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Blood flows and nutrient uptakes in growth-restricted pregnancies induced by overnourishing adolescent sheep
Abstract
To establish physiological mechanisms for fetal growth restriction in pregnant adolescent ewes we studied uterine, fetal, and uteroplacental metabolism in ewes offered a high (n = 12) or moderate (n = 10) dietary intake. High intakes decreased placental (226 vs. 414 g, P < 0.001) and fetal weight (3,323 vs. 4,626 g, P < 0.01). Uterine blood flow was reduced absolutely (-36%) but proportional to conceptus weight; umbilical blood flow was reduced absolutely (-37%) and per fetal weight (-15%). Uterine oxygen uptake was decreased per conceptus weight (-14%); there was no change in fetal weight oxygen consumption. Uteroplacental oxygen consumption and clearance were reduced proportional to weight. Similar changes were measured for glucose fluxes and fetal glucose concentration; fetal insulin concentration was reduced. In this model of fetal growth restriction, therefore, maintenance of fetal weight-specific glucose and oxygen consumption rates are producing relative hypoglycemia and hypoxemia. This indicates that increased fetal glucose clearance and/or insulin sensitivity may be operating as compensatory mechanisms to preserve normal fetal metabolism while fetal growth is sacrificed.
... Substantial research has been carried out to determine the effects of feeding level or liveweight change of the dam in late pregnancy on birth weight of the calf and the incidence of dystocia (Laster, 1974;Wiltbank & Remmenga, 1982;Spitzer et al., 1995); however, little is known about the effect of nutrition in early pregnancy on foetal and placental development in cattle. In adolescent ewes, over-nourishment during pregnancy was associated with decreased foetal and placental weight at days 95 and 128 of gestation (Wallace et al., 1996;Wallace et al., 2002). ...
... The greater foetal weight of the low group in the absence of an increase in cotyledon or caruncle weight indicated that more nutrients were being transferred from the dam to the foetus per gram of placentome tissue in these heifers. This was consistent with the results of Wallace et al. (2002) who reported that overnourished hoggets displayed reduced uterine blood flow, which restricted nutrient availability to the foetus. Rapidly growing adolescent dams may maintain an established anabolic drive to maternal tissue synthesis at the expense of the gradually evolving nutrient requirements of the gravid uterus (Wallace et al., 1996). ...
... In conclusion, a moderate rate compared with a low rate of maternal liveweight gain from 21 days prior to conception and for the first trimester of pregnancy tended to result in decreased foetal weight and resulted in decreased weight of foetal membranes in 15-month-old beef heifers. This difference occurred in the absence of any differences in the weight of cotyledons and may be explained by the finding of Wallace et al. (2002), that over-nourishment of adolescent dams led to decreased uterine blood flow. Additional studies are required to determine whether an accelerated rate of maternal liveweight gain in early pregnancy offers a practical tool to minimise the incidence of dystocia in 2-year-old beef heifers. ...
Dystocia in 2-year-old beef heifers is a major factor limiting the willingness of farmers to breed 15-month-old heifers in New Zealand. Foetal oversize relative to the size of the heifer is a contributor to dystocia. This study aimed to determine the effect on foetal weight of maternal liveweight change during joining and early pregnancy. Sixteen 15-month-old Angus heifers were allocated to moderate (444 textpm 30 g/day) or low (109 textpm 28 g/day) liveweight-gain treatments for 21 days prior to and 91 days after insemination. Gravid uteri were recovered on day 91 of pregnancy. Foetuses from the low-fed heifers tended to be heavier than foetuses from the moderate-fed heifers (215.6 textpm 6.7 g and 198.4 textpm 6.8 g, respectively; P=0.09). Foetal weight per 100 kg maternal weight was greater (P<0.01) in foetuses from the low treatment (58.9 textpm 2.5 g/100 kg) than in foetuses from the moderate treatment (47.4 textpm 2.6 g/100 kg). Weight of foetal membranes was greater (P<0.05) in the low treatment (262 textpm 16 g) than the moderate treatment (213 textpm 16 g). Foetal weight was correlated with cotyledon weight (r=0.59; P<0.05). Moderate compared with low maternal liveweight gain reduced foetal weight relative to maternal live weight.
... Age of dams at gestation has been suggested to influence the nutritional enviro of the embryo and fetal growth in several species [5,6]. A retrospective cohort st approximately four million nulliparous pregnant women <25 years of age show young maternal age is associated with increased risk of low birth weight babie pendently of socioeconomic status, prenatal care and weight gain during pregnan Studies in sheep have shown that juvenile ewes reduce nutrient delivery to their fe in fact shuttle nutrients towards their own body growth [20,21]. In addition, Kam [22] suggested that the intrauterine environment could limit fetal growth due to n partition in growing ewes. ...
... A retrospective cohort study of approximately four million nulliparous pregnant women <25 years of age showed that young maternal age is associated with increased risk of low birth weight babies independently of socioeconomic status, prenatal care and weight gain during pregnancy [19]. Studies in sheep have shown that juvenile ewes reduce nutrient delivery to their fetus and in fact shuttle nutrients towards their own body growth [20,21]. In addition, Kamal et al. [22] suggested that the intrauterine environment could limit fetal growth due to nutrient partition in growing ewes. ...
... In this sense, the overfeeding of young ewes is associated with a reduction in the development of the placenta, the uterus and the umbilical blood flow. (Wallace et al., 2002), that directly impact the supply of glucose, oxygen, and amino acids, leading to a decrease in fetal growth (Wallace et al., 2003(Wallace et al., , 2002. The liver was the organ most affected by maternal nutrition, as weight changes are observed not only during pregnancy but at birth and the postnatal period. ...
... In this sense, the overfeeding of young ewes is associated with a reduction in the development of the placenta, the uterus and the umbilical blood flow. (Wallace et al., 2002), that directly impact the supply of glucose, oxygen, and amino acids, leading to a decrease in fetal growth (Wallace et al., 2003(Wallace et al., , 2002. The liver was the organ most affected by maternal nutrition, as weight changes are observed not only during pregnancy but at birth and the postnatal period. ...
The present systematic review and meta-analysis aim to summarize the effects of maternal undernutrition or overnutrition during pregnancy on the absolute weight and relative weight of the organs (liver, kidneys, heart, spleen, and lung) and glands (adrenal, pancreas, and thyroid) measured during gestation, birth and the postnatal period in lambs. After completing the search, selection, and data extraction steps, the measure of effect was generated by the individual comparison of each variable response compared with the average of the control and treated group (undernutrition or overnutrition) using the DerSimonian and Laird method for random effects. The liver was the organ most affected by maternal undernutrition, as the absolute weight of the liver was reduced during pregnancy, birth, and the postnatal period. The extent of this effect is related to the duration of the intervention. Reductions in the absolute fetal weight of the lungs and spleen have also been observed. No change in organs weight were observed when the results were expressed as relative weight. For overnutrition, the fetal weight of the liver was reduced to both absolute and relative values. In contrast, the relative weight of the kidneys has been increased. For the glands analyzed, no changes in weight were observed in either scenario (absolute or relative weight). Thus, the organs are more likely to suffer weight changes, especially during pregnancy, as a result of maternal nutrition. However, this change in organ weight seems to be closely related to the reduction in body weight of the progeny as a whole.
... Age of dams at gestation has been suggested to influence the nutritional enviro of the embryo and fetal growth in several species [5,6]. A retrospective cohort st approximately four million nulliparous pregnant women <25 years of age show young maternal age is associated with increased risk of low birth weight babie pendently of socioeconomic status, prenatal care and weight gain during pregnan Studies in sheep have shown that juvenile ewes reduce nutrient delivery to their fe in fact shuttle nutrients towards their own body growth [20,21]. In addition, Kam [22] suggested that the intrauterine environment could limit fetal growth due to n partition in growing ewes. ...
