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1 Laboratory of Anatomy and Physiology of Domestic Animals,
2 Laboratory of Animal Nutrition,
3 Laboratory of Animal Breeding, Department of Animal Science, Agricultural University of Athens, 75, Iera odos, 11855 Athens, Greece
(Requests for offprints should be addressed to S E Chadio; Email: shad{at}aua.gr)
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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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It has been shown that maternal nutrient restriction, which has no effect on birth weight, can alter the function of the hypothalamic–pituitary–adrenal (HPA) axis (Hawkins et al. 1999, 2000), which has been suggested to play a role in programming of the later disease (Seckl 1997). Studies examining the impact of maternal nutrient restriction on HPA axis have been mostly limited to the late-gestation fetus or young lambs (Hawkins et al. 2000, Edwards et al. 2001, Edwards & McMillen 2002, Bloomfield et al. 2004) and only a few have been undertaken to establish the long-term effects of maternal undernutrition on HPA function in the adult sheep. Brief undernutrition for 10 but not 20 days during late gestation altered the HPA function in adult offspring, further emphasizing the fact that the timing, type, and duration of fetal nutrient restriction are each important in determining the nature of the fetal adaptive responses and their pathophysiological sequelae in later life (Bloomfield et al. 2003). More recently periconceptional undernutrition was shown to exert a minor influence on HPA axis function in young adult sheep (Gardner et al. 2006).
It has been suggested that HPA axis function may undergo developmental changes, since prenatal glucocorticoid exposure in sheep resulted in different HPA axis responsiveness between 6 months and 1 year postnatal age, which highlights the importance of studying outcome at several different times postnatal (Sloboda et al. 2002).
To our knowledge, no study has investigated the age-related changes on stimulated HPA axis function in sheep offspring as a result of maternal undernutrition at different discrete times during pregnancy.
Therefore, the present study was undertaken in order to characterize the effects of 50% maternal nutrient restriction during two (0–30 and 31–100 days) periods of gestation on the HPA axis responsiveness to exogenously administered corticotropin-releasing hormone at three different ages in postnatal life in sheep.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Twenty-two ewes (Ovies aries) of the Chios breed, of similar age (2.0 ± 0.3 years) and body weight (63.0 ± 0.6 kg), were used. Housing and care of animals conformed to Faculty of Animal Science guidelines. Ewes were housed indoors and were mated following estrus synchronization with intravaginal progestagen sponges (Chronogest, Intervet, Holland). At the time of mating, they were randomly allocated to one of the following treatments. Control group (C, n = 8) fed 100% of the recommended metabolizable energy (ME) and crude protein (CP) requirements (9 MJ ME/day and 104 g CP/day for the maintenance of a 60 kg non pregnant ewe, National Research Council (NRC 1985) for the whole of gestational period, nutrient restricted group 1 (R1, n = 7) offered 50% of the control nutrient allowance during the first 30 days of pregnancy, and nutrient restricted group 2 (R2, n = 7) fed to 50% of the control nutrient allowance from day 31 to day 100 of pregnancy. Feed was provided at an individual basis in two equal portions at 0800 and 1600 h daily and animals had free access to water. Feed residues were recorded every day. The diet consisted of lucerne chaff, wheat straw, and a commercial concentrate mixture (in pellets) containing barley, corn, wheat bran, cottonseed meal, limestone, bicalcium phosphate, sodium chloride, and mineral–vitamin premix. The lucerne chaff, wheat straw and pelleted concentrate provided 7.2, 5.5, 10 MJ metabolizable energy/kg and contained 135, 32 and 115 g crude protein/kg respectively.
Pregnancy and fetal number were confirmed by ultrasound at day 70 of gestation. Only twin-bearing ewes were used, while two singleton-bearing ewes from group R2 were excluded from the study. All nutritional regimens were adjusted for gestational age and fetal number, while maintaining the treatment difference and taking into account the increasing fetal burden.
Ewes were weighed weekly before morning feeding throughout gestation. Blood samples were collected at 10-day intervals before feeding for the measurement of cortisol and insulin concentrations, from day 40 until parturition. All blood samples were centrifuged at 2800 r.p.m. for 15 min and plasma was separated into aliquots and stored at –20 °C for subsequent analysis.
Lambs were delivered naturally. After delivery they were dried, ear tagged, and weighed and the date of birth and sex were recorded. Two days after birth, newborns were separated from their mothers and reared on artificial milk containing coconut oil, whey powder, wheat starch, soya protein, and vitamin–antioxidants premix (Capragno, Serval S.A., France). Milk was offered ad libitum, in order to ensure that lambs met their daily requirements, until the age of 45 days. After this age, lambs’ diet consisted of lucerne hay and a commercial pellet mixture containing barley, corn, soya meal, sunflower meal, wheat bran, powder milk, limestone, bicalcium phosphate, and mineral–vitamin premix. Lambs were weighed biweekly from birth to the end of experiment. Three lambs from the control and one from the R2 group were weighed until weaning and therefore treatment groups were: C (male (m) = 7/female (f) = 6), R1 (m = 7/f = 7), R2: (m = 5/f = 4).
