Maternal Periconceptional Undernutrition Research Articles

Effect of maternal periconceptional undernutrition in sheep on cortisol regulation in offspring from mid-late gestation, through to adulthood.

Maternal periconceptional undernutrition (PCUN) alters fetal hypothalamic-pituitary-adrenal axis (HPAA) function and placental glucocorticoid metabolism in sheep. The effects of PCUN on HPAA function in adult life are not known. We investigated the effects of PCUN on fetal adrenal development across gestation and on cortisol regulation in adult offspring. Ewes were undernourished from 61 days before to 30 days after conception ('PCUN') or fed ad libitum ('N'). mRNA expression in the fetal adrenal gland of ACTH receptor (ACTHR), steroidogenic acute regulatory protein (STAR), cytochrome P450 17A1 (CYP17A1), 11beta-hydroxysteroid-dehydrogenase type 2 (11βHSD2), insulin-like growth factor-2 (IGF2), and in the fetal hippocampus of 11βHSD1, 11βHSD2, mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) was determined at 50 (adrenal only), 85, 120 and 131 days of gestation (term=148 days). In adult offspring (≥ 3 years, N; 10 female, 5 male, PCUN; 10 female, 10 male) a combined arginine vasopressin (AVP, 0.1 μg/kg) and corticotropin-releasing hormone (CRH, 0.5 μg/kg) challenge and a metyrapone (40 mg/kg) challenge were undertaken. mRNA expression of ACTHR, STAR and CYP17A1 were determined in adult adrenals. Fetal adrenal STAR, CYP17A1 and IGF2 mRNA expression were not different between groups in early gestation but were higher in PCUN than N at 131 days' gestation (all p<0.01). PCUN reduced fetal hippocampal MR and GR mRNA expression by 50% at 85 day, but not in later gestation. Adult offspring plasma cortisol responses to AVP+CRH or metyrapone were not different between groups. Plasma ACTH response to AVP+CRH was lower in PCUN males but ACTH response to metyrapone was not different between groups. Adult adrenal ACTHR, STAR, and CYP17A1 mRNA expression were not affected by PCUN. We conclude that the effects of PCUN on fetal HPAA function that became apparent in late gestation, are not reflected in adrenal cortisol secretion in mid-adulthood.

Effects of maternal periconceptional undernutrition in sheep on offspring glucose-insulin axis function into adulthood.

Maternal periconceptional undernutrition (PCUN) affected fetal pancreatic maturation in late gestation lambs and impaired glucose tolerance in 10-month-old sheep. To examine the importance of the timing of maternal undernutrition around conception, a further cohort was born to PCUN ewes [undernourished for 61 d before conception (PreC), 30 d after conception (PostC), or 61 d before until 30 d after conception (PrePostC)], or normally fed ewes (Control) (n = 15-20/group). We compared glucose tolerance, insulin secretion, and sensitivity at 36 months of age. We also examined protein expression of insulin signalling proteins in muscle from these animals and in muscle from a fetal cohort (132 d of gestation; n = 7-10/group). Adult PostC and PrePostC sheep had higher glucose area under the curve than Controls (P = 0.07 and P = 0.02, respectively), whereas PreC sheep were similar to Controls (P = 0.97). PostC and PrePostC had reduced first-phase insulin secretion compared with Control (P = 0.03 and P = 0.02, respectively). PreC was similar to Control (P = 0.12). Skeletal muscle SLC2A4 protein expression in PostC and PrePostC was increased 19%-58% in fetuses (P = 0.004), but decreased 39%-43% in adult sheep (P = 0.003) compared with Controls. Consistent with this, protein kinase C zeta (PKCζ) protein expression tended to be increased in fetal (P = 0.09) and reduced in adult (P = 0.07) offspring of all PCUN ewes compared with Controls. Maternal PCUN alters several aspects of offspring glucose homeostasis into adulthood. These findings suggest that maternal periconceptional nutrition has a lasting impact on metabolic homeostasis of the offspring.