... A retrospective cohort study of approximately four million nulliparous pregnant women <25 years of age showed that young maternal age is associated with increased risk of low birth weight babies independently of socioeconomic status, prenatal care and weight gain during pregnancy [19]. Studies in sheep have shown that juvenile ewes reduce nutrient delivery to their fetus and in fact shuttle nutrients towards their own body growth [20,21]. In addition, Kamal et al. [22] suggested that the intrauterine environment could limit fetal growth due to nutrient partition in growing ewes. ...
This study aimed to determine the effects of age at first gestation on offspring growth performance, glucose metabolism, and IGF1 concentration. Heifers impregnated by AI from a single bull at 15 months of age (15 M, n = 20), or 27 months of age (27 M, n = 20), and multiparous cows (adult, n = 20) were used. Dams from all groups were managed in a single group during gestation and lactation. Gestational length was longer in the 15 M and 27 M than in adult dams (p = 0.009). Bodyweight at birth, at weaning and ADG during lactation were higher in calves from adult dams than in those from 27 M dams, and higher in calves from the latter than in 15 M calves (p < 0.001). Calves from 15 M dams had an increased head circumference/BW ratio compared to calves from 27 M dams, while calves from this latter group had an increased ratio compared to calves from adults (p = 0.005). Body mass index was greater in calves from adults than in those from 15 M and 27 M dams (p = 0.002). Milk production from 15 M and 27 M dams was similar but lower than that from adults (p = 0.03). Calves born from adult dams had greater blood glucose concentrations than those from 15 M and 27 M dams (p < 0.05). Serum IGF1 concentrations were higher in calves from adults than in calves from 15 M and 27 M dams (p = 0.01). This study showed that age at first gestation affects offspring postnatal growth performance, glucose metabolism and IGF1 concentration.
... Also, maternal overfeeding of young sheep is associated with reduced placental development and uterine and umbilical blood flow (Wallace et al., 2002), directly impacting the uptake of glucose, oxygen, and amino acids, causing a decrease in fetal growth in the final third of pregnancy (Wallace et al., 2002(Wallace et al., , 2003. The overnutrition of primiparous ewes causes premature births of lambs with low birth weight (Wallace et al., , 2018. ...
... Also, maternal overfeeding of young sheep is associated with reduced placental development and uterine and umbilical blood flow (Wallace et al., 2002), directly impacting the uptake of glucose, oxygen, and amino acids, causing a decrease in fetal growth in the final third of pregnancy (Wallace et al., 2002(Wallace et al., , 2003. The overnutrition of primiparous ewes causes premature births of lambs with low birth weight (Wallace et al., , 2018. ...
This systematic review and meta-analysis aim to summarize the effects of maternal under or overnutrition during pregnancy on fetal weight and morphometric measurements during pregnancy, at birth and postnatal period in sheep. After completing the search, selection and data extraction steps, the measure of effect was generated by the individual comparison of each indicator with the average of the control and treated group (undernutrition or overnutrition) using the DerSimonian and Laird method for random effects. Subgroup analyses were also performed for lambing order, litter size, sex, as well as level, timing and duration of the intervention. Fetal weight during the first third of pregnancy was not affected by maternal under or overnutrition. On the other hand, undernutrition in the second and last third of gestation reduces the weight of the lamb both during pregnancy, at birth and during the postnatal period, requiring at least 120 postnatal days to achieve the same weight as its contemporaries in the control treatment. However, this reduction in weight is not accompanied by reductions in morphometric measurements, demonstrating that the animals were lighter, but of equal size. In overnutrition, there is an increase in fetal weight in the second third of gestation. However, in the last third of the gestational period, there are no differences in fetal weight for the multiparous subgroup, but it was reduced in primiparous ewes. There are no effects of overnutrition on birth weight, however, this result is highly heterogeneous. Thus, maternal nutrition of ewe during pregnancy has effects on fetal and postnatal weight, but not on size. Furthermore, the effects of undernutrition are more homogeneous while overnutrition showed heterogeneous responses.
... Insulin secretion reduction may be associated with reduced transport of nutrients coming from maternal circulation to the developing fetus. When placental and uterine blood flow was reduced in overfed pregnant ewes, a concomitant decrease in fetal insulin concentration was observed [23]. Reduced insulin could also be relative to the younger dams ( 4 yr) used in the present study. ...
... In observations by Bellows and Short [24], calves experienced decreased birth weight more consistently from heifers that were more responsive to nutrient restriction during the last third of gestation than cows. Overall, mature females have been reported to tolerate nutrient restriction better than immature females [23,24]. ...
Research on the effects of nutrient restriction in beef cows on fetal pancreatic development is limited. To address this, multiparous Angus-cross cows (n = 22) were fed either control (CON; to gain 1 kg/wk) or nutrient-restricted (NR; 0.55% NEm) diets based on NRC requirements. On d 30 of gestation, cows were blocked by body condition and randomly assigned to one of three nutritional regimes: CON fed from d 30 to 190 (n = 8), or NR/C (n = 7) or C/NR (n = 7) fed either the CON or NR diet from d 30 to 110 followed by CON or NR from d 110 to 190 of gestation. Cows were harvested on d 190 of gestation, and blood samples, fetal weights, and fetal tissue weights and samples were collected. Pancreas samples were embedded in paraffin and sectioned for standard immunohistochemistry procedures to quantify insulin-positive β cells and number of apoptotic β cells using TUNEL staining. Data were analyzed via ANOVA using the general linear model procedure of SAS. At harvest, empty carcass weights were decreased (P = 0.036) in fetuses of C/NR and NR/C fed dams compared to fetuses of CON fed dams. Pancreas weight was decreased (P = 0.028) in fetuses of C/NR fed dams compared to CON fetuses; however, fetuses of NR/C fed dams were not different (P > 0.05) from fetuses of CON fed dams. Maternal and fetal serum insulin concentrations were not different (P > 0.05) in NR/C fed compared to CON fed; however, concentrations of insulin were decreased (P = 0.036 and P = 0.40, respectively) in C/NR fed compared to CON fed. Beta cell number was decreased (P = 0.009) in fetuses of NR/C and C/NR fed dams compared to fetuses of CON fed dams. Percentage of apoptotic cells was increased (P < 0.0001) in fetuses of NR/C and C/NR fetuses than fetuses of CON fed dams. This evidence suggests that nutrient restriction either during early- or mid-gestation can negatively impact fetal pancreatic development. However, mid-gestational nutritional insult is potentially recovered by reacclimation to a diet that meets requirements of the dam, thus reducing negative outcomes in fetal offspring.
... to midgestation, and complete by day 90 [39]. Increased PF4 may have a role in altered angiogenesis and vascularization during this timeframe, potentially having negative consequences on the formation and transport capacity of blood to and across the placenta to affect fetal development [40,41]. Previous models of maternal overnutrition have associated reduced uterine and umbilical blood flow in ewes with reduced fetal nutrient delivery [40][41][42]. ...
... Increased PF4 may have a role in altered angiogenesis and vascularization during this timeframe, potentially having negative consequences on the formation and transport capacity of blood to and across the placenta to affect fetal development [40,41]. Previous models of maternal overnutrition have associated reduced uterine and umbilical blood flow in ewes with reduced fetal nutrient delivery [40][41][42]. Additionally, in ewes who were nutrient restricted during the first 40% of gestation, placental vasoconstriction contributed to fetal intrauterine growth restriction [42]. ...
Inflammation may be a mechanism of maternal programming because it has the capacity to alter the maternal environment and can persist postnatally in offspring tissues. This study evaluated the effects of restricted- and over-feeding on maternal and offspring inflammatory gene expression using RT-PCR arrays. Pregnant ewes were fed 60% (Restricted), 100% (Control) or 140% (Over) of NRC requirements beginning on day 30.2 ± 0.2 of gestation. Maternal (n = 8 to 9 ewes per diet) circulating NEFA and expression of 84 inflammatory genes were evaluated at five stages during gestation. Offspring (n = 6 per diet per age) inflammatory gene expression was evaluated in the circulation and liver at day 135 of gestation and birth. Throughout gestation, circulating NEFA increased in Restricted mothers but not Over. Expression of different pro-inflammatory mediators increased in Over and Restricted mothers, but was diet dependent. Maternal diet altered offspring systemic and hepatic expression of genes involved in chemotaxis at late gestation and cytokine production at birth, but the offspring response was distinct from the maternal. In the perinatal offspring, maternal nutrient restriction increased hepatic chemokine (CC motif) ligand 16 and tumor necrosis factor expression. Alternately, maternal over-nutrition increased offspring systemic expression of factors induced by hypoxia, whereas expression of factors regulating hepatocyte proliferation and differentiation were altered in the liver. Maternal nutrient restriction and over-nutrition may differentially predispose offspring to liver dysfunction through an altered hepatic inflammatory microenvironment that contributes to immune and metabolic disturbances postnatally.
