup, respectively, and LDEX received syrup and DEX, respectively. Although treatment is by im injection in the clinic, and im dosing has also been used in animal studies, here we administered DEX orally to circumvent the additional stressor of im injection. On postnatal day (PND) 2, neonates were removed from the parent carrying them and sexed and weighed (36). In cases of triplet or quadruplet births (Table 1Go), one or two infants were killed, respectively, such that, whenever possible, the study twins were one male and one female, and for each sex, the heaviest neonate was selected for the study. To allow for differentiation between these neonates during behavioral observations, the hair tips on the back and part of the tail of one neonate were shaved to expose the black-colored hair layer; this was counterbalanced for sex within treatments. Culling litters to twins and selecting the heaviest of each sex is the routine procedure in our colony. Killing of the animals was conducted by administering an intrahepatic overdose (0.2 ml) pentobarbital (Vetanarcol; Veterinaria AG, Zurich, Switzerland; 50 mg/ml). When an infant is removed, marmoset parents exhibit acute anxiety for as long as they can see and/or hear the infant. This is a transient response and there is no long-term effect of such a removal on parental physical status or behavior, including their behavior toward the remaining infants (36). In some litters, one neonate is quite markedly smaller than the other two, such that retaining this neonate would probably increase the likelihood of infant mortality and would increase the variability within neonatal body weights. In the present study, killed neonates weighed 27.7 ± 2.4 g, and we did not observe any consistent effect of DEX treatments on the body weights of these killed triplets/quadruplets (P > 0.1).

Morphometric and physiological sampling
At 1200 h on PND 2, 14, 28, and 56, the parent carrying the infant was caught in the home cage and briefly held so that the infant could be removed. The infant was then taken to an adjacent room and weighed, and then the knee-heel length of the left hind-limb was measured with a caliper. The anogenital region was then gently stimulated with a Pasteur pipette to collect a urine sample; urine samples (0.1–1.0 ml) were not always obtained (see Results). Within 2 min of catching, the infant was returned to the home cage and immediately retrieved by a parent. The urine sample was stored at –20 C for 1 wk maximum and then transferred to –80 C before RIA (see below). At PND 84–85, the infant was caught and the above procedures conducted. In addition, a blood sample (0.2 ml) was obtained via puncture of the femoral vein within 2 min of catching; plasma was collected by centrifugation (15 min, 2500 rpm, 4 C), and kept at –80 C until RIA (see below). Therefore, up to late infancy, we avoided exposing infants to the additional stress of venepuncture and obtained cortisol levels from urine samples that provide a fairly accurate and minimally invasive indication of cortisol in the circulation (see below). In late infancy we collected a single blood sample in accordance with our schedule of catching subjects once per month and determined both ACTH and cortisol titers in this sample.

Urinary creatinine and cortisol RIA
In the common marmoset, urinary total (i.e. unconjugated + conjugated) cortisol titers, expressed relative to creatinine, are positively correlated with plasma unconjugated cortisol titers: in matched blood and urine samples obtained from subjects aged 2 d to adulthood, in a cross-sectional design, the product-moment correlation coefficient was 0.72 (n = 70, P < 0.0001), and 50–70% of urinary cortisol was conjugated (Pryce, C. R., and M. Doebeli, unpublished data). Urine samples were assayed in duplicate for total cortisol, and values expressed relative to creatinine to control for variability in urine volume/concentration, as described by Dettling et al. (37) and Pryce et al. (38). Briefly, total urinary cortisol was measured using an in-house RIA after enzyme hydrolysis. A rabbit antiserum was raised against cortisol-3-BSA (Cambridge Medical Technology, Billerica, MA). [1,2,6,7-3H]cortisol (SA, 82.0 Ci/mmol; TRK 407; Amersham International, Little Chalfont, UK) was used as tracer, and cortisol (H-4001, Sigma, Buchs, Switzerland) as reference standard (39–2500 pg per 100 µl). Assay sensitivity was 250 pg/ml. Using aliquots of an infant-marmoset urine pool, for the entire hydrolysis and RIA procedure, intraassay precision was 4.3% (n = 10) and interassay precision was 12.8% (n = 10).

