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1 Centre for Reproduction and Early Life, Schools of Veterinary Medicine and Science,
2 Human Development and
3 Nursing, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire LE12 5RD, UK
4 Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
(Requests for offprints should be addressed to D S Gardner; Email: david.gardner{at}nottingham.ac.uk)
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Glucocorticoid hormones have many metabolic and cardiovascular actions on the body, reflecting the almost ubiquitous tissue distribution of their receptors (Dallman et al. 1993, Sapolsky et al. 2000). In the fetus, these actions are clearly age-dependent but, in general, intrauterine glucocorticoids (GC; of fetal and/or maternal origin) promote functional maturation over, or at the expense of, functional differentiation (Fowden et al. 1998, Fowden & Forhead 2004). Thus, GC in high doses may retard intrauterine growth (Redmond 1979), but rescue babies threatened with preterm labour and respiratory complications (Cummings et al. 1989, Ballard & Ballard 1996). GC have long been thought to act as intermediary factors that transcribe the developmental programming sequalae of maternal NR (Langley-Evans et al. 1996) and there is much evidence in humans and animal models to suggest such a role (Langley-Evans 1997, Phillips et al. 1998, Reynolds et al. 2001, 2003). In sheep, the change in maternal cortisol with undernutrition appears age-dependent, being elevated with late gestation undernutrition (Edwards & McMillen 2001) and reduced with early to mid-gestation undernutrition (Bispham et al. 2003). Interestingly, periconceptional under-nutrition has been shown to markedly activate fetal hypothalamic–pituitary–adrenal (HPA) axis activity in late gestation leading to preterm birth in sheep (Bloomfield et al. 2003b). However, to date, only the effects of late gestation undernutrition on adult HPA axis function (Bloomfield et al. 2003a) have been examined. No study has examined resting or stimulated HPA axis function in adult offspring following a periconceptional nutritional challenge. Furthermore, in this study, we propose to pilot, in sheep, a novel remote sampling technique (Goddard et al. 1998, Sakkinen et al. 2004) for characterisation of maternal cortisol concentrations during the period of undernutrition and of resting plasma cortisol in the young offspring to avoid potential artefacts associated with manual restraint and sampling.
In addition, sex-specific regulation of the fetal (Giussani et al. 2001) and adult (Bloomfield et al. 2003a) HPA axis per se has been noted previously (for review, see Matthews et al. 2004). Furthermore, it is clear that responses to challenges that have been shown to incur developmental consequences exhibit a distinct sex-specific bias. For example, after maternal restraint stress in rats during late gestation (resulting in maternal HPA axis activation), only the adult female offspring are affected; males appear largely unaffected (McCormick et al. 1995). Prenatal alcohol exposure again leads to an increase in adult female, but not male, HPA axis activity (Lee & Rivier 1996).
Hence, the present study was established to address the hypothesis that periconceptional undernutrition of sheep elevates adult HPA axis sensitivity. It is proposed that the programming of adult HPA axis responses would also exhibit a distinct sex-specific bias. These twin hypotheses were addressed as follows: (1) the resting plasma concentrations of adrenocorticotrophin (ACTH) and cortisol were analysed together with (2) ACTH and cortisol responses to a bolus dose of corticotrophin-releasing hormone (CRH) and vasopressin (AVP). (3) To separate pituitary from adrenal responsiveness we also, on a different day, administered a separate bolus dose of synthetic ACTH. Given the cardiopressor actions of AVP in high concentrations (Cowley 1988) and that periconceptional undernutrition has been shown to influence blood pressure regulation (Gardner et al. 2004), then the fourth aim of the study was to examine the cardiovascular responses to a CRH and AVP bolus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All procedures were performed under the UK Animals (Scientific Procedures) Act, 1986. Twenty Blue-faced Leicester x Swaledale ewes were used in the study. All ewes were of similar age (7–8 months), body weight and fat distribution as assessed from physical characteristics in the lumbar spine and loin. Ewes were mated with a single ram and within 12 h of mating were individually housed and randomly assigned to one of two groups: (1) ewes were fed to adequately meet 100% metabolisable