... Almost all of the nitrogen acquired by the foetus is in the form of amino acids, but a small net umbilical uptake of ammonia is derived from placental deamination of amino acids during the latter half of gestation (Holzman et al. 1977;Bell et al. 1989). About 60% of these amino acids are used for tissue protein synthesis, which accounts for ~18% of foetal energy expenditure hypoxaemia and hypoglycaemia during late gestation (Creasy et al. 1972;Harding et al. 1985;Bell et al. 1987b;Wallace et al. 2002). A detailed assessment of influences on placental transport of nutrients is beyond the scope of this review, but is provided in Bell et al. (2003). ...
... Placental insufficiency during late gestation is generally characterized by foetal hypoxaemia and hypoglycaemia, whether caused by surgical reduction (carunclectomy; Harding et al. 1985), placental embolisation (Creasy et al. 1972), maternal heat stress (Bell et al. 1987b), or overfeeding of adolescent ewes (Wallace et al. 2002). Associated endocrine changes include decreased foetal plasma concentrations of insulin ) and IGF1 and 2 (Owens et al. 1994), and increased concentrations of cortisol (Phillips et al. 1996). ...
... to midgestation, and complete by day 90 [39]. Increased PF4 may have a role in altered angiogenesis and vascularization during this timeframe, potentially having negative consequences on the formation and transport capacity of blood to and across the placenta to affect fetal development [40,41]. Previous models of maternal overnutrition have associated reduced uterine and umbilical blood flow in ewes with reduced fetal nutrient delivery [40][41][42]. ...
... Increased PF4 may have a role in altered angiogenesis and vascularization during this timeframe, potentially having negative consequences on the formation and transport capacity of blood to and across the placenta to affect fetal development [40,41]. Previous models of maternal overnutrition have associated reduced uterine and umbilical blood flow in ewes with reduced fetal nutrient delivery [40][41][42]. Additionally, in ewes who were nutrient restricted during the first 40% of gestation, placental vasoconstriction contributed to fetal intrauterine growth restriction [42]. ...
... Several animal models of fetal and placental growth restriction have been developed to better unravel the relationships between uteroplacental blood flow, placental vascularity, and nutrient delivery to the fetus (Thureen et al., 1992;Wallace et al., 2002;Regnault et al., 2003;Kwon et al., 2004;Reynolds et al., 2005;Lemley et al., 2012). In sheep, increasing uterine blood flow during the second half of gestation is vital for maintaining the delivery of sufficient oxygen and nutrients to the exponentially growing fetus (Meschia, 1983;Ford, 1995;Redmer et al., 2004;Reynolds et al., 2005Reynolds et al., , 2006Lemley et al., 2012). ...
Previous research demonstrated that maternal nutrient restriction during mid- to late-gestation influenced net umbilical uptakes of glucose and amino acids in sheep. However, it is unclear how the timing and duration of nutrient restriction during mid- to late-gestation influences net uterine, uteroplacental, and fetal flux of glucose and amino acids. On day 50 of gestation, 41 adolescent ewe lambs carrying singletons were randomly assigned to one of six dietary treatments: 1) 100% of nutrient requirements from day 50 to day 90 of gestation (CON; n=7); 2) 60% of nutrient requirements (RES; n=7) from day 50 to day 90 of gestation; 3) 100% of nutrient requirements from day 50 to day 130 of gestation (CON-CON; n=6); 4) 100% of nutrient requirements from day 50 to day 90 of gestation and 60% of nutrient requirements from day 90 to day 130 of gestation (CON-RES; n=7); 5) 60% of nutrient requirements from day 50 to day 90 of gestation and 100% of nutrient requirements from day 90 to day 130 of gestation (RES-CON; n=7); or 6) 60% of nutrient requirements from day 50 to day 130 of gestation (RES-RES; n=7). On day 90 (n=14) and day 130 (n=27), intraoperative procedures were performed to evaluate uteroplacental blood flows, collect blood samples, and then ewes were euthanized. Net uterine, uteroplacental, and umbilical fluxes of glucose and amino acids were calculated by multiplying blood flow by the arterial-venous concentration difference. Data from day 90 and day 130 were analyzed separately using ANOVA in SAS. Maternal nutrient restriction during mid-gestation increased (P = 0.04) net umbilical glucose uptake but, maternal nutrient restriction during late-gestation decreased (P = 0.02) net umbilical glucose uptake. Net umbilical essential amino acid uptake decreased (P = 0.03) with nutrient restriction during mid-gestation; however, net umbilical uptakes of Phe (P = 0.02), Thr (P = 0.05), Met (P = 0.09), and His (P = 0.08) increased or tended to increase after nutrient restriction during late-gestation. These data demonstrate that net umbilical glucose and amino acid uptakes was influenced by the timing of nutrient restriction during mid- to late-gestation. Elevated net umbilical glucose uptake after mid-gestational nutrient restriction was sustained throughout late-gestation, independent of late-gestational feeding level. Long-term adaptations in umbilical glucose uptake may have implications for prenatal and postnatal growth and development of the offspring.
... As a consequence, placental development during pregnancy is significantly influenced by nutrition. Additionally, heat stress lowers blood levels of pregnancy-specific protein B (Thompson et al., 2013), and placental hormones (Collier et al., 1982) and reduces the exchange of amino acids, glucose, and oxygen between the cow and the fetus (Wallace et al., 2002;de Vrijer et al., 2004) indicating a dysfunction and delay in placental development and as a result affect the embryo development (Ouellet et al., 2021). Multiple factors caused by heat stress, such as altered blood flow, reduced nutrient intake, and alterations in placental structure and function, can lead to a restricted intrauterine environment for fetal nutrition and thermal regulation (Ji et al., 2017). ...
Heat stress becomes a serious problem in the livestock sector as it affects cows' performance negatively. The objective of this paper review is to investigate the effects of heat stress during the different phases of the life cycle of cows; embryos, calves, heifers, and cows. Heat stress during early maternal gestation affects the ability of embryos to develop increasing the risk of abortion and early embryonic death. Heat stress during late maternal gestation affects the performance of calves and heifers later in their life, as it reduces growth performance, conducts physiological changes, impaired immunity, changes the behavior, and reduces the length and intensity of the estrus in heifers with decreasing in milk production in the first lactation. On the level of cows, milk quality and production, meat quality, and the final body weight decrease under hot temperatures. Heat stress decreases the conception rate, alters follicle growth, and estrous symptoms. Hormones secretion and physiological changes because of the heat stress conduct to impair the immunity system, and in oxidative stress and death in some cases. Same as for calves and heifers a change in the behavior of cows was detected in order to decrease their temperature.
... Although studies have not shown increases in pregnancy losses in obese ewes, there is evidence that pregnancies may be compromised in obese ewes. Specifically, there is a reduction in placental vascularization and impaired uteroplacental blood flow at mid and late gestation in obese ewes (Wallace et al., 2002(Wallace et al., , 2008Redmer et al., 2009). However, a clear understanding of the direct effects of obesity on ovine endometrial function early in gestation is lacking. ...