Periconceptional undernutrition affects in utero methyltransferase expression and steroid hormone concentrations in uterine flushings and blood plasma during the peri-implantation period in domestic pigs.

Female undernutrition during early pregnancy may affect the physiological pattern of genomic DNA methylation. We hypothesised that in utero DNA methylation may be impaired in females fed a restrictive diet in early pregnancy. In this study we evaluated whether poor maternal nutritional status, induced by applying a restricted diet during the peri-conceptional period, may influence: (1) the potential for in utero DNA methylation, expressed as changes in the mRNA expression and protein abundance of methyltransferases: DNA methyltransferase 1 (DNMT1) and DNMT3a in the endometrium and the myometrium, (2) the intrauterine microenvironment, measured as oestradiol 17β (E2) and progesterone (P4) concentrations in uterine flushings and (3) plasma concentration of E2 and P4 during the peri-implantation period. Our results indicate that maternal peri-conceptional undernutrition affects maintenance and de novo DNA methylation in the endometrium, de novo methylation in the myometrium and a results in a decrease in intrauterine E2 concentration during the peri-implantation period. The intrauterine concentration of P4 and plasma concentrations of E2 and P4 did not change. These findings suggest that undernutrition during the earliest period of pregnancy, and perhaps the pre-pregnancy period, may create changes in epigenetic mechanisms in the uterus and intrauterine milieu of E2 during the peri-implantation period.

Periconceptional undernutrition increases quantity and quality of oocyte population, but not cognitive or emotional response of 60‐day‐old lambs

Maternal periconceptional undernutrition is associated with altered development and increased risks of adverse outcomes in the offspring. The aim of this work was to determine the effect of periconceptional undernutrition on behavioural and reproductive aspects of the offspring. Fifty ewes were synchronized in oestrus (day 0) and allocated to two groups (n = 25) to be fed diets that provided 1.5 (C) or 0.5 (L) times the requirements for maintenance until day 15. Ewes were mated and fed the control diet from day 16 until lambing. Two months after lambing, 26 lambs were exposed to tests to determine their cognitive/emotional responses. Six ewe lambs were euthanized and in vitro oocyte maturation and fertilization procedures performed. The experimental diets produced no changes of mean live weight (LW) of C ewes, L ewes presenting a reduction in their initial LW with significant differences at day 15, in comparison with C ewes (p < 0.05). L ewes experienced a significant reduction in their body condition (BC) in comparison with C ewes (p < 0.05). Fourteen days after the onset of the experimental diets, mean LW and BC of L ewes was significantly lower than those of C ewes (p < 0.05). Undernourished ewes presented a trend to a reduction of prolificacy and fecundity (p < 0.10) in comparison with C ewes. Emotional and cognitive test revealed a similar response between groups. Ewe lambs from the undernourished ewes presented a population of oocytes 1.7 times higher than ovaries from control ewe lambs (66.0 ± 0.73 vs. 113.7 ± 15.6 oocytes; p < 0.05) and had more oocytes in the 'good' (p < 0.05) and 'healthy' (p < 0.05) categories. In conclusion, a low plane of nutrition around conception significantly increases quantity and quality of the oocyte population of 60-day-old female descendants. Modifications of the cognitive and emotional responses of the progeny have not been evidenced.

The effect of periconceptional undernutrition of sheep on the cognitive/emotional response and oocyte quality of offspring at 30 days of age.