energy (ME) requirements as defined by the Agricultural and Food Research Council (AFRC) throughout gestation to term (term 147 days gestational age; controls n = 12) and (2) ewes were fed to 50% AFRC ME requirements from days 1 to 30 gestation and thereafter to 100% ME requirement to term (nutrient restricted, NR; n = 8). All ewes were bedded on wood shavings and fed a diet consisting of chopped hay (ME content of 8.9 MJ/kg dry matter (DM) and a digestible crude protein (DCP) content of 45 g/kg DM) and a barley-based concentrate (ME 8.9 MJ/kg DM, DCP 218 g/kg DM). All ewes were weighed and body condition was scored at fortnightly intervals and the nutritional regimen for each individual ewe was adjusted according to gestation age (to allow for growth of the conceptus) and twinning (n = 6 controls, n = 3 NR). At term, lambs were delivered naturally and birth weights recorded. For twin-bearing ewes, only one lamb was kept with the ewe during lactation to avoid the confounding influence of differences in nutrient intake and its effects on postnatal growth rate. In the control group (n = 12), there were six males and six females and for NR (n = 8), the sex ratio was four males and four females. The offspring were ewe reared until weaning at 3 months and thereafter grass-fed until aged 1 year. During this time, the weights and growth of individual lambs were recorded monthly. At 1 year of age, all sheep were group-housed indoors for 1 week prior to surgery. For 24 h prior to surgery all food, but not water, was withdrawn from the animals. Anaesthesia was induced with sodium thiopentone (20 mg/kg i.v. intraval sodium; Rhone Mérieux, Dublin, Ireland) and maintained with 1–2% halothane in 50:50 O2/N2O. Carotid and jugular catheters were inserted into each sheep and the incision closed. All sheep received a dose of long-acting antibiotic (15 mg/kg i.m. amoxycillin (Duphamox); Fort Dodge Animal Health Ltd, Southampton, UK) and analgesia (1 mg/kg flunixin meglumine (Finadyne); Shering-Plough, Kenilworth, UK) postoperatively. Catheter patency was maintained by daily flushing with heparinised saline (50 IU heparin/ml). All sheep had established normal feeding patterns within 1–2 h after surgery and showed no visible signs of discomfort for the duration of the experimental period.
Experimental protocols
Remote blood sampling of pregnant ewes and their offspring The automated blood-sampling equipment (ABSE) was used as described previously (Goddard et al. 1998). In brief, the ABSE is mounted in a small rucksack on the ewes back and programmed with a microprocessor to sample (5 ml from connected jugular vein catheter) at hourly intervals for 14 h from 0900 h. The unit automatically withdraws a set quantity of blood into a heparinised syringe and flushes the line with 1 ml heparinised NaCl after each sample. A total of 14 samples may be taken at prespecified intervals. The following day, the unit was removed and blood samples spun at 3000 r.p.m. for 10 min for decanting of resultant plasma. Pregnant ewes were sampled at days 2 and 30 of gestation, i.e. to cover the start and end of the maternal undernutrition period, while offspring were ABSE sampled at 4 months of age.
HPA axis function in offspring of periconceptionally undernourished ewes A period of 2–4 days postoperative recovery was allowed before any experiment being performed. The investigator was blinded to the dietary origin of the sheep prior to any experiment or plasma analysis being performed. The experiments were conducted on separate days with 1–2 days interval between challenges and the order in which sheep received the challenges was randomised.
Experiment 1: CRH/AVP challenge. Baseline samples were taken at –30 and –15 min prior to a bolus i.v. injection of CRH (0.5 µg/kg) and vasopressin (AVP; 0.1 µg/kg) at time 0. Thereafter, regular blood samples were withdrawn at +5, 15, 30, 45, 60, 90, 120, 150 and 180 min. All blood samples were collected into chilled heparinised tubes, centrifuged for 5 min at 4 °C and, after decanting of the supernatant plasma, were stored at –20 °C for further analysis of plasma ACTH and cortisol concentrations. Before (30 min) and during this experiment, the arterial catheter was connected to a precalibrated pressure transducer (SensorNor 840; S 4925) attached at heart level and linked to a data acquisition system (Po-Ne-Mah; Version 3, Linton Instruments, Diss, Norfolk, Uk). Analogue signals for real-time systolic, diastolic, mean arterial pressure and heart rate were recorded at 1-s intervals, digitised and stored on an Excel spreadsheet for further analysis. From these data, pulse pressure (systolic–diastolic) was derived.