Exposure to maternal obesity in utero is associated with marked developmental effects in offspring that may not be evident until adulthood. Mechanisms regulating the programming effects of maternal obesity on fetal development have been reported, but little is known about how maternal obesity affects the earliest periods of embryonic development. This work explored how obesity influences endometrial gene expression during the peri-implantation period using a sheep model. Ewes were assigned randomly to diets that produced an obese state or maintained a lean state. After 4 mo, obese and lean ewes were bred and then euthanized at day 14 post-breeding. The uterus was excised, conceptuses were flushed, and endometrial tissue was collected. Isolated RNA from endometrial tissues (n = 6 ewes/treatment) were sequenced using an Illumina-based platform. Reads were mapped to the Ovis aries genome (Oar_4.0). Differential gene expression was determined, and results were filtered (false discovery rate ≤ 0.05 and ≥2-fold change, ≥0.2 reads/kilobase/million reads). Differentially expressed genes (DEGs) were identified (n = 699), with 171 downregulated and 498 upregulated in obese vs. lean endometrium, respectively. The most pronounced gene ontology categories identified were cellular process, metabolic process, and biological regulation. Enrichments were detected within the DEGs for genes involved with immune system processes, negative regulation of apoptosis, cell growth, and cell adhesion. A literature search revealed that 125 DEGs were associated with either the trophoblast lineage or the placenta. Genes within this grouping were involved with wingless/integrated signaling, angiogenesis, and integrin signaling. In summary, these data indicate that the peri-implantation endometrium is responsive to maternal obesity. Transcript profile analyses suggest that the endometrial immune response, adhesion, and angiogenesis may be especially susceptible to obesity. Thus, alterations in uterine transcript profiles during early embryogenesis may be a mechanism responsible for developmental programming following maternal obesity exposure in utero.
... To generate this model, embryos derived from mature ewes are transferred into adolescent ewes immediately following puberty, then the pregnant ewes are fed at 200% of their daily requirements (Carr et al., 2012). If this approach is maintained over the duration of pregnancy, and those pregnancies are studied under steady-state conditions, both uterine and umbilical blood flows are reduced, as well as umbilical oxygen and glucose uptakes (Wallace et al., 2002). While this maternal overnutrition model might initially show commonalities with maternal hyperthermia in terms of blood flow and nutrient uptake reductions, subtler critical distinctions exist which can be further elucidated by manipulating glucose concentrations in those pregnancies. ...
The placenta facilitates the transport of nutrients to the fetus, removal of waste products from the fetus, immune protection of the fetus and functions as an endocrine organ, thereby determining the environment for fetal growth and development. Additionally, the placenta is a highly metabolic organ in itself, utilizing a majority of the oxygen and glucose derived from maternal circulation. Consequently, optimal placental function is required for the offspring to reach its genetic potential in utero. Among ruminants, pregnant sheep have been used extensively for investigating pregnancy physiology, in part due to the ability to place indwelling catheters within both maternal and fetal vessels, allowing for steady-state investigation of blood flow, nutrient uptakes and utilization, and hormone secretion, under non-stressed and non-anesthetized conditions. This methodology has been applied to both normal and compromised pregnancies. As such, our understanding of the in vivo physiology of pregnancy in sheep is unrivalled by any other species. However, until recently, a significant deficit existed in determining the specific function or significance of individual genes expressed by the placenta in ruminants. To that end, we developed and have been using in vivo RNA interference (RNAi) within the sheep placenta to examine the function and relative importance of genes involved in conceptus development (PRR15 and LIN28), placental nutrient transport (SLC2A1 and SLC2A3), and placenta-derived hormones (CSH). A lentiviral vector is used to generate virus that is stably integrated into the infected cell’s genome, thereby expressing a short-hairpin RNA (shRNA), that when processed within the cell, combines with the RNA Induced Silencing Complex (RISC) resulting in specific mRNA degradation or translational blockage. To accomplish in vivo RNAi, day 9 hatched and fully expanded blastocysts are infected with the lentivirus for 4 to 5 h, and then surgically transferred to synchronized recipient uteri. Only the trophectoderm cells are infected by the replication deficient virus, leaving the inner cell mass unaltered, and we often obtain ~70% pregnancy rates following transfer of a single blastocyst. In vivo RNAi coupled with steady-state study of blood flow and nutrient uptake, transfer and utilization can now provide new insight into the physiological consequences of modifying the translation of specific genes expressed within the ruminant placenta.
... Relative to optimally nourished control adolescents of equivalent age, those who are overnourished exhibit high gestational weight gains and fat accrual at the expense of the conceptus. Placental development and the fetal nutrient supply chain are compromised and premature delivery of low birthweight lambs ensues [17][18][19][20]. Furthermore, colostrum supply immediately after parturition is attenuated and together these unfavourable pregnancy outcomes form a perfect storm for increased lamb morbidity and mortality. ...
The competition for nutrients in overnourished and still-growing adolescent sheep negatively impacts gestation length, colostrum supply and lamb birthweight, all of which may affect neonatal morbidity and survival to weaning. Herein perinatal complications and the requirement for supplementary feeding were analysed in relation to gestational-intake, and the degree of premature delivery and prenatal growth-restriction exhibited. Pregnancies were established by embryo transfer and the mean/standard deviation (SD) gestation length and birthweight of the optimally-fed control group (n = 100) was used to define early delivery and reduced birthweight categories (1.5 and 3.0 SDs below the control mean for each aspect). Control lambs were largely delivered at term (94%), and had a normal birthweight (92%), while very preterm (≤139days, 18.5%) and preterm delivery (140-142days, 54.8%), extremely low birthweight (ELBW; females ≤2838g and males ≤3216g, 21.1%) and low birthweight (LBW; females 2839 to ≤4001g and males 3217 to ≤4372g, 32.2%), were common in the overnourished group (n = 270, P
... For young maternal age, previous studies have only focused on the associations of young maternal age with placental weight and showed conflicting findings [24,25]. In a study among 31 adolescent pregnancies, young maternal age had no effect on placental weight, morphometry or cell turnover [25]. ...
Objective
To examine the associations of maternal age at the start of pregnancy across the full range with second and third trimester uterine and umbilical artery flow indices, and placental weight.
Study design
In a population-based prospective cohort study among 8271 pregnant women, we measured second and third trimester uterine artery resistance and umbilical artery pulsatility indices and the presence of third trimester uterine artery notching using Doppler ultrasound.
Results
Compared to women aged 25−29.9 years, higher maternal age was associated with a higher third trimester uterine artery resistance index (difference for women 30−34.9 years was 0.10 SD (95% Confidence Interval (CI) 0.02 to 0.17), and for women aged ≥40 years 0.33 SD (95% CI 0.08 to 0.57), overall linear trend 0.02 SD (95% CI 0.01 to 0.03) per year). Compared to women aged 25−29.9 years, women younger than 20 years had an increased risk of third trimester uterine artery notching (Odds Ratio (OR) 1.97 (95% CI 1.30–3.00)). A linear trend was present with a decrease in risk of third trimester uterine artery notching per year increase in maternal age (OR 0.96 (95% CI 0.94 to 0.98)). Maternal age was not consistently associated with umbilical artery pulsatility indices or placental weight.
Conclusions
Young maternal age is associated with higher risk of third trimester uterine artery notching, whereas advanced maternal age is associated with a higher third trimester uterine artery resistance index, which may predispose to an increased risk of pregnancy complications.
... Color Doppler evaluations have thus focused to evaluate uterine blood flow throughout gestation in cows (Bollwein et al., 2002;Pancarce et al., 2006) and to a limited extent in buffaloes (Singh et al., 2018a) [34] . The uterine blood flow is altered in compromised sheep (Wallace et al., 2002;Redmer et al., 2005;Reynolds et al., 2006) [33] and bovine (Camacho et al., 2014) [8] pregnancies. Several environmental factors have been shown to negatively impact placenta development and blood flow during the pregnancy, all of which can hinder offspring health and vigor (Lemley, 2017) [25] . ...