Plasma ACTH, cortisol, and estrone conjugates RIA
The plasma sample obtained from each infant was analyzed for immunoreactive ACTH and cortisol. Plasma ACTH titers were determined in a single 25-µl sample aliquot using a commercial RIA kit [DiaSorin, Stillwater, MN; modified as described in Pryce et al. (39)]. Assay sensitivity was 16.3 pg/ml. Intraassay precision was 9.0% (n = 10) and interassay precision was 10.6% (n = 7).

Plasma unconjugated cortisol titers, in pregnant females and infants, were determined in duplicate using the aforementioned in-house RIA and methodology detailed elsewhere (38). Plasma samples were not exposed to prior enzyme hydrolysis but were heated for protein denaturation; we performed this latter step, even though corticosteroid-binding globulin levels are negligible in the marmoset and the majority of cortisol remains unbound in the circulation (40, 41). Intraassay precision was 5.3% (n = 8) and interassay precision was 4.8% (n = 8).

Plasma estrone conjugates were measured directly using a rabbit antiserum raised against estrone-glucuronide sodium salt-BSA with a high cross-reactivity (0.26) with estrone sulfate; both estrone glucuronide and estrone sulfate are abundant estrogen metabolites in the common marmoset (42, 43). Estrone sulfate sodium salt was used as standard and [6,7-3H]estrone sulfate ammonium salt as tracer. Plasma samples (5 µl) were assayed in duplicate. Intraassay precision was 6.3% (n = 10) and interassay precision was 7.6% (n = 10). Further details are given elsewhere (35).

Observation of infant home-cage behavior
Behavior of subjects relative to their social and physical environments was measured in the home cage across postnatal wk 1–12 (PND 2–84). The ethogram used was based on that already published for the marmoset (44), supplemented by some of our own defined behavioral elements (45). For each group separately, observations of 60 min duration were performed three times per week in wk 1–4, two times per week in wk 5–8, and one time per week in wk 9–12. Behavioral observations were scheduled so that they were evenly and randomly distributed between morning (1000–1300 h) and afternoon (1300–1600 h). The observer sat behind a one-way viewing screen to which families were habituated, and coded data were entered into a handheld computer (Workabout; PSION, London, UK), running the Observer Mobile Support Package software (Noldus Information Technology, Wageningen, The Netherlands). The twin infants were the focal subjects, with behaviors recorded using 30-sec instantaneous sampling and expressed as percent time using the formula (score/120) x 100 or as frequency per hour. Relationships and behavior elements (given in parentheses) of interest were parent-infant (carry, rub-off); infant-parent (infant in suckling position, proximity); infant–infant (social play); and infant alone (distress and tsik/chuck vocalization, tail hair piloerection, eat, solitary play).

Data analysis
Power analysis for the available sample size of eight subjects per treatment was performed based on primate data for DEX effects on birth weight. G*power freeware was used (http://www.psycho.uni-duesseldorf.de/aap/projects/gpower/). First, an analysis of effect size was performed, using the method elaborated by Cohen and described elsewhere (46). Briefly, the effect size index (f) is calculated as f = sigma m/sigma, with sigma m = the SD of the Z score of the group means (based on the grand population mean) and sigma = grand SD . The f score was calculated using: 1) the reported DEX-induced reduction of birth weight of 10.5% in primates (averaged from Refs. 18 , 20 , 22) for the late treatment and, due to possible compensatory mechanisms, half this reduction, 5.25%, for the early treatment, and 2) our marmoset colony mean ± SD birth weight of 31.1 ± 2.5 g. This yielded an f value of 1.33. With this value and n = 8 per treatment, an ANOVA power of 0.99 for a two-tailed P = 0.05 was obtained, providing a priori support for the sample size used. The fact that the study was conducted with 12 groups meant that they could all be contained in the same colony room and studied during the same time period, thereby reducing the contribution of these two important factors to variance in the data.