Maternal periconceptional undernutrition is associated with altered development and increased risks of adverse outcomes in the offspring. This circumstance is normal in flocks under extensive farming systems, which depend on natural forage resources. The aim of this study was to determine the effect of periconceptional undernutrition in sheep on behavioral and reproductive aspects of the offspring. Eighty ewes were synchronized in estrus and allocated to two groups (n=40) to be fed diets that provided 1.5 (C) or 0.5 (L) times the requirements for maintenance. Ewes were mated and 7 days later fed the control diet until lambing. One month after lambing, 32 lambs were exposed to tests to determine their cognitive and emotional responses. Six ewe lambs were euthanized and in vitro maturation and fertilization procedures were performed. L ewes presented a significant reduction in prolificacy and fecundity (P<0.05) in comparison with C ewes. Mean LW at lambing of L lambs was significantly higher than C lambs (C: 3.80 ± 0.11; L: 4.24 ± 0.15 kg, P<0.05). Lambs born from C ewes spent more time walking than L lambs (P<0.05) in the isolation test, revealing a decrease in the locomotor activity of lambs born from undernourished ewes around conception. Ewe lambs from the undernourished ewes presented a total population of oocytes 2.3 times higher than ovaries from control ewe lambs (60.0 ± 7.8 v. 140.0 ± 18.5 oocytes; P<0.05). In conclusion, periconceptional undernutrition is able to produce an increment in the body weight and the oocyte population, and an alteration of the locomotor activity of the offspring.

Maternal periconceptional undernutrition in Merinos d'Arles sheep: 1. Effects on pregnancy and reproduction results of dams and offspring growth performances

Maternal undernutrition during gestation can condition offspring adult health, with the periconceptional period pointed out as a key period. The aim of this study was to evaluate the effects of maternal periconceptional undernutrition on pregnancy and offspring growth performance in sheep.52 Merinos d'Arles ewes were fed to requirements (control group, C), whereas 64 ewes received 50% of their dietary needs from −15 to +30 days post-conception (restricted group, R). Thereafter, both groups were fed according to needs. Maternal body weight (BW), body condition score (BCS) and Non Esterified Fatty Acids (NEFA), progesterone, leptin and cortisol plasma concentrations were monitored weekly during the restriction period and the following month, then monthly until weaning. Lambs were weighed weekly until weaning at 22 kg BW, then monthly. Plasma leptin was monitored monthly in lambs.The BW, BCS, and leptin concentrations were significantly decreased, whereas NEFA and cortisol concentrations were increased in R dams. Maximum progesterone concentration was higher in R ewes that had a high (10–25%) vs. low (0–10%) BW loss during restriction (27.9 ± 2.59 vs. 20.8 ± 2.00 ng/mL, P < 0.05). Overall, gestation was significantly longer in the R group (151.0 ± 0.3 vs. 149.4 ± 0.4 days, P < 0.001). There was no difference between groups for pregnancy rates, prolificacy, birth weight and lamb mortality, but the proportion of male lambs was significantly higher in the R group, only for singletons (16/26 vs. 9/26, P < 0.05). Lamb growth was not significantly modified by treatment. Leptin concentrations at birth were significantly lower in R vs. C males (6.15 ± 0.13 ng/mL vs. 7.42 ± 0.36 ng/mL, P < 0.05), whereas in females, leptin concentrations were significantly higher in R vs. C lambs at 4 mo of age (7.31 ± 0.27 ng/mL vs. 6.41 ± 0.29 ng/mL, P < 0.05).These results indicate that maternal periconceptional undernutrition in a hardy breed does not significantly affect lamb birth weight and growth rates, in contrast to previous reports in other breeds, suggesting that caution must be taken when extrapolating programming data between breeds and breeding conditions.

Epigenetic modifications may play a role in the developmental consequences of early life events.

Many aspects of postnatal development are influenced by events before birth, including cognitive and language development. An adverse intrauterine environment, for example secondary to poor maternal nutritional status, multiple pregnancy, or late preterm birth, is associated with increased risks of delayed or impaired childhood development and altered physiology in adulthood that may predispose to increased risk of adult disease. Maternal periconceptional undernutrition and twin conception can both result in late preterm birth, but it is less clear whether cases of late preterm birth not following a recognized early pregnancy event may still have their origin in the periconceptional period. Thus, the very earliest periods of pregnancy, and perhaps even the pre-pregnancy period, may be an important period determining the developmental trajectory of the fetus, and thus both pregnancy and later health outcomes. Profound epigenetic modifications to the genome occur in the early embryo as a normal part of development. Recent evidence suggests that environmental signals acting during early development may also result in epigenetic changes which may play a role in mediating the association between early life exposures and later phenotype.