Corticotropin releasing hormone (CRH) challenges
At three different ages (2, 5.5, and 10 months) lambs were injected with 0.5 mg ovine CRH/kg body weight (Sigma Chemical). Blood samples were collected at 15 and 0 min before and at 15, 30, 60, and 180 min after the CRH challenge, in heparinized tubes kept on ice, centrifuged at 2800 r.p.m. for 15 min and stored at –20 °C until hormone analysis. All challenges were administered between 0800 and 0900 h in order to minimize the impact of circadian variability on measurements of plasma adrenocorticotropic hormone (ACTH) and cortisol. In addition, before the last CRH challenge at 10 months female lambs were subjected to estrus synchronization using intravaginal progesterone sponges to ensure that changes in circulating steroid hormones due to variations in the estrous cycle did not confound interpretation of the results.
Measurement of plasma insulin, cortisol and ACTH levels
Plasma insulin concentrations were measured using a commercial RIA kit (Linco Research Inc, St.Charles, MO, USA). The sensitivity of the method was 0.1 ng/ml and the intra- and interassay coefficients of variation were 4.6 and 9.4% respectively.
Cortisol concentrations in both maternal and lamb plasma samples were measured by a coated-tube RIA kit (Coat-a-Count cortisol, DPC, Biermann GmbH, Germany) as described previously (Bispham et al. 2003). The sensitivity of the method was 1 µg/dl. The intra- and interassay coefficients of variation were 4.4 and 6.4% respectively.
Plasma ACTH levels were measured by a commercial RIA kit that detects ACTH1–24 (DiaSorin Inc., Stillwater, MN, USA) and that has previously been validated for use in the sheep (Jeffray et al. 1998). The sensitivity of the assay was 15 pg/ml. The coefficients of variation were 6.3 and 6.7% respectively.
Statistical analysis
All data are presented as least square means ± S.E.M. and were analyzed using the SAS Statistical Program (Statistical Analysis System 2005). Maternal body weight and hormone levels throughout gestation were analyzed using a General Linear Model (GLM) for repeated measures with treatment and time (gestational age) as fixed effects and their interactions. Offspring body weight data were analyzed using the same procedure, which included treatment, sex, and time (lamb age) as fixed effects and their interactions.
Data for the area under the response curve (AUC), calculated by a baseline-corrected trapezoidal integration method for cortisol and ACTH after CRH challenge were initially analyzed using a GLM appropriate for repeated measures per subject with fixed effects for treatment, sex, lamb age and their interactions. In addition, data for cortisol and ACTH values (response curve) at each age were also analyzed by a GLM, which included the effects of treatment, sex, and sampling time and their interactions. Birth and current body weight were used as covariates in the initial statistical models but were excluded since no significant effect was revealed. Post hoc analyses were performed, when appropriate, using Duncan’s method for pairwise comparisons and statistical significance was set at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Feed restriction during the first 30 days (group R1) had no effect on body weight throughout pregnancy. In contrast, body weight of the R2 group decreased from day 70, becoming significantly lower than control and R1 groups from day 92 to 99 (P < 0.05). After feed restoration body weight increased, but remained lower (P < 0.05), relative to the other two groups until parturition (Fig. 1
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). On the other hand, insulin levels of ewes undernourished from days 31–100 of gestation (R2 group) were significantly lower compared with control from 40 to 120 days of gestation (P < 0.05) (Fig. 3).
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Birth weight of both male and female lambs was not affected by the maternal nutritional manipulation. At 2, 5.5 and 10 months of age there was no difference in body weight between the three groups of animals. In addition, no sex effect was detected (Table 1).
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ACTH response
Three-way (age x treatment x sex) repeated measures ANOVA for ACTH response (AUC) revealed significant effect of age (P < 0.001) and a significant age x sex interaction (P < 0.001). The bases for all of these effects were the decrease in ACTH response of both sexes at 5.5 months compared with the response at 2 months and significantly higher ACTH response of female than male lambs at 5.5 months of age (P < 0.01), (Fig. 4). However, no significant treatment x sex interaction was revealed. A significantly higher (P < 0.05) ACTH response (AUC) to CRH challenge was observed in animals of R1 group at the age of 2 months compared with the other two groups (Table 2), but no sex effect was detected. In addition, at 120 and 180 min after the challenge ACTH concentration was higher (P < 0.05) in R1 compared with control and R2 groups (Fig. 5). At the age of 5.5 and 10 months, no treatment effect was revealed for the ACTH response (Table 2, Figs 6 and 7).