With an objective to record the vascularity changes in the umbilicus, placentomes dimensions, and blood flow to the uterus, Surti buffaloes (n=42) were inseminated during natural estrus during the breeding season and scanned by transrectal B mode and color flow mode ultrasonography every 3-4 days till Day 90 of gestation and then at 15 days interval for the complete gestation in the buffaloes that were pregnant (n=24). The umbilical cord color Doppler wavefronts could first be obtained on Day 46 and became increasingly distinct thereafter. The placentomes could first be identified at Day 76 of gestation. The placentome diameters increased from Day 76 till 8 th month with significant increases (P<0.05) during Day 80, then 4 th , 5 th and 6 th month of gestation; thereafter the increase was not significant. The vascularity of placentomes could also be recognized at Day 76 and this increased with increasing months of gestation. The blood flow to the middle uterine arteries could be identified after the 2 nd month of gestation. The resistive index (RI) values of the middle uterine artery ipsilateral to the gravid horn showed an almost linear decline with a significant (P<0.05) drop in the 4 th month and 9 th month of the gestation. Similarly, RI values of the middle uterine artery contra-lateral to the gravid horn revealed significant (P<0.05) decrease in 3 rd month, 5 th month and sixth month. A significant decrease in the pulsatility index (PI) values of the middle uterine artery ipsilateral to the gravid horn were observed for the 3 rd , 6 th and 8 th month of the gestation. However, the PI index values for the middle uterine artery contralateral to the gravid horn showed a non-significant decrease. It was concluded that the placentome dimensions can be used to diagnose the stage of gestation up to 8 months in buffaloes. The umbilical and uterine blood flow evaluation parameters during normal pregnancy increase sequentially and can serve as the basis for evaluating compromised pregnancies.
... However, these studies did not differentiate fetuses by sex. Further the brain : liver ratio in this study was higher in LPost male fetuses, providing additional evidence of brain sparing as noted in IUGR models in sheep (Wallace et al. 2002;Field et al. 2015). Together, the observed differences in fetal measures and indices of growth suggest protein restriction resulted in both sex-specific IUGR and asymmetric development in the fetuses by 98 dpc. ...
Few studies have investigated the effects of nutrition during the periconception and early gestation periods on fetal and placental development in cattle. In this study, nulliparous yearling heifers (n=360) were individually fed a diet high or low in protein (HPeri and LPeri) beginning 60 days before conception. From 24 to 98 days after conception, half of each treatment group was changed to the alternative high- or low-protein diet (HPost and LPost) yielding four groups in a 2×2 factorial design. A subset of heifers (n=46) was necropsied at 98 days after conception and fetoplacental development assessed. Placentome number and volume decreased in response to LPeri and LPost diets respectively. Absolute lung, pancreas, septum and ventricle weights decreased in LPost versus HPost fetuses, whereas the post-conception diet altered absolute and relative liver and brain weights depending on sex. Similarly, changes in fetal hepatic gene expression of factors regulating growth, glucose output and lipid metabolism were induced by protein restriction in a sex-specific manner. At term, neonatal calf and placental measures were not different. Protein restriction of heifers during the periconception and early gestation periods alters fetoplacental development and hepatic gene expression. These changes may contribute to functional consequences for progeny, but this may not be apparent from gross morphometry at birth.
... Color Doppler evaluations have thus focused to evaluate uterine blood flow throughout gestation in cows (Bollwein et al., 2002;Pancarce et al., 2006) and to a limited extent in buffaloes (Singh et al., 2018a) [34] . The uterine blood flow is altered in compromised sheep (Wallace et al., 2002;Redmer et al., 2005;Reynolds et al., 2006) [33] and bovine (Camacho et al., 2014) [8] pregnancies. Several environmental factors have been shown to negatively impact placenta development and blood flow during the pregnancy, all of which can hinder offspring health and vigor (Lemley, 2017) [25] . ...
With an objective to record the appearance, vascularity changes in umbilicus, placentomes, and blood flow to the uterus, adult (age 5-10 yr) Surti buffalo (parity=2-6; n=24) were inseminated during natural oestrus during the breeding season and scanned by transrectal B mode and colour flow mode ultrasonography every 3-4 days till Day 90 of gestation and then at an interval of 15 days for the complete gestation. The umbilical cord was first visible on Day 38; however, colour Doppler wave fronts could first be obtained on Day 46, which became increasingly distinct thereafter. The placentomes could first be identified at Day 76 of gestation. The placentome diameters increased from Day 76 until the month 7 with significant increases (P<0.05) during Day 80, and months 4, 5, and 6 of gestation; thereafter, the increase was not significant. The vascularity of placentomes could also be recognised at Day 76 and this increased with increasing months of gestation. The blood flow to the middle uterine arteries could be identified after month 2 of gestation. The resistive index values of the middle uterine artery ipsilateral to the gravid horn showed an almost linear decline with a significant (P<0.05) drop at months 4 and 9 of gestation. Similarly, resistive index values of the middle uterine artery contra-lateral to the gravid horn revealed a significant (P<0.05) decrease on month 3, 5, and 6. A significant decrease for pulsatility index values of the middle uterine artery ipsilateral to the gravid horn was observed in months 3, 6, and 8 of gestation. However, the pulsatility index values for the middle uterine artery contralateral to the gravid horn showed a nonsignificant decrease. It was concluded that the umbilicus and placentomes are first visible at 38 and 76 days of gestation and the vascularity of the umbilicus, placentomes, and middle uterine artery increases with advancement of gestation in Surti buffalo.
... Cattle 1-21: (Ballarin et al., 2016;Bellmann et al., 2004;Crile and Quiring, 1940;Ellis et al., 2016;Holt et al., 1968;Holtenius and Björnhag, 1989;Hunter, 2010;Jenkins and Ferrell, 1997;Jurie et al., 2007;Long et al., 2010Long et al., , 2012Martinez et al., 2006;McDowell et al., 1987;Morris et al., 2010;Nephawe et al., 2004;Pfuhl et al., 2007;Ren et al., 2002;Rotta et al., 2015;Swett, 1937;von Soosten et al., 2012;Wood et al., 2013). Sheep 22-53: (Barnes et al., 1983;Bennett, 1973;Boxenbaum, 1980;Brown and Swan, 2014;Burrin et al., 1990;Carlson et al., 2009;Charismidou et al., 2000;Clarke et al., 2001;Delavaud et al., 2007;Ebinger, 1974;Gardner et al., 2005;Grace, 1983;Graham et al., 1982;Hales and Fawcett, 1993;Holt et al., 1968;Holtenius and Björnhag, 1989;Jenkinson et al., 1995;Juca et al., 2016;Kamalzadeh et al., 1998;Louey et al., 2005;Mahgoub and Lodge, 1998;McCutcheon et al., 1993;Metcalfe et al., 1962;Moss et al., 2005;Neville et al., 2008;Norberg et al., 2005;Pethick and Lindsay, 1982;Reed et al., 2007;Sinclair et al., 2010;Swanson et al., 2008;Tilahun et al., 2014;Wallace et al., 2002). Swine 54-76: (Andersson-Eklund et al., 1998;Fraga et al., 2009;García-Valverde et al., 2008;He et al., 2015;Holt et al., 1968;Hunter, 2010;Kerr et al., 1995;Kruska and Rohrs, 1974;Martinez et al., 2006;Martinsen et al., 2015;Minervini et al., 2016;Moughan et al., 1990;Müller et al., 2000;Nieto et al., 2012;Njoku et al., 2015;Orcutt et al., 1990;Pekas, 1983;Quinious and Noblet, 1995;Razmaite et al., 2009;Ruusunen et al., 2007;Thein et al., 2003;Tranquilli et al., 1982;Wiseman et al., 2007;Yang and Lin, 2010). ...
Physiologically based kinetic (PBK) models for farm animals are of growing interest in food and feed safety with key applications for regulated compounds including quantification of tissue concentrations, kinetic parameters and the setting of safe exposure levels on an internal dose basis. The development and application of these models requires data for physiological, anatomical and chemical specific parameters. Here, we present the results of a structured data collection of anatomical and physiological parameters in three key farm animal species (swine, cattle and sheep). We performed an extensive literature search and meta-analyses to quantify intra-species variability and associated uncertainty of the parameters. Parameters were collected for organ weights and blood flows in all available breeds from 110 scientific publications, of which 29, 48 and 33 for cattle, sheep, and swine, respectively. Organ weights were available in literature for all three species. Blood flow parameter values were available for all organs in sheep but were scarcer in swine and cattle. Furthermore, the parameter values showed a large intra-species variation. Overall, the parameter values and associated variability provide reference values which can be used as input for generic PBK models in these species.