Periconceptional Events Perturb Postnatal Growth Regulation in Sheep

Periconceptional undernutrition and twin conception alter intrauterine growth and metabolism and are associated with later adverse metabolic outcomes. The contribution of postnatal growth to these outcomes is less well defined. We investigated whether maternal periconceptional undernutrition or twin conception altered postnatal growth regulation in ways that could lead to metabolic disease. Single and twin offspring of ewes undernourished (UN) from 61 d before until 30 d after mating, fed to achieve and maintain 10-15% weight loss (UN), were compared with offspring of maintenance-fed controls (N). At 2 h and 1, 6, and 12 wk after birth, lambs were weighed and plasma hormone and metabolite concentrations analyzed. Milk intake, measured by deuterium oxide dilution, was inversely related to birth weight only in N singles, although twins had the greatest postnatal growth velocity. Positive associations were seen between milk intake, growth velocity, and leptin concentrations in N, but not UN, offspring. We conclude that periconceptional undernutrition alters the relationships between regulators of postnatal growth, including nutrient intake and key hormonal axes, in both singles and twins without affecting size at birth or postnatal growth velocity. Dissociation of growth from its key regulators is one possible mechanism underlying adverse metabolic outcomes after periconceptional undernutrition.

Effects of periconceptional undernutrition on maternal taurine concentrations in sheep

Taurine has an important role in numerous physiological processes, including many aspects of fetal development such as development of the pancreas and brain, and requirements increase during pregnancy. Periconceptional undernutrition has long-term effects on pancreas and brain function of the offspring, but the effects on maternal taurine economy are unknown. We, therefore, studied the effects of different periods of periconceptional undernutrition on maternal plasma and urine taurine concentrations before and during pregnancy. Four groups of singleton-bearing ewes were studied (n 10-11): controls fed ad libitum, and groups undernourished from 60d before until mating (PreC), from 2d before mating until 30d after mating (PostC) or from 60d before until 30d after mating (Pre+PostC). In PreC ewes, plasma taurine concentrations remained at control levels for the first 30d, and then decreased through the remainder of undernutrition, but recovered by 30d after mating; urinary taurine excretion was low at mating, but recovered similarly. In PostC ewes, plasma taurine concentrations recovered after 2 weeks despite ongoing undernutrition; urinary taurine excretion had recovered by 30d after mating. Pre+PostC ewes followed the same pattern as PreC for the first 60d, but plasma taurine concentrations and urinary excretion recovered slowly, and did not reach the control levels until 97d. These data suggest that different periods of mild periconceptional undernutrition in sheep have different but substantial effects on maternal taurine homoeostasis. These effects may be one mechanism by which maternal periconceptional undernutrition alters development of the offspring with implications for adult health.