Data were analyzed using the Statistical Package for the Social Sciences (SPSS, version 13; Chicago, IL) running on a WindowsXP environment. ANOVA was based on the general linear model. Maternal body weight and endocrine titers across pregnancy were analyzed using prenatal treatment (VEH, EDEX, LDEX) as a between-subject factor and stage (conception, first trimester, late second trimester, birth) and wk (1–3 within each stage) as within-subject factors, resulting in a 3 x 4 x 3 ANOVA. Univariate ANOVAs were run to assess prenatal treatment effects on estimated gestation period and litter size. With regard to effects of prenatal DEX on offspring, physical development was analyzed using prenatal treatment and sex as between-subject factors and age (PND 2, 14, 28, 56, and 84) as a within-subject factor in a 3 x 2 x 5 ANOVA. Because it was not always possible to obtain urine samples from each subject at each age, offspring hormonal data were analyzed using univariate ANOVAs at each age separately with prenatal treatment and sex as between-subject factors. Analysis at PND 56 was not possible because for the LDEX group, n = 1 only; otherwise, the number of subjects per prenatal treatment was 3 or greater. Home-cage behavioral elements were analyzed using prenatal treatment and sex as between-subject factors and age (months 1–3) as a within-subject factor. Because it was not possible to include both litter and sex as factors in the ANOVA model (the typical litter comprised one male and one female), dizygotic twins were treated as independent subjects without controlling for litter effect. It is important to note therefore that the main effects of treatment reported below were obtained with four twin, typically male-female, pairs rather than eight subjects from eight separate breeding pairs and pregnancies. P < 0.05 was considered as a significant effect, and a P > 0.05 and P < 0.1 were considered as a noteworthy trend to an effect. Whenever prenatal treatment yielded a significant effect or interaction, pair-wise post hoc least significant difference (LSD) tests were applied.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Maternal status and gestation outcome
Maternal body weight increased throughout pregnancy until birth and then returned to preconception values; this was supported by a significant stage effect [F (3, 27) = 11.41; P < 0.001] and a significant stage x weeks interaction [F (6, 54) = 42.91; P < 0.001; Fig. 1AGo]. There was no significant effect of prenatal treatment on maternal body weight (P > 0.1).


Figure 1
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  		FIG. 1. Pregnancy follow-up. Pregnant marmoset (n = 4 per treatment) values for body weight (A), plasma cortisol titers (B), and estrogen titers (C) (mean ± SEM) from the week before, during, and after the following stages: estimated conception, early treatment (gestation wk 7), late treatment (gestation wk 13), and birth, according to prenatal treatment. Due to the treatment schedule (daily for 7 d) and the blood sampling schedule (once every 7 d), animals were sampled between 1 and 7 d before, after the onset of, and after the completion of the 7-d treatment. *, Significant effect of treatment (P < 0.05).

 
For maternal plasma cortisol titers (Fig. 1BGo), there was a significant prenatal treatment x stage interaction [F (6, 27) = 4.98; P < 0.01], a significant stage x week interaction [F (6, 54) = 7.63; P < 0.001] and a significant main effect of stage [F (3, 27) = 20.87; P < 0.001]. In VEH, maternal plasma cortisol titers increased monotonically across pregnancy and peaked at birth and then decreased to close to preconception values. During the first trimester in EDEX females and during the late second trimester in LDEX females, there was a decrease in plasma cortisol. Separate ANOVAs performed for each week of pregnancy yielded a significant prenatal treatment effect for 2 wk only, namely the week of first-trimester treatment [F (2, 9) = 4.33; P < 0.05] due to low values in EDEX vs. LDEX (LSD post hoc P < 0.05), and the week of late second trimester treatment [F (2, 9) = 11.96; P < 0.005] due to low values in LDEX vs. VEH (LSD post hoc P < 0.005) and EDEX (LSD post hoc P < 0.005).

For maternal plasma estrone conjugate titers (Fig. 1CGo), there was a significant main effect of stage [F (3, 27) = 20.87; P < 0.001] and a significant stage x weeks interaction [F (6, 54) = 9.46; P < 0.001], with values stable during the conception stage, increasing during first-trimester treatment to a peak during late second trimester and returning to preconception values the week after birth. There was no significant effect of either first- or late second-trimester treatment on plasma estrone conjugate titers (P > 0.1). Based on the observed acute effects of DEX treatment on plasma cortisol titers (see above), one-way ANOVAs of prenatal treatment during DEX treatment weeks were performed and yielded a significant effect during LDEX treatment [F (2, 9) = 14.12; P < 0.005], reflecting the decrease in estrone conjugate titers in LDEX, compared with VEH (LSD post hoc P < 0.005) and EDEX (LSD post hoc P < 0.005).