... Fetal growth restriction, resulting in low birth weight, is one of the most important factors, associated with lamb mortality at birth (Alexander, 1974). Several sheep models have been developed to better understand the relationship between fetal growth restriction with maternal nutrition, hypoxia, and fetal number (Wallace et al., 2002;Regnault et al., 2003;Wu et al., 2004). From some of these studies, the use of melatonin supplementation to overcome fetal growth restriction in sheep has arisen as a potential intervention strategy; however, no studies have yet covered the use of melatonin from a practical point of view for farmers. ...
Fetal hypoxia, resulting in oxidative stress in pregnancies contributes to reduced fetal growth. Melatonin, a potent antioxidant has been associated with improved oxidative status. Maternal oral melatonin supplementation in sheep from day 50 of gestation ameliorates the consequences of fetal growth restriction in sheep. In rats, melatonin supplementation increases fetal weight via improved placental efficiency and reduction of oxidative stress. The objective of this study was to evaluate whether melatonin supplementation of single (S)- or twin-bearing (T) ewes using either 0 (0MEL), 1 (18 mg MEL) or 2 (36 mg MEL) slow release 18-mg melatonin implants (Regulin®) from 100 to 140 days of pregnancy (n=8 per group) influenced fetal oxygen supply and fetal weight. Fetal umbilical vein blood samples were collected at P140 and partial pressure of oxygen (PO2) and hemoglobin saturation by oxygen (SatHb) measured. The placenta from each fetus was excised and placentomes individually weighed and typed (A-D). Pregnancy rank, sex of the fetus, number of implants and their interaction on fetal weight, blood gases and placentome weight were analyzed using ANOVA. A 22% and 14% increase (P < 0.05) in body weight was obtained in 36 and 18 mg MEL compared to 0 MEL twin male fetuses, respectively but no treatment effects were observed in singletons or females from twin pregnancies. Fetuses from ewes receiving 36 mg MEL had an 18–20% increase in cord PO2 (P < 0.05) compared to 18 mg MEL and 0MEL fetuses, which in turn did not differ. Fetal weight was positively correlated with PO2 (r = 0.37; P = 0.02), SatHb (r = 0.26; P = 0.03) and O2 content (r = 0.236; P = 0.048). No treatment effect on placentome average weight, total placentome weight per fetus or per ewe nor total number of placentomes per fetus was observed. However, placentae from 36 mg MEL fetuses had a greater proportion of Type C (P < 0.05) than 0MEL and 18 mg MEL ewes, and tended to have lower proportion of Type A (P = 0.1), and greater proportion of Type D (P = 0.06) placentomes, compared to 0MEL ewes. These results indicate that maternal melatonin implants, independently of sex, improve oxygen supply to the fetus, which could potentially improve lamb vigour at birth. In addition, melatonin can increase fetal weight of twin males, by improving placental adaptation and fetal blood oxygenation.
... Corticosteroids (stress hormones with abundant receptors in the placenta) exert strong effects on the tone of peripheral blood vessels, which deliver blood, oxygen, and nutrients to the mother's muscles and organs and to the fetus. Activation of the sympathetic nervous system as described above reduces blood flow to the placenta, leading to reduced levels of oxygen and water in the placenta and decreased fetal uptake of glucose (Wallace, Bourke, Aitken, Leitch, & Hay, 2002), restricting fetal growth (Nusken et al., 2011). Restricted growth in utero (also called Intra-Uterine Growth Retardation or IUGR) may be reflected in low birthweight for length of gestation (small for gestational age or SGA). ...
Background:
Programming of the stress response system during gestation has lifelong effects that put the infant at risk for multiple stress-related pathologies. Populations most vulnerable to prenatal stress are African-Americans and individuals of low socioeconomic status.
Methods:
The Pregnancy Risk Assessment Monitoring System (PRAMS) research project, a collaboration between the Centers for Disease Control and Prevention and individual state health departments, was employed for this study. Tennessee data from 2009 were compiled from individual birth certificates and PRAMS questionnaire responses to examine the influence of maternal stressors, race and low income on birth outcomes.
Results:
The number of stressors was only a significant predictor of having an infant small for gestational age when moderated by Medicaid status. Medicaid status was a positive predictor of both problematic birth and preterm delivery, but did not predict small or large for gestational age. The relationship between race and birth outcomes overall was moderated by age, with young African-American mothers less likely than European-Americans and older African-American mothers to have adverse birth outcomes.
... All five lambs demonstrated long-term haemodynamic stability and stable circuit flows and oxygenation parameters (CA/UV group in Fig. 2). However, flow to the oxygenator in CA/UV lambs was well below the normal physiologic flow to the placenta (70-120 versus 150-200 ml kg À 1 min À 1 ) [26][27][28] , primarily due to the inherently small-caliber carotid artery. The limiting problem of carotid vascular inflow led to the development of our final device to achieve physiologic fetal support ( Fig. 1 and Supplementary Movie 1). ...
In the developed world, extreme prematurity is the leading cause of neonatal mortality and morbidity due to a combination of organ immaturity and iatrogenic injury. Until now, efforts to extend gestation using extracorporeal systems have achieved limited success. Here we report the development of a system that incorporates a pumpless oxygenator circuit connected to the fetus of a lamb via an umbilical cord interface that is maintained within a closed 'amniotic fluid' circuit that closely reproduces the environment of the womb. We show that fetal lambs that are developmentally equivalent to the extreme premature human infant can be physiologically supported in this extra-uterine device for up to 4 weeks. Lambs on support maintain stable haemodynamics, have normal blood gas and oxygenation parameters and maintain patency of the fetal circulation. With appropriate nutritional support, lambs on the system demonstrate normal somatic growth, lung maturation and brain growth and myelination.
... * significantly different from control animals as identified in the individual studies. Data derived from Chandler et al., 1985;Owens, Falconer, & Robinson, 1987a;Owens et al., 1987b;Carver & Hay, 1995;Thureen et al., 1992;Aldoretta et al., 1994;Aldoretta & Hay, 1999;Carver et al., 1997;Wallace, Bourke, Aitken, Leitch, & Hay, 2001;Ward et al., 2004;Regnault et al., 2007; Data derived from Comline & Silver, 1976;Reynolds et al., 1985;Ferrell, 1991;Fowden et al., 1997;Aldoretta & Hay, 1999 T A B L E 1 Average weight-specific rates of consumption (or production a ) of oxygen, glucose and lactate by the placenta (calculated using uteroplacental values expressed per unit of total weight of whole placentomes) and foetus (using body weight) of different species during late gestation (≥80% gestation) nutritional stresses but may adapt when the O 2 supply is restricted chronically by hypoxia or low uterine blood flow. ...
Contents
The placenta is a dynamic, metabolically active organ with significant nutrient and energy requirements for growth, nutrient transfer and protein synthesis. It uses a range of substrates to meet its energy needs and has a higher rate of oxygen (O 2 ) consumption than many other foetal and adult tissues. Placental metabolism varies with species and alters in response to a range of nutritional and endocrine signals of adverse environmental conditions. The placenta integrates these signals and adapts its metabolic phenotype to help maintain pregnancy and to optimize offspring fitness by diversifying the sources of carbon and nitrogen available for energy production, hormone synthesis and foeto‐placental growth. The metabolic response of the placenta to adversity depends on the nature, severity and duration of the stressful challenge and on whether the insult is maternal, placental or foetal in origin. This review examines placental metabolism and its response to stresses common in pregnancy with particular emphasis on farm species like the sheep. It also considers the consequences of changes in placental metabolism for the supply of O 2 and nutrients to the foetus.
... Serial assessments of uterine blood flow (UBF) and ultrasound markers of placental size reveal reductions in overnourished pregnancies from mid-pregnancy onwards [11,12]. By the final third of gestation, placental weight is significantly lower, mirrored by reductions in placental glucose transport and fetal nutrient uptakes, ultimately constraining fetal growth [13]. ...