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). Similar to the ACTH response, no treatment x sex interaction was revealed.
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). In the same group cortisol levels were significantly higher at 60, 120, and 180 min after the challenge (P < 0.05, P < 0.01 and P < 0.05 respectively), (Fig. 5).
At the age of 5.5 months cortisol response to CRH challenge (AUC) did not differ between treatment groups (Table 2), but the basal cortisol levels were higher (P < 0.01) in R1 group, followed by elevated, although not significant concentrations at each sampling time (Fig. 6). This latter effect was not more apparent at the age of 10 months, when no differences between treatments were observed (Fig. 7).
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Discussion |
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Maternal cortisol levels exhibited a significant increase between 40 and 90 days of gestation in ewes undernourished from conception to day 30 of gestation (group R1). Previous data in sheep have shown a suppression of maternal HPA axis during periconceptional undernutrition with decreased ACTH and cortisol levels, which returned to normal or even elevated levels after cessation of undernutrition (Bloomfield et al. 2004). In the present study the significantly elevated cortisol levels detected after refeeding in ewes of R1 group support the hypothesis of an increased HPA axis activity after cessation of undernutrition. In contrast, under-nutrition from 31 to 100 days of gestation had no effect on maternal cortisol levels. However, Bispham et al.(2003) reported that ewes undernourished at 60% of their requirements from day 28 to day 80 of gestation exhibited lower cortisol levels throughout the period of undernutrition, compared with well-fed ewes. The differences in maternal cortisol response to nutrient restriction between the present and other studies may be due to variations in the time, duration and intensity of the feed restriction. Maternal insulin concentrations were significantly lower in R2 group during undernutrition and for the next 20 days after cessation, which is in good agreement with the data reported by McMullen et al.(2005).
Lambs’ birth weights were not affected by either nutritional manipulation. No effect on birth body weight has been reported in a number of previous studies in which ewes were fed at 50 or 85% of their requirements at different periods up to 90 days of gestation (Hawkins et al. 1999, 2000, Whoorwood et al. 2001, Gopalakrishman et al. 2004). On the contrary a reduction in the birth body weight was evident in newborn lambs from mothers undernourished from 105 to 115 days of gestation (Bloomfield et al. 2003). It is clear that the body weight at birth is affected only when undernutrition is imposed on mothers after day 100 of gestation, when rapid growth of the fetus occurs.
It has been shown that maternal nutritional insults that have no effect on birth weight can have pronounced effects on fetal metabolism (Harding & Johnston 1995) and hormonal responses (Oliver et al. 2001), including alterations in fetal hypothalamic adrenal axis function (Hawkins et al. 1999, 2000). To date, the majority of studies have focused on the effects of maternal undernutrition in late-gestation fetal sheep, which vary from enhanced, when periconceptional under-nutrition was imposed (Edwards & McMillen 2002) to reduced pituitary–adrenal response following CRH administration after early- to mid-gestation undernutrition (Hawkins et al. 1999, 2000). However, the timing and duration of maternal undernutrition required to produce postnatal consequences have received limited study. Nutritional restriction for a very brief (10 days), but not longer (20 days) period during late gestation resulted in increased responsiveness of HPA axis in adult (30 months old) female sheep (Bloomfield et al. 2003). In a more recent study Gardner et al.(2006) showed that periconceptional under-nutrition, similar to that imposed in our study had a minor influence on HPA axis function in young adult (1 year old) offspring, with females responding differently to males and a clear influence of periconceptional nutritional environment on this response. However, the main object of the present study was to examine the age-related alterations of HPA axis responsiveness after undernutrition in utero imposed during different gestational periods. Feed restriction from conception to 30 days of gestation (R1 group) resulted in enhanced ACTH and cortisol response after CRH administration at the age of 2 months, a result no more apparent at the age of 5.5 and 10 months. On the contrary, undernutrition from early- to mid-gestation (31–100 days) had no effect on HPA axis responsiveness at any age postnatal. These differences strongly indicate that both timing and duration of nutritional insults during gestation may differently affect the HPA axis function in offspring.
The above enhanced ACTH and cortisol response detected at 2 months of age are in accordance with the results of Hawkins et al.(2000), who reported that undernutrition during early gestation led to enhanced pituitary and adrenal responsiveness at 85 days postnatal, probably through reduced number of glucocorticoid receptors (GR) in the pituitary, indicating decreased glucocorticoid-mediated negative feedback of the axis (Hawkins et al. 1998).