All pregnancies resulted in at least two viable offspring, with triplets and a male to female ratio of 2:1 being the typical situation in this study cohort (Table 1Go). There was no significant effect of treatment on either litter size or sex ratio (P > 0.1). In all but two cases, the study litter comprised one male and one female, with one EDEX and one LDEX study litter comprising 2 males. There was a significant main effect of treatment on the estimated gestation period [F (2, 9) = 5.29; P < 0.05, Table 1Go], with this being shorter and similar in EDEX and LDEX subjects, compared with VEH (LSD post hoc P = 0.057 and P < 0.05, respectively).

Infant morphometric and endocrine development
For the three morphometric measurements, body weight, knee-heel length, and body weight to knee-heel length ratio, there was no effect of prenatal treatment on the best available estimate of birth status, namely PND 2 data. For example, body weights (in grams, mean ± SEM) were as follows: VEH 31.5 ± 0.9, EDEX 30.7 ± 0.5, LDEX 30.3 ± 1.1 (P > 0.1). Morphometric measures increased across the study period, confirmed by a significant main effect of age on body weight [F (4, 72) = 1172.72, P < 0.001, Fig. 2AGo] on knee-heel length [F (4, 72) = 1734.16, P < 0.001, Fig 2BGo] and body weight to knee-heel length ratio [F (4, 72) = 650.82, P < 0.001, Fig. 2 CGo]. For body weight and body weight to knee-heel length ratio, there was a significant treatment x age interaction [respectively, F (8, 72) = 5.36; P < 0.005 and F (8, 72) = 5.31; P < 0.005], reflecting the relatively greater increase in these measures in EDEX at PND 56 and 84 relative to VEH and LDEX. ANOVAs performed for each PND separately yielded, for body weight, a significant treatment effect at PND 56 [F (2, 18) = 4.55; P < 0.05] and 84 [F (2, 18) = 5.41; P < 0.05] with EDEX infants demonstrating increased weight, compared with both VEH and LDEX (LSD post hoc P < 0.05 for both) and for body weight to knee-heel length ratio, also at PND56 [F (2, 18) = 4.56; P < 0.05] and 84 [F (2, 18) = 6.32; P < 0.01], with EDEX infants demonstrating increased ratios, compared with both VEH and LDEX (LSD post hoc P < 0.05 for both). For body weight there was also a trend to a sex x age interaction [F (4, 72) = 3.21; P = 0.05]; separate ANOVAs performed for each PND yielded a trend to females being heavier than males at PND 84 [F (1, 19) = 3.53; P = 0.076]. There was no significant effect of sex or treatment for knee-heel length (P > 0.1).


Figure 2
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  		FIG. 2. Infant morphometric and endocrine measurements. Morphometric developmental measures (mean ± SEM) of infants (n = 8 per treatment) in terms of body weight (A), knee-heel length (B), and the ratio between these two measures (C) from PND 2 to 84. Endocrine development of the infants in terms of urinary cortisol from PND 2 to 56 (D) (n = 4–5 for PND 2, 3–4 for PND 14 and 28, and 1–4 for PND 56), and plasma ACTH and cortisol for PND 84 (E) (n = 8 per treatment). *, Significant effect of treatment, P < 0.05.

 
Based on midday urinary titers of cortisol at PND 2–28, there was no significant effect involving treatment or sex (P > 0.1, Fig. 2DGo). Although age effects could not be analyzed statistically, we observed relatively high urinary cortisol titers at PND 2 that had decreased markedly by PND 14 and remained stable thereafter. For midday plasma cortisol titers at PND 84, there was no significant effect of treatment or sex (Fig. 2EGo) and the same was true for plasma ACTH titers (Fig. 2EGo).