Experiment 2: ACTH challenge. Two baseline blood samples (2 ml) were withdrawn before all sheep were administered a bolus dose of synthetic ACTH (Synacthen 1.25 µg/kg, Abbott Laboratories) at time 0. Thereafter, regular blood samples were withdrawn at +5, 15, 30, 60, 120 and 150 min. Blood samples were treated as described for Experiment 1 for further analysis of plasma cortisol concentration only.
Experiment 3: AVP challenge. To address whether the cardiovascular responses to combined CRH and AVP (Experiment 1) could be elicited by AVP alone, a proportion of sheep (n = 4) received an identical AVP bolus (i.v., 0.1 µg/kg in 0.9% NaCl) and cardiovascular variables recorded as described previously.
Biochemical analyses
Cortisol An RIA was used for the quantitative measurement of total cortisol in plasma (Coat-a-Count, DPC, Caernarfon, Wales) as described previously (Edwards et al. 2001b, Bispham et al. 2003). In brief, the kit contained cortisol antibody coated tubes, 125I cortisol and cortisol standards. Suitable dilutions were made of standards to improve accuracy at the lower end of the standard scale; in total seven standards varying from 0 to 276 nmol/l were used. Duplicate 25 µl plasma samples were incubated with 125I cortisol in each tube for 45 min at 37 °C, decanted and counted for 1 min/tube with a gamma counter. The detection limit, defined as the apparent concentration at 95% B/B0, was 0.2 µg/dl. The intra- and interassay coefficients of variation were 5.6 and <10%.
ACTH An RIA was used for the quantitative measurement of ACTH in plasma (Diasorin, Slough, UK) as described previously (Gardner et al. 2001). The kit contained ACTH calibrators, rabbit anti-ACTH serum, 125I ACTH, Precipitating Complex (GAR-PPT) and ACTH standards. In brief, duplicate 100 µl samples, 200 µl ACTH antiserum and 200 µl tracer were combined and incubated for 16–24 h at 2–8 °C. After this time, the precipitating complex was added to separate the bound/unbound tracer and the samples incubated for a further 15 min at 20–25 °C, centrifuged and decanted. The precipitate of each tube was counted for 1 min using a gamma counter. The minimum detectable concentration was 15 pg/tube. The intraassay coefficient of variation was 11.8%. The interassay coefficient of variation was not measured because only two assays were performed. However, routinely the same assay has an interassay variation of 10–15% in our hands (Gardner et al. 2001).
Plasma concentrations for both cortisol and ACTH were calculated from interpolation of a semi-log standard curve with B/B0 (%) on the y-axis and either ACTH or cortisol on the x-axis.
Microscopy
At least 2 days after the ACTH challenge, all sheep were injected i.v. with a terminal anaesthetic (20 mg/kg sodium pentobarbitone) and body and adrenal weights were determined. In a proportion of these sheep, one adrenal gland was fixed in 10% formaldehyde and, within 2 days, embedded in paraffin wax for sectioning (male n = 8, female n = 5). Each adrenal gland was cut in half along its longitudinal axis and between 4 and 8 x 8 µm sections from the midline were taken with a microtome, mounted on individual slides and stained with haematoxylin and eosin. Adrenocortical and adrenomedullary areas (mm2) were then determined on each section with a calibrated eye-piece graticule under low-power (4 x ) light microscopy. At least six measurements were taken from each of the adrenal sections.