Introduction
Placental vascularity may be important in the development of fetal growth restriction (FGR). The overnourished adolescent ewe is a robust model of the condition, with ∼50% of offspring demonstrating FGR (birthweight >2 standard deviations below optimally-fed control mean). We studied whether placental vascularity, angiogenesis and glucose transport reflect FGR severity.
Methods
Singleton pregnancies were established in adolescent ewes either overnourished to putatively restrict fetoplacental growth (n = 27) or control-fed (n = 12). At 131d (term = 145d) pregnancies were interrupted and fetuses classified as FGR (n = 17, <4222 g, -2SD below control-fed mean) or non-FGR (n = 10). Placentome capillary area density (CAD), number density (CND), surface density (CSD), and area per capillary (APC) in the fetal cotyledon (COT) and maternal caruncle (CAR) were analysed using immunostaining. COT/CAR mRNA expression of angiogenic ligands/receptors and glucose transporters were measured by qRT-PCR.
Results
Fetal weight was reduced in FGR vs. Non-FGR/Control groups. Total placentome weight was Control > Non-FGR > FGR and fetal:placental weight ratios were higher in overnourished versus Control groups. COT vascular indices were Non-FGR > FGR > Control. COT-CAD, CSD and APC were significantly greater in Non-FGR overnourished versus Control and intermediate in FGR groups. CAR vascularity did not differ. CAR-VEGFA/FLT1/KDR/ANGPT1/ANGPT2/SLC2A1/SLC2A3 mRNA was lower and COT-ANGPT2 higher in overnourished versus Control groups.
Discussion
Relative to control-intake pregnancy, overnourished pregnancies are characterised by higher COT vascularity, potentially a compensatory response to reduced nutrient supply, reflected by higher fetal:placental weight ratios. Compared with overnourished pregnancies where fetal growth is relatively preserved, overnourished pregnancies culminating in marked FGR have less placental vascularity, suggesting incomplete adaptation to the prenatal insult.
... This leads to a decrease in placental mass and 92 premature delivery of low birth weight lambs [30][31][32]. These pregnancies are also characterized 93 by reduced blood flow and nutrient uptake resulting in fetal hypoxia, hypoglycemia, 94 hypoinsulinemia and asymmetric growth restriction [32, 33]. For example, Wallace et al. [34] 95 demonstrated that overnourishing pregnant adolescent ewes resulted in compromised 96 fetoplacental size at term. ...
Uteroplacental development is a crucial step facilitating conceptus growth. Normal placental development comprises extensive placental angiogenesis to support fetoplacental transport, meeting the metabolic demands of the fetus. Compromised pregnancies due to maternal stressors such as over or undernutrition, maternal age or parity, altered body mass index, or genetic background result in altered vascular development of the placenta. This negatively affects placental growth and placental function and ultimately results in poor pregnancy outcomes. Nonetheless, the placenta acts as a sensor to the maternal stressors and undergoes modifications, which some have termed placental programming, to ensure healthy development of the conceptus. Sex steroid hormones such as estradiol-17β and progesterone, chemokines such as chemokine ligand 12, and angiogenic/vasoactive factors such as vascular endothelial growth factors, placental growth factor, angiopoietins, and nitric oxide regulate uteroplacental development and hence are often used as therapeutic targets to rescue compromised pregnancies. Interestingly, the presence of sex steroid receptors has been identified in the fetal membranes (developing fetal placenta). Environmental steroid mimetics known as endocrine disrupting compounds disrupt conceptus development and lead to transgenerational impairments by epigenetic modification of placental gene expression, which is another area deserving intense research efforts. This review attempts to summarize current knowledge concerning intrinsic and extrinsic factors affecting selected reproductive functions with the emphasis on placental development.
The objective of this study was to evaluate the effects of diets with two energy levels fed to Ile de France ewes during the last third of gestation on the performance, carcass, and meat traits of their offspring. Treatments were: D0: maternal diet meeting the requirements for the last third of gestation, and D20: maternal diet containing an additional 20% energy requirements. Twenty single-born male lambs, ten from each group of ewes, were weaned at 60 d (18.3 ± 1.4 kg initial BW) and fed a common finishing diet. Animals were slaughtered when they reached 32 kg BW. Dry matter intake, average daily gain, feed conversion, and days on feed were unaffected by treatments (P≥0.09). No effects were observed on hot and cold carcass weights, dressing percentage, chilling loss, commercial cuts yields, and loin-eye area (P≥0.17). Meat pH, thawing loss, cooking loss, shear force, and water holding capacity were also not affected by treatments (P≥0.09). Temperature and meat color, as well as centesimal composition were similar between treatments (P≥0.27). Adding 20% energy on top of the requirements of Ile de France ewes during the last third of gestation does not influence the performance, carcass traits, nor meat traits of their offspring.
Nowadays, at the point reached in the field of health, a lot of information is rapidly emerging, changing and needs to be known. In addition, it is very important for many people to access this up-to-date information quickly. In this context, it is necessary to follow up-to-date information. Although the information mentioned in the book are current issues, each of them is supported with appropriate visuals to make it easier for the readers to understand. In addition, the chapters have been kept as short as possible in accordance with the learning objective. We would like to thank and present our respects to the authors of the chapters who contributed to the preparation of this book, believing that it will contribute to the students of medicine, dentistry and biology, as well as to those related to the field of health, since this book is easy to understand.
In the space of one generation major changes have begun to take place in the field of human reproduction. A rapid increase in the control of fertility and the understanding and treatment of sexual health issues have been accompanied by an emerging threat to reproductive function linked to increasing environmental pollution and dramatic changes in lifestyle. Organised around four key themes, this book provides a valuable review of some of the most important recent findings in human reproductive ecology. Major topics include the impact of the environment on reproduction, the role of physical activity and energetics in regulating reproduction, sexual maturation and ovulation assessment and demographic, health and family planning issues. Both theoretical and practical issues are covered, including the evolution and importance of the menopause and the various statistical methods by which researchers can analyse characteristics of the menstrual cycle in field studies.
In the space of one generation major changes have begun to take place in the field of human reproduction. A rapid increase in the control of fertility and the understanding and treatment of sexual health issues have been accompanied by an emerging threat to reproductive function linked to increasing environmental pollution and dramatic changes in lifestyle. Organised around four key themes, this book provides a valuable review of some of the most important recent findings in human reproductive ecology. Major topics include the impact of the environment on reproduction, the role of physical activity and energetics in regulating reproduction, sexual maturation and ovulation assessment and demographic, health and family planning issues. Both theoretical and practical issues are covered, including the evolution and importance of the menopause and the various statistical methods by which researchers can analyse characteristics of the menstrual cycle in field studies.
In the space of one generation major changes have begun to take place in the field of human reproduction. A rapid increase in the control of fertility and the understanding and treatment of sexual health issues have been accompanied by an emerging threat to reproductive function linked to increasing environmental pollution and dramatic changes in lifestyle. Organised around four key themes, this book provides a valuable review of some of the most important recent findings in human reproductive ecology. Major topics include the impact of the environment on reproduction, the role of physical activity and energetics in regulating reproduction, sexual maturation and ovulation assessment and demographic, health and family planning issues. Both theoretical and practical issues are covered, including the evolution and importance of the menopause and the various statistical methods by which researchers can analyse characteristics of the menstrual cycle in field studies.
In the space of one generation major changes have begun to take place in the field of human reproduction. A rapid increase in the control of fertility and the understanding and treatment of sexual health issues have been accompanied by an emerging threat to reproductive function linked to increasing environmental pollution and dramatic changes in lifestyle. Organised around four key themes, this book provides a valuable review of some of the most important recent findings in human reproductive ecology. Major topics include the impact of the environment on reproduction, the role of physical activity and energetics in regulating reproduction, sexual maturation and ovulation assessment and demographic, health and family planning issues. Both theoretical and practical issues are covered, including the evolution and importance of the menopause and the various statistical methods by which researchers can analyse characteristics of the menstrual cycle in field studies.