241 EFFECT OF MATERNAL PERICONCEPTIONAL UNDERNUTRITION ON MALE OFFSPRING PHYSIOLOGY AND TESTICULAR DEVELOPMENT

Epidemiological studies in humans, as well as animal models, have shown that maternal environment at critical periods of fetal development can condition offspring adult health. Previous studies have shown effects of maternal undernutrition during early to mid gestation on Sertoli cell proliferation and seminiferous tubule diameter in male lambs of 10 months of age. Delayed follicular maturation and meiosis in female fetuses have been reported after maternal undernutrition from mating. The aim of this project was to evaluate the long-term effects of maternal periconceptional undernutrition on offspring physiology and reproductive function. Postnatal development of male offspring is presented here. Fifty-two control females of Merinos d’Arles breed (R100) were fed a normal diet adapted to their needs, and 64 restricted females (R50) received 50% of their dietary needs from 15 days before until 30 days after synchronized breeding. Thereafter, both groups were fed to meet their nutritional requirements. Males were weighed at birth and every week. Blood samples were collected monthly to monitor plasma leptin and cortisol concentrations. Organ weights were recorded at commercial slaughter (35 kg) and histological analysis was performed on testicles and adrenals. Data were analysed by ANOVA or Student’s test. Twenty-two live R100 and 34 live R50 male lambs were obtained. Gestation was significantly longer in the restricted group (P &lt; 0.01). Growth rate, live weight, and age at slaughter were not significantly different between groups. Plasma leptin concentrations were significantly lower at birth (P &lt; 0.001) and tended to be higher at 4 months of age (P = 0.09) in R50. There was a significant interaction between group, age, and litter size for basal cortisol concentrations: in singletons (n = 15 R50 and n = 8 R100), cortisol was significantly lower in R50 at 3 months of age (P &lt; 0.05) and tended to be higher at 4 months whereas in twins (n = 17 R50 and n = 10 R100), cortisol was significantly lower at birth (P &lt; 0.05) but not thereafter (triplets were not considered here because of low numbers). There was no statistical difference for carcass, testicle, or kidney weight. In contrast, carcass to live weight ratio and perirenal fat to live weight ratio were increased in all R50 (P &lt; 0.05). Adrenal to live weight ratio tended to be increased in R50 lambs (P = 0.06). Histological examination revealed no statistical difference between groups for adrenal corticomedullary ratio, zona glomerulosa to medulla ratio, and zona fasciculata to medulla ratio. There was no significant difference for the analysis of testicular tissue (diameter and surface of seminiferous tubules). The expression of genes involved in testicular differentiation (SRY, 3β-HSD, OCT3/4, VASA, stra8, SOX9) is currently being studied by quantitative PCR and will be presented. These results confirm the effects of periconceptional undernutrition on metabolic function but so far, no effect has been demonstrated on testicular histology. Litter size seems to play an important role, because effects were different between singletons and twins.

Effects of sex, litter size and periconceptional ewe nutrition on offspring behavioural and physiological response to isolation

Maternal periconceptional undernutrition alters fetal hypothalamic–pituitary–adrenal (HPA) axis development. However, the effects of this early nutritional insult on postnatal HPA axis function and stress-related behaviours are unknown. We investigated in sheep the effects of different periods of undernutrition, and of sex and litter size, on offspring behavioural and cortisol responses to isolation stress. We studied four nutritional groups: controls well nourished throughout pregnancy ( n = 39), or ewes undernourished (UN, 10–15% body weight reduction) before mating (−60 to 0 d, n = 26), after mating (−2 to + 30 d, n = 20) or both (−60 to + 30 d, n = 36). At 4 and 18 months of age, offspring were isolated for 5 min, their behaviour video recorded, and plasma cortisol concentrations measured. Offspring of all undernourished groups demonstrated 50% fewer escape attempts than controls at 4 months of age, and offspring of UN−60 + 30 ewes had 20% lower plasma cortisol area under the curve in response to isolation at 18 months. Females had higher cortisol concentrations and vocalised more than males at 4 and 18 months, and were more active at 18 months. After isolation, UN−2 + 30 males had higher cortisol concentrations than UN−2 + 30 females whereas in all other groups males had lower concentrations than females. Singleton males made more escape attempts than females, whereas in twins females made more escape attempts than males. These findings suggest that maternal periconceptional undernutrition in sheep can suppress behavioural reactions and cortisol secretion in response to isolation stress in the offspring into adulthood, and that these effects differ between males and females.

Do Alterations in Placental 11β-Hydroxysteroid Dehydrogenase (11βHSD) Activities Explain Differences in Fetal Hypothalamic-Pituitary-Adrenal (HPA) Function Following Periconceptional Undernutrition or Twinning in Sheep?