Home-cage social behaviors
The average scores for each behavior are reported in Table 2Go. There were no significant effects involving sex. Across postnatal months 1–3, significant main effects of infant age indicated monotonic decreases in time spent being carried [F (2, 36) = 531.27; P < 0.001], nursing [F (2, 36) = 32.89; P < 0.001], and the number of rub-off events [F (2, 36) = 18.12; P < 0.001]. Further significant main effects of age indicated monotonic increases in time spent mobile [F (2, 36) = 333.94; P < 0.001], in social contact [as carrying declined, F (2, 36) = 33.74; P < 0.001], time spent eating [as nursing declined, F (2, 36) = 53.84; P < 0.001], tail hair piloerection [F (2, 36) = 23.72; P < 0.001], and solitary play [F (2, 36) = 20.03; P < 0.001] and social play [F (2, 36) = 12.33; P < 0.005]. There were also significant main effects of age on time spent in distress calling [F (2, 36) = 11.11; P < 0.001] and tsik/chuck calling [F (2, 36) = 4.77; P < 0.05]; both behaviors exhibited an inverted U-shaped curve with highest durations in month 2.


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  		TABLE 2. Home-cage behavioral scores

 
With respect to significant treatment effects, there was a main effect on time spent mobile [F (2, 18) = 3.74; P < 0.05], with EDEX infants demonstrating increased mobility, compared with both VEH (LSD post hoc P < 0.05) and LDEX (LSD post hoc P < 0.05) infants. There was a main effect on time spent eating [F (2, 18) = 8.27; P < 0.01], reflecting increased eating by EDEX infants, compared with VEH (LSD post hoc P < 0.01) and LDEX (LSD post hoc P < 0.005). At trend level, the EDEX infants also exhibited an increase in solitary play [F (2, 18) = 3.47; P = 0.053]. For tail hair piloerection, there was a trend to a treatment x age interaction [F (4, 36) = 2.42; P = 0.089] and a main effect of treatment [F (2, 18) = 2.84; P = 0.085]: VEH peaked at month 2 and then decreased, LDEX reached a stable asymptote in month 2, and EDEX exhibited a monotonic increase with age, thereby demonstrating relatively high levels at month 3. There was a trend to a main effect of treatment on nursing [F (2, 18) = 2.7; P = 0.094], with LDEX tending to spend less time in the nursing position than VEH and EDEX.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
To the best of our knowledge, this is the first longitudinal nonhuman primate study of the postnatal effects of prenatal DEX exposure, with the effects on morphopometric measures, HPA activity, and behavior across infancy being reported on here. In the marmoset monkey, DEX was administered during the first or late-second trimester and effects assessed relative to a control group and each other. An acute DEX effect was obtained in terms of decreased cortisol in the maternal circulation in EDEX and LDEX and in terms of decreased estrogen in LDEX specifically, without any influence on maternal body weight. Gestation length was slightly but consistently reduced in EDEX and LDEX relative to VEH. Litter size, sex ratio, and birth morphometric measures were similar across groups. From PND 56 on, EDEX infants were heavier but did not differ in terms of skeletal size, compared with VEH and LDEX infants, which were similar. DEX treatments did not yield significant effects on midday urinary cortisol output across infancy or midday plasma levels of ACTH or cortisol at the end of infancy. EDEX infants spent relatively high amounts of time in a mobile state and spent more time eating than both VEH and LDEX infants, which were similar.

DEX treatment elicited an acute reduction in maternal plasma cortisol titers, directly in line with what has been reported several times in rhesus macaques (20, 21, 47, 48) and reflecting treatment efficacy in terms of HPA-negative feedback (4), albeit in the circulation of the pregnant female rather than the fetuses. There was no effect of either EDEX or LDEX on the weight of the female, which included the fetoplacental unit; in the rhesus macaque, there is no effect of GCs on fetal body weight after cesarean delivery (20, 21, 24). Despite this evidence for a classical GR agonist effect of DEX, it needs to be acknowledged when considering the DEX effects discussed below that high DEX doses were used such that DEX may have interacted, and mediated some of the observed effects, by interacting with other neurosteroid receptors or membrane receptors (49).