The underlying mechanisms responsible for the altered hypothalamo–pituitary–adrenal function, as a result of maternal undernutrition are not yet clear. It has been shown that prenatal glucocorticoid exposure resulted in significant alterations in glucocorticoid receptor mRNA levels in the HPA axis, thus linking glucocorticoid exposure with alterations in negative feedback control of the axis (Levitt et al. 1996). Altered expression of central GR and mineralo corticoid receptors (MR) systems leading to decreased negative feedback at the paraventricular nucleus (PVN) and enhanced facilitation of the HPA response has also been reported after prenatal stress in rats and piglets (Henry et al. 1994, Maccari et al. 1995, Barbazanges et al. 1996, Kanitz et al. 2003). In the present study, given the higher cortisol concentrations detected after feeding restoration in association with data that placental 11ßHSD2 activity is reduced at the day 50 of gestation after periconceptional undernutrition (Jaquiery et al. 2006), it is tempting to speculate that the enhanced HPA axis function seen at 2 months post partum was due to increased exposure to excess cortisol in utero. Moreover, other components of the HPA axis, such as CRH mRNA expression in hypothalamus, ACTH-R expression and/or steroidogenic enzymes expression in adrenals might have been altered by maternal undernutrition, as has also been suggested in fetal sheep (Hawkins et al. 2001, Edwards et al. 2001).
The fact that the effects on HPA axis function were detected in lambs of R1, but not R2, group further emphasizes the possibility that there must be a critical window or windows during which the fetus is susceptible to maternal stress.
The lack of an effect on cortisol and ACTH response in lambs of R1 group at the age of 5.5 and 10 months points to the fact that the altered HPA axis function seen early in postnatal life, as a result of periconceptional undernutrition, changes with age. However, at the age of 5.5 months basal cortisol levels were still significantly higher in lambs of R1 group and a tendency for higher, although not significant, cortisol levels was evident at all time points. This gradual attenuation of HPA axis responsiveness indicates that there must be some factors contributing to this enhanced control of HPA axis activity with increasing age. A possible mechanism for this shift in HPA axis response is the resetting of the axis by hypercortisolaemia observed in early postnatal life, as has also been suggested by Poore & Fowden (2003) in their studies with juvenile and adult pigs. In addition, the possibility that the sensitivity to glucocorticoid negative feedback may have been influenced by alterations in the gonadal steroid milieu as animals underwent transition from pre-to postpubertal stage cannot be ruled out, since it has been shown that sex steroids potentiate and buffer glucocorticoid feedback on the gene expression of CRH, MR and, GR in a gender-specific manner (Patchev & Osborne 1996). Interestingly, in the present study a significant sex effect was observed at 5.5 and 10 months of age, with females exhibiting higher ACTH and cortisol levels after CRH administration, confirming earlier reports of gender-related differences in hypothalamo–pituitary–adrenal axis (Viau & Meaney 1996, Owen & Mathews 2003). The absence of an interaction between treatment and gender early in postnatal life, but the significant gender effect at the age of 5.5 months further emphasizes the impact of puberty-related changes on HPA axis responsiveness, with estrogens exerting stimulatory effects on stress-induced ACTH and glucocorticoid release (Lund et al. 2004). A well-characterized interaction between gender and puberty on the stress-induced response has recently been reported in rats (Viau et al. 2005). The results of the present study do not support the hypothesis that programming of the adult HPA axis is sex specific, as was the case with guinea pigs (Lingas & Matthews 2001) and sheep (Gardner et al. 2006). However, the main finding of the present study is that the effects of maternal undernutrition on HPA axis function changes with age, thus highlighting the importance of studying outcome at several different times during the life course. Furthermore, the differences detected between the two experimental groups points at the significant influence that the timing of imposing insult could exert on the programming of the HPA axis. Further studies are required to identify the impact of prenatal feed restriction on development and subsequent function of the hypothalamo–pituitary–gonadal (HPG) axis, particularly with respect to the interaction between the HPG and the HPA axes in both males and females.
In conclusion the present study showed that the first month of pregnancy is very critical for the HPA axis development, as indicated by the enhanced HPA axis activity after birth. This effect may be a consequence of fetal cortisol exposure resulting in early life hypersensitivity to glucocorticoid action and altered regulation of the HPA axis. However, this heightened hypothalamic drive decreases with age, indicating the resetting of the axis to adulthood and further emphasizing the importance of identifying the impact of nutritional restriction in utero at several time points after birth. Whether or not this effect, although transient, is sufficient to program alterations to other systems needs to be further elucidated.
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Acknowledgements |
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Funding |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Received in final form 28 November 2006
Accepted 6 December 2006
Made available online as an Accepted Preprint 27 December 2006
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P < 0.001.