Periconceptional undernutrition (UN) in sheep accelerates fetal hypothalamic-pituitary-adrenal (HPA) axis activation, resulting in preterm birth. In contrast, twin conception suppresses fetal HPA function and delays prepartum HPA activation. We hypothesized that these dissimilar effects on fetal HPA activity result from different influences of maternal glucocorticoid (GC) on maturation of the fetal HPA axis, mediated via different activities of placental 11beta-hydroxysteroid dehydrogenase (11betaHSD) isozymes. We examined the effects of twinning and maternal periconceptional UN from 60 days before until 30 days after mating on the ontogeny of placental 11betaHSD-1 and -2 enzyme activities. At day 85 of gestation, placental 11betaHSD-2 activity was lower in UN than in normally nourished (N) fetuses (P < .05) and was higher in twins than in singletons (P < .05). Furthermore, placental 11betaHSD-1 activity was not different between nutritional groups but was higher in twins than in singletons (P = .01). At day 85, fetal plasma cortisol (P < .001) and cortisone (P < .001) concentrations were lower in UN than in N fetuses, but the cortisol to cortisone ratio was higher in UN than in N fetuses (P = .01). There was no effect of fetus number on plasma cortisol or cortisone concentrations or on the ratio of cortisol to cortisone at day 85. Therefore, periconceptional UN and twinning may result in the alterations of placental 11betaHSD isozyme activities at particular times during gestation. Changes in these activities during critical periods of fetal development could affect transplacental transfer or placental generation of GCs that reach the fetus, potentially influencing the timing of activation of the fetal HPA axis, fetal maturation, and hence the development and health later in life.

Effect of Periconceptional Undernutrition in Sheep on Late Gestation Expression of mRNA and Protein From Genes Involved in Fetal Adrenal Steroidogenesis and Placental Prostaglandin Production

In sheep, maternal periconceptional undernutrition precociously activates fetal hypothalamic-pituitary-adrenal function in a high proportion of animals, resulting in preterm birth. We investigated whether the effects of periconceptional undernutrition were mediated through genes encoding enzymes involved in adrenal steroidogenesis and in placental production and metabolism of steroids and prostaglandins. Singleton-bearing ewes were fed ad libitum (control, N) throughout gestation or undernourished from 60 days before until 30 days after mating. Fetal adrenal and placentome tissues were collected on gestational day 131. Fetal adrenal P450C17 protein expression was significantly increased with undernutrition. Placental prostaglandin endoperoxide synthase-2 expression was not different between groups. In undernourished pregnancies, there were significant positive correlations between fetal plasma adrenocorticotrophic hormone and cortisol concentrations and between fetal plasma adrenocorticotrophic hormone concentrations and placental prostaglandin endoperoxide synthase-2 messenger RNA (mRNA) and protein. These studies suggest that periconceptional undernutrition affects fetal adrenal P450C17, consistent with an elevation in plasma cortisol, and this occurs prior to activation of placental prostaglandin endoperoxide synthase-2 expression at gestational day 131.

Effects of sex, litter size and periconceptional ewe nutrition on the ewe–lamb bond

Undernutrition restricted to the time around conception in sheep alters endocrine and metabolic responses in the offspring. Studies in rats suggest that such an early insult can also alter the behaviour of the offspring. We studied the effects of mild maternal periconceptional undernutrition (10–15% body weight reduction) on the lamb's response to separation from and reunion with the mother, and on the ewe–lamb bond, evaluated as the preference for each other over an alien ewe/lamb in a test enclosure, at 24 h, 1 and 4 weeks of age. Lamb birth weight was not affected by maternal nutrition. Maternal periconceptional undernutrition did not affect the lambs’ responses to separation and reunion (number of vocalisations, times to leave pen and achieve proximity with ewes) or the bond between ewes and lambs (percentage of time spent near their own dam/lamb). However, there were effects of sex, litter size and time on lambs’ responses to separation and reunion and on the ewe–lamb bond. Female lambs vocalised more during separation ( P ≤ 0.01) and left the holding pen faster than males ( P ≤ 0.05), and twins vocalised more than singletons ( P ≤ 0.05). The time to leave the holding pen, achieve proximity with the ewes and number of vocalisations decreased with increasing postnatal age of the lamb (all P ≤ 0.001). Ewes showed a stronger preference for the lamb at 24 h and 1 week than at 4 weeks postpartum ( P ≤ 0.001), whereas lambs followed an opposite trend, showing a lower preference for the mother at 24 h and 1 week and increased preference at 4 weeks of age ( P ≤ 0.001). We conclude that periconceptional undernutrition does not affect offspring response to separation from the mother or the bond between ewes and lambs, but that these behaviours are affected by sex and litter size for up to 4 weeks after birth.