Statistical analysis
All data are expressed as means ± S.E.M. unless otherwise stated. Baseline values and concentrations measured after each challenge were analysed as absolute concentrations and concentrations as a deviation from baseline (i.e. minus average baseline concentrations). With the baseline set at 0, the values for each hormone as a change from baseline were graphically represented using Prism (GraphPad version 3, San Diego, CA, USA). In addition to average resting concentrations for each hormone, other derived variables were peak cortisol and ACTH concentration achieved and absolute cortisol and ACTH secretion (measured as the area above fasting plasma cortisol and ACTH concentration under the plasma cortisol and ACTH curve; cortisol/ACTHAUC). Derived (dependent) variables were then statistically tested using SPSS v14.0 by one-or two-way repeated measures ANOVA with nutritional group and gender as fixed effects. For all comparisons, statistical significance was accepted when P<0.05.
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Results |
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Details of maternal weight gain/loss during the period of undernutrition are as described previously (Gardner et al. 2004). Plasma concentrations of maternal cortisol were similar on days 2 and 30 of gestation in both control and NR ewes, and for clarity these data are presented in Fig. 1
at 30 days only, i.e. the last day of undernutrition when the greatest difference in maternal plasma cortisol would be expected. In addition, over the 14-h ABSE sampling period, there was no evidence of an ultradian rhythm in maternal plasma cortisol.
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All sheep gave birth at the appropriate stage for this breed (~147 ± 2 days). Details of birth weights and postnatal growth rates are as described previously (Gardner et al. 2004, 2005). At 1 year of age, there was no difference in body weight between the two nutritional groups, but weights were higher in males relative to females (control male 57 ± 5, control female 43 ± 2 kg, NR male 57 ± 4, NR female 45 ± 2 kg, F 14.0, P = 0.001). At 4 months of age, resting plasma cortisol was similar in all groups regardless of prenatal nutritional experience or sex (control male 17.6 ± 2.9, control female 17.2 ± 0.4, NR male 16.5 ± 3.1, NR female 21.7 ± 4.0 nmol/l). Repeated ABSE sampling revealed no effect of time in any of the groups (Fig. 2; data for control vs NR included only for clarity).
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; P<0.001). For ACTH, the response was similar for group and gender, but there was a significant (F 24.3, P<0.001) interaction between group x gender, i.e. for controls females exhibited increased plasma ACTH relative to males, but for NR this trend was reversed (control male 7415 ± 1222, control female 18 378 ± 2575; NR male 13 142 ± 417, NR female 6709 ± 2082 AUC units; Fig. 3A). For cortisol, there was a trend for an effect of group (P = 0.06), but significant effects of gender (F 5.3, P = 0.03) and the gender x group (F 12.1, P = 0.003) interaction (control male 10 751 ± 1717, control female 21 998 ± 2006; NR male 13 877 ± 528, NR female 11 648 ± 2753 AUC units; Fig. 3B).
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illustrates the responses in control and NR offspring only for clarity.
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). In addition, there was a significant effect of gender, but not nutritional group, on the peak cortisol level achieved during the challenge (control male 159 ± 7, control female 240 ± 17; NR male 158 ± 29, NR female 183 ± 26 nmol/l, F 7.44, P = 0.01).