The estimated length of gestation was similarly reduced in both EDEX and LDEX, compared with VEH infants. Given that this was not associated with reduced neonatal weight (see below), it might reflect increased fetal maturation, in line with the maturation-enhancing effect of BETA reported for the rhesus macaque (21). More rapid maturation could result in an earlier onset of the fetoplacental endocrine changes associated with the onset of labor. There is strong evidence that estrogens and cortisol are important in the timing of parturition in primates, and that levels of these steroids are positively associated with fetal maturation (50); however, in the present study, there was no significant evidence for DEX effects on estrogen or cortisol, at least in the maternal plasma, at the end (birth stage) of gestation. It is certainly important from the clinical point of view that a treatment used prophylactically in cases of putative premature birth is causally associated with reduced gestation length in a primate species. Neither EDEX nor LDEX led to an effect on morphopometric measures at birth. This is in line with the conclusion of a metaanalysis of clinical trials reporting an absence of effect of antenatal synthetic GR agonist exposure on birth weight (27). In a recent Australian randomized, controlled clinical trial of repeated antenatal BETA treatment, not included in the above metaanalysis, Crowther et al. (51) reported a reduction of birth weight and head circumference relative to placebo, although these BETA effects were observed only when the values analyzed were expressed as Z-scores relative to standard growth references. Two studies in rhesus monkeys report reduced birth weight after 13 (22) or 37 d (18) GC treatment. It has been interpreted that GC treatment of such long durations yields reduced somatic growth through the inhibitory action of GCs on DNA synthesis in dividing cells (52).

Starting at PND 56, EDEX animals showed increased body weight and increased eating behavior relative to VEH and LDEX, without concomitant increased knee-heel length. This could indicate increased fat mass and a propensity to develop obesity for which prenatal programming has been proposed to be a risk factor in humans (53). The increase in time spent eating by these heavier EDEX infants could reflect DEX effects on the appetite network, given that central and peripheral components of appetite control/feeding motivation are under GC modulation (54, 55, 56, 57). However, it is also possible that the increased body weight of EDEX infants was attributable to increased muscle mass; unfortunately, we did not collect data on this parameter.

In our study, prenatal exposure to DEX did not lead to any alteration of basal HPA activity. Whereas our findings are in agreement with human clinical studies (27, 51), experimental animal studies demonstrated evidence of altered HPA activity after prenatal synthetic GC exposure. Thus, in rats and rhesus monkeys, prenatal GC exposure led to increased basal and challenged HPA activity (19, 58). In the guinea pig, there are sex-specific effects, with prenatal GR activation leading to decreased basal and challenged HPA activity in males and a cycle-dependent modulation in females (14). Finally, in sheep, there is a complex, age-dependent effect, with prenatal GR activation leading to no changes at 6 months, increased basal and challenged cortisol titers at age 1 yr (16), and a decrease in both of these parameters at age 3 yr (17). The absence of such an effect in our study could be related to the infantile hypercortisolemia, which we demonstrated previously in the common marmoset (38) and which was replicated here in terms of urinary cortisol profiles. This negative conclusion is based primarily on urinary cortisol, which provides a fairly good predictor of plasma cortisol levels in the marmoset. A single estimate was obtained for plasma ACTH and cortisol, which also indicated no effect of prenatal DEX: more plasma samples per individual would clearly increase confidence in this finding, but, as is typical for longitudinal, multiparameter studies, we wanted to avoid potential confounding effects of overfrequent blood sampling. Given that cortisol levels are spontaneously high in infancy in the marmoset relative to older postnatal stages, it is possible that the HPA system is less sensitive to pharmacological manipulation relative to other species. It is not known whether the marmoset fetus also exhibits relatively high cortisol levels. Of course, any effects of prenatal DEX in terms of programming, such as increased appetite and obesity, would be predicted to occur through altered expression of GR. The observed absence of effect of EDEX or LDEX on postnatal circulating cortisol levels should not be interpreted as evidence for the absence of postnatal effects on GR expression, given that compensatory processes could occur during development. So far, the effects of prenatal DEX on central GR expression have not been studied in infancy in the marmoset or, to the best of our knowledge, any other primate.