Periconceptional Undernutrition of Ewes Impairs Glucose Tolerance in Their Adult Offspring

Maternal undernutrition throughout pregnancy can have long-term effects on the health of adult offspring. Undernutrition around the time of conception alters growth, metabolism, and endocrinology of the sheep fetus, but the impact on offspring after birth is largely unknown. We determined the effect of maternal periconceptional undernutrition in sheep on glucose tolerance in the offspring before and after puberty. Undernourished (UN) ewes were fed individually to maintain weight loss of 10-15% bodyweight from 61 d before until 30 d after mating. Offspring (24 UN, 30 control) underwent an i.v. glucose tolerance test at 4 and 10 mo of age. Glucose tolerance was similar in both groups at 4 mo. Insulin area under the curve increased by 33% between 4 and 10 mo (101 +/- 8 versus 154 +/- 12 ng x min x mL(-1), p < 0.0001). At 10 mo, UN offspring had a 10% greater glucose area under the curve than controls (809 +/- 22 versus 712 +/- 20 mM x min, p < 0.01), a reduced first phase insulin response (p = 0.003) which was particularly apparent in females and in singletons, and a decreased insulin:glucose ratio (p = 0.01). We conclude that maternal undernutrition around the time of conception results in impaired glucose tolerance in postpubertal offspring.

P2-134 Regulation of postnatal growth is altered by maternal periconceptional undernutrition

P2-134 Regulation of postnatal growth is altered by maternal periconceptional undernutrition

P2-54 Effect of maternal periconceptional undernutrition and twinning on placental 11β-hydroxysteroid dehydrogenase (HSD)-1 and -2 activity across gestation

P2-54 Effect of maternal periconceptional undernutrition and twinning on placental 11β-hydroxysteroid dehydrogenase (HSD)-1 and -2 activity across gestation

Periconceptional undernutrition in sheep accelerates maturation of the fetal hypothalamic-pituitary-adrenal axis in late gestation.

We investigated the effects of moderate maternal periconceptional undernutrition from 60 d before to 30 d after mating on fetal hypothalamic-pituitary-adrenal axis function in late gestation. Ewes were sampled regularly during the period of undernutrition for circulating hormone levels. Vascular catheters were inserted into ewes and their singleton fetuses at 112 d gestation (term, 145 d), and fetal ACTH(1-24) and metyrapone challenge tests were performed at 127 and 128 d. Postmortems were performed at 132 d. Fetuses of undernourished ewes (UN, n = 12) had elevated baseline cortisol concentrations (P < 0.05), compared with fetuses of ad libitum-fed ewes (n = 10). There were no differences between groups in fetal responses to ACTH challenge, but only UN fetuses demonstrated ACTH and 11-deoxycortisol responses to metyrapone (P < 0.05). UN fetuses had increased mRNA levels for proopiomelanocortin and prohormone convertase-1, but not -2, in the pars intermedia of the pituitary gland (P < 0.05). Glucocorticoid receptor mRNA levels were not different between groups in pituitary or hypothalamus. Maternal cortisol and ACTH levels during undernutrition were profoundly suppressed (P < 0.001), rather than elevated, in UN ewes. Furthermore, the normal pregnancy rise in maternal serum progesterone concentrations was delayed in undernourished mothers. These data demonstrate that events around the time of conception have profound effects on fetal hypothalamic-pituitary-adrenal development in late gestation and that factors other than fetal exposure to excess glucocorticoids may be important.