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vs Fig. 4
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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GC have, from early in the genesis of the programming of health and disease hypothesis, been thought to act as intermediary factors that transcribe the developmental programming sequelae of maternal undernutrition. From the early rodent studies (Gardner et al. 1998) to later large animal models (Challis et al. 2000, Edwards et al. 2001a, Bloomfield et al. 2004), a role for increased GC exposure or altered regulation of the HPA axis in fetal through to adult life, after variations in the maternal diet, has been proposed and intensively studied. However, for a number of reasons outlined below, a causal relationship has proved difficult to ascertain. For example, first, there are two HPA axes to consider (maternal and fetal), each of which show home-orrhetic regulation through gestation, i.e. the pregnant state alters HPA axis function per se and this changes as gestation progresses. Furthermore, the fetal HPA axis develops increased function with gestation from a tonic dependence on maternal GC to gradual autonomy (Challis & Brooks 1989). Secondly, the placenta in some species can both produce corticotrophin-releasing factor, stimulating fetal HPA axis development (Florio et al. 2002), and further act as a control point for maternal GC entry into the fetal compartment through the expression and activity of the two 11ß-hydroxysteroid dehydrogenase (11ß-HSD) isoforms 1 and 2 (Seckl 1997). In addition, further levels of complexity in the axis exist in the form of binding globulins, which prevent access of GC to the GC receptor (Challis et al. 1995) and the developing regional-specific tissue expression of 11ß-HSD within the fetus (Seckl & Chapman 1997, Whorwood et al. 2001). Consequently, the initial response of maternal–fetal HPA axes to maternal (perhaps fetal) undernutrition has only been partially described and appears gestational age-dependent. Thus, early to mid-gestation undernutrition reduces maternal resting plasma cortisol levels (Bispham et al. 2003), whereas late gestation undernutrition appears to elevate them (Edwards & McMillen 2001). In the present study, we have shown that undernutrition (50% estimated requirement) of the ewe for the first 30 days of pregnancy has no effect on the resting plasma cortisol concentration when assessed without external interference. This is important, as it has recently been demonstrated that a greater level of undernutrition in sheep (fed to 30% control intake), for a longer period (–60 to +30 days gestation), reduces maternal plasma cortisol during the challenge (Jaquiery et al. 2006).
To date, the effects of such maternal–fetal nutritional challenges on HPA axis function have largely been explored in the short term, i.e. in the fetus itself, rather than in the resultant adult offspring. In the fetus, periconceptional undernutrition enhances fetal ACTH production in late gestation (Edwards & McMillen 2002) to such an extent that marked preterm birth is induced in 50% of the offspring (Bloomfield et al. 2003b, 2004). In contrast, moderate undernutrition postconception, but restricted to early–mid-gestation, has the opposite effect, blunting HPA axis sensitivity to a CRH and AVP stress test (Hawkins et al. 1999). When undernutrition is confined to late gestation alone then increased fetal plasma cortisol has been observed (Edwards & McMillen 2001). In the adult, follow-up of HPA axis function after maternal undernutrition has only been considered when the period(s) of undernutrition are confined to late gestation alone (Bloomfield et al. 2003a). Here, a short (10 days), but not longer (20 days) nutritional challenge programmed an increased ACTH response in female offspring to an identical CRH and AVP challenge as used in the present study (Bloomfield et al. 2003a). The present study is the first to report on juvenile and adult HPA axis activity in male and female offspring after early gestation, postconception under-nutrition. We show no effect on resting plasma cortisol concentrations, assessed remotely, during juvenile life, but increased resting plasma cortisol in females, relative to males, in the resultant young adult offspring despite no difference in plasma ACTH. This apparent increase in resting adrenocortical sensitivity in females is exacerbated by periconceptional undernutrition, i.e. the ACTH:cortisol ratio is greatest in female NR. The stimulated pituitary response reveals significant gender x nutritional group interactions, i.e. for controls, females exhibit increased plasma ACTH or cortisol relative to males, but for NR this trend is either not present or reversed. However, the specific adrenocortical response to synthetic ACTH was gender-dependent only, being greater in female offspring.
It is interesting to note that the plasma concentrations of cortisol in juvenile offspring in the present study are much lower than those observed at 6–7 months, when the sheep were studied under more controlled experimental conditions in a metabolic crate. Clearly, this may be either an age-related effect or an effect of manual sampling. Concentrations at one year of age are similar to those observed in one other study in adult sheep under similar conditions (Bloomfield et al. 2003a). Given that the ABSE has been extensively trialled in deer to show a stimulatory effect of manual sampling (Goddard et al. 1998, Sakkinen et al. 2004) then we would suggest that sheep, perhaps less so than deer, do show enhanced HPA axis activity with manual sampling and this explains the higher plasma cortisol at one year in the present study. Clearly, however, this elevated activity is particularly apparent in female offspring that were periconceptionally undernourished.