In addition to increased time spent in eating behavior, the EDEX infants demonstrated increased mobility relative to VEH and LDEX and trends toward reduced nursing (vs. VEH) and increased solitary play and tail hair piloerection. The increased mobility observed in EDEX marmosets was probably related to the more rapid increase in body weight as follows: as infants being carried by the parents age, grow, and become more mobile, then the parents exhibit weaning behaviors, such as gentle biting and rubbing off the infant on the substrate, that stimulate the infant to leave the parent and move independently on the substrate. Mobility is the most common state observed on the substrate, whereas carried infants are often immobile (45). Therefore, it is possible to postulate a sequence of EDEX infants exhibiting increased mobility, this promoting earlier/more weaning behavior, more time on the substrate, more mobility, more eating solid food, increased weight gain, and so on. The trend to increased time spent in solitary play in the EDEX infants could also be a correlate of their earlier weaning. In a clinical pilot study (29), human infants that were diagnosed with congenital adrenal hyperplasia and exposed to DEX during gestation exhibited less sociability including greater social avoidance. Therefore, the observed tendency toward a relative increase in solitary play is interesting from a comparative viewpoint. However, it was not the case that increased solitary play cooccurred with reduced social play, precluding a clear interpretation of reduced sociability. Tail hair piloerection indicates activation of the sympathetic autonomic nervous system in the common marmoset (36), as has also been reported for the closely related Goeldi’s monkey (37) and the insectivorous tree shrew (59). In the common marmoset, tail hair piloerection provides a measure of arousal but does not reflect a specific emotional state, such as fear or anxiety in tree shrew (59) and California ground squirrel (60). Rather, it is observed during a range of activities, including social play (presumably associated with a positive emotional state), home-cage exploration (mildly anxiogenic), and social isolation (strongly anxiogenic) (37). As such, it is possible that the increased level of tail hair piloerection observed in EDEX infants reflected their increased mobility and increased exploration of the physical and social environment.

In summary, both prenatal DEX treatments yielded viable neonates that were not altered in terms of morphometric or endocrine status. EDEX, aiming at targeting the neurogenesis peak, resulted in increased weight gain in the absence of increased skeletal growth, increased eating, and possibly increased sympathetic autonomic nervous system arousal, phenotypes that are also observed in human metabolic syndrome (61). An association between fetal environment and the metabolic syndrome was first proposed by Barker et al. in 1989 (62), but the mediating mechanisms are not well understood. Our novel primate findings provide some support for a link between early fetal GR activation and postnatal development of some of the characteristics that are symptoms of the metabolic syndrome. LDEX treatment, aiming at an equivalent developmental stage to human fetuses at risk of preterm delivery, was largely without effect on physical, endocrine, and behavioral measures across infancy. These EDEX-specific postnatal effects of fetal DEX exposure highlight the importance of increased understanding of the relationship between clinical use of prenatal synthetic GC and long-term development and well-being of offspring and mediating mechanisms of long-term effects and symptoms, most notably prenatal programming.


   Acknowledgments
 
We are extremely grateful to Jeanne Michel, Pascal Guela, Dana Ryser-Stokes, and Jonas Schwank for animal maintenance; Peter Schmid, Else-Marie Pedersen-Christensen, and Corinne Späte for technical assistance; Frank Bootz for veterinary supervision; Monika Leonhard for scientific support; and Eberhard Fuchs for scientific and administrative support.


   Footnotes
 
This work was supported by the European Commission Human Potential Programme, 5th Framework, Glucocorticoid Hormone Programming in Early Life and its Impact on Adult Health, EUPEAH, Grant QLRI-CT-2002-02758.

Disclosure Statement: The authors have nothing to disclose.

First Published Online January 11, 2007

Abbreviations: BETA, Betamethasone; DEX, dexamethasone; EDEX, early DEX group; f, effect size index; GC, glucocorticoid; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal; LDEX, late DEX group; LSD, least significant difference; PND, postnatal day; VEH, vehicle group.

Received September 22, 2006.

Accepted for publication December 28, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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