Many previous studies have established sex-specific differences in the regulation of the HPA axis. The differences occur at virtually all levels of the axis, from feedback in the brain (Owen & Matthews 2003) to the adrenal gland itself (Silva et al. 2002, van Lier et al. 2003). In the sheep, Canny et al(1999) specifically examined gender-related differences in HPA axis function in vitro and found increased adrenal steroidogenic potential and corticotrophin sensitivity in female relative to male sheep, a difference that appeared to occur at a postreceptor level. The present study supports these findings in the intact animal and confirms similar previous observations (Roelfsema et al. 1993, Andrew et al. 1998, Silva et al. 2002, van Lier et al. 2003). We show that female sheep per se have a relatively greater cortisol response to a specifically adrenal orientated challenge. The increased appearance of cortisol in the circulation after a synthetic ACTH bolus was not related to adrenal size, and thus steroidogenic capacity, since the area occupied by the cortex was proportionately smaller in female sheep. Also increased storage of a labile, readily released form of cortisol in females is unlikely as there is little storage of steroid within the zona fasiculata (Robinson et al. 1983). Rather, in females there would appear to be either: (1) increased adrenocortical synthetic potential, (2) enhanced sensitivity to extra-adrenal trophic hormones (Canny et al. 1999) or (3) reduced sensitivity to central feedback mechanisms (Matthews et al. 2004). Of the potential candidate hormones, the greater oestrogen presence in females relative to males is the most likely (Handa et al. 1994, Lee & Rivier 1996, Ogilvie & Rivier 1997). Indeed, in hypogonadal males and females, i.e. genetically male or female but resting similar steroid hormone levels, specific differences in the adrenal responses exist, but are reversed; males show greater adrenal cortisol output (Roca et al. 2005). It is interesting to note that the reverse is also true in fetal life, i.e. female sheep fetuses in utero have relatively blunted HPA axis responses to hypoxic stress (Giussani et al. 2001).
In the present study, we observed a group x sex interaction for the appearance of ACTH in the plasma after administering a CRH and AVP bolus. In control sheep, the trend was for greater ACTH output in females relative to males, but this was reversed when those sheep were exposed to a nutritionally restricted diet during early gestation. The mechanism for this effect is currently unknown. There are a number of contradictory reports on gender differences in ACTH output after various stressors that invariably lie with the nature of the stressor employed and the species studied. Staying with the sheep as an experimental model, the analysis of POMC in corticotrophs revealed increased expression in males relative to females but, in stark contrast, increased actual ACTH output in females relative to males (Canny et al. 1999), illustrating that even in isolated corticotrophs in vitro, there is a marked complexity of function between the sexes.
Finally, high concentrations of AVP have been shown to have clear cardiopressor actions, hence its name (Cowley 1988). However, a similar independent role for ACTH in high concentrations has also been proposed (Whitworth et al. 2001). In the present study, we clearly show that AVP alone is capable of exerting equivalent cardiopressor responses to combined CRH and AVP, indicating that it is AVP rather than the combination of AVP and high ACTH produced after the CRH and AVP bolus, which is responsible for the cardiovascular responses observed in the present study.
In conclusion, our study has first illustrated a novel means for assessing true resting cortisol status in unrestrained, non-manually sampled sheep. Secondly, the plane of maternal nutrition around the time of conception and implantation can have effects on the function and sensitivity of the offspring’s HPA axis as young adult sheep. The nature of these effects, however, are sexually dimorphic, with female sheep appearing to show enhanced adrenal steroidogenic potential, despite no obvious adrenal morphological differences relative to males. The study provides further clear data that females respond differently to stress than males and that the periconceptional nutritional environment may influence this response.
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Acknowledgements |
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References |
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Received 10 January 2006
Received in final form 29 March 2006
Accepted 7 April 2006
Made available online as an Accepted Preprint 10 May 2006
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mean arterial blood pressure (A) and heart rate (B) response to a combined CRH and AVP bolus in control and nutrient-restricted (NR) sheep at 1 year of age. Values are means ± S.E.M. for control (n = 12) and NR (n = 8) sheep. CRH and AVP elicited a significant (P<0.001) hypertension and sustained bradycardia in all sheep. There was no effect of periconceptional undernutrition or gender on the cardiovascular response to CRH and AVP.