In the space of one generation major changes have begun to take place in the field of human reproduction. A rapid increase in the control of fertility and the understanding and treatment of sexual health issues have been accompanied by an emerging threat to reproductive function linked to increasing environmental pollution and dramatic changes in lifestyle. Organised around four key themes, this book provides a valuable review of some of the most important recent findings in human reproductive ecology. Major topics include the impact of the environment on reproduction, the role of physical activity and energetics in regulating reproduction, sexual maturation and ovulation assessment and demographic, health and family planning issues. Both theoretical and practical issues are covered, including the evolution and importance of the menopause and the various statistical methods by which researchers can analyse characteristics of the menstrual cycle in field studies.
In the space of one generation major changes have begun to take place in the field of human reproduction. A rapid increase in the control of fertility and the understanding and treatment of sexual health issues have been accompanied by an emerging threat to reproductive function linked to increasing environmental pollution and dramatic changes in lifestyle. Organised around four key themes, this book provides a valuable review of some of the most important recent findings in human reproductive ecology. Major topics include the impact of the environment on reproduction, the role of physical activity and energetics in regulating reproduction, sexual maturation and ovulation assessment and demographic, health and family planning issues. Both theoretical and practical issues are covered, including the evolution and importance of the menopause and the various statistical methods by which researchers can analyse characteristics of the menstrual cycle in field studies.
In the space of one generation major changes have begun to take place in the field of human reproduction. A rapid increase in the control of fertility and the understanding and treatment of sexual health issues have been accompanied by an emerging threat to reproductive function linked to increasing environmental pollution and dramatic changes in lifestyle. Organised around four key themes, this book provides a valuable review of some of the most important recent findings in human reproductive ecology. Major topics include the impact of the environment on reproduction, the role of physical activity and energetics in regulating reproduction, sexual maturation and ovulation assessment and demographic, health and family planning issues. Both theoretical and practical issues are covered, including the evolution and importance of the menopause and the various statistical methods by which researchers can analyse characteristics of the menstrual cycle in field studies.
In the space of one generation major changes have begun to take place in the field of human reproduction. A rapid increase in the control of fertility and the understanding and treatment of sexual health issues have been accompanied by an emerging threat to reproductive function linked to increasing environmental pollution and dramatic changes in lifestyle. Organised around four key themes, this book provides a valuable review of some of the most important recent findings in human reproductive ecology. Major topics include the impact of the environment on reproduction, the role of physical activity and energetics in regulating reproduction, sexual maturation and ovulation assessment and demographic, health and family planning issues. Both theoretical and practical issues are covered, including the evolution and importance of the menopause and the various statistical methods by which researchers can analyse characteristics of the menstrual cycle in field studies.
In the space of one generation major changes have begun to take place in the field of human reproduction. A rapid increase in the control of fertility and the understanding and treatment of sexual health issues have been accompanied by an emerging threat to reproductive function linked to increasing environmental pollution and dramatic changes in lifestyle. Organised around four key themes, this book provides a valuable review of some of the most important recent findings in human reproductive ecology. Major topics include the impact of the environment on reproduction, the role of physical activity and energetics in regulating reproduction, sexual maturation and ovulation assessment and demographic, health and family planning issues. Both theoretical and practical issues are covered, including the evolution and importance of the menopause and the various statistical methods by which researchers can analyse characteristics of the menstrual cycle in field studies.
Environmental perturbations during gestation can alter fetal development and postnatal animal performance. In humans, intrauterine growth restriction (IUGR) resulting from adaptive fetal programming is known as a leading cause of perinatal morbidity and mortality and predisposes offspring to metabolic disease, however, the prevalence and impact in livestock is not characterized as well. Multiple animal models have been developed as a proxy to determine mechanistic changes that underlie the postnatal phenotype resulting from these programming events in humans but have not been utilized as robustly in livestock. While the overall consequences are similar between models, the severity of the conditions appear to be dependent on type, timing, and duration of insult, indicating that some environmental insults are of more relevance to livestock production than others. Thus far, maternofetal stress during gestation has been shown to cause increased death loss, low birth weight, inefficient growth, and aberrant metabolism. A breadth of this data comes from the fetal ruminant collected near term or shortly thereafter, with fewer studies following these animals past weaning. Consequently, even less is known about how adaptive fetal programming impacts subsequent progeny. In this review, we summarize the current knowledge of the postnatal phenotype of livestock resulting from different models of fetal programming, with a focus on growth, metabolism, and reproductive efficiency. We further describe what is currently known about generational impacts of fetal programming in production systems, along with gaps and future directions to consider.
With global warming, the incidence of heat stress in dairy cows is increasing in many countries. Temperatures outside the thermoneutral zone (heat stress) are one of the environmental factors with the greatest impact on milk production and reproductive performance of dairy cows. In addition to several biological mechanisms that may contribute to the effects of fetal programming, epigenetic modifications have also been investigated as possible mediators of the observed associations between maternal heat stress during late gestation and performance and health later in life. In utero programming of these offspring may coordinate changes in thermoregulation, mammary gland development, and milk production ability at different developmental stages. This review examines the effects of prenatal and postnatal hyperthermia on the developmental outcomes of dairy cows, as well as the physiological and molecular mechanisms that may be responsible for the negative phenotypic consequences of heat stress that persist throughout the neonatal and adult periods and may have multigenerational implications. The physiological and molecular mechanisms underlying the negative phenotypic consequences of heat stress are discussed. Research challenges in this area, future research recommendations, and therapeutic applications are also discussed. In summary, strategies to reduce heat stress during the dry period should consider not only the productivity of the pregnant cow but also the well-being of the newborn calf.
Extreme prematurity remains a major cause of neonatal mortality and severe long‐term morbidity. Current neonatal care is associated with significant morbidity due to iatrogenic injury and developmental immaturity of extreme premature infants. A more physiologic approach, replacing placental function and providing a womb‐like environment is the foundational principle of artificial placenta and womb technology. The concept has been studied during the past 60 years with limited success. However recent technological advancements and a greater emphasis on mimicking utero‐placental physiology have improved the success of experimental models, bringing the technology closer to clinical translation. Here we review the rationale for, and history of artificial placenta and womb technology, discuss the challenges that needed to be overcome, and compare recent successful models. We conclude by outlining some remaining challenges to be addressed on the path towards clinical translation and opportunities for future research. This article is protected by copyright. All rights reserved.
The competition for nutrients that arises when pregnancy coincides with continuing or incomplete growth in young adolescent girls increases the risk of preterm delivery and low birthweight with negative after-effects for mother and child extending beyond the perinatal period. Sheep paradigms involving nutritional management of weight and adiposity in young biologically immature adolescents have allowed the consequences of differential maternal growth status to be explored. Although nutrient reserves at conception play a modest role, it is the dietary manipulation of the maternal growth trajectory thereafter which has the most negative impact on pregnancy outcome. Overnourishing adolescents to promote rapid maternal growth is particularly detrimental as placental growth, uteroplacental blood-flows and fetal nutrient delivery are perturbed leading to a high incidence of fetal growth-restriction and premature delivery of low birthweight lambs, whereas in undernourished adolescents further maternal growth is prevented and depletion of the maternal body results in a small reduction in birthweight independent of placental size. Maternal and placental endocrine systems are differentially altered in both paradigms with downstream effects on fetal endocrine systems, organ development and body composition. Approaches to reverse these effects have been explored, predominantly targeting placental growth or function. After birth, growth-restricted offspring born to overnourished adolescents and fed to appetite have an altered metabolic phenotype which persists into adulthood whereas offspring of undernourished adolescents are largely unaffected. This body of work using ovine paradigms has public health implications for nutritional advice offered to young adolescents before and during pregnancy, and their offspring thereafter.
The placenta is a key organ in pregnancy because during this period it supports normal fetal growth and development. The placenta is responsible for nutrient and oxygen transport to the fetus and also secretes several hormones and growth factors important for fetal development. An alteration in placental functions or development could lead to pregnancy disorders (preeclampsia, FGR, miscarriage, and gestational diabetes, among others). It is known that the placenta alters the expression levels of several placental biomarkers, “opening a door” to the study of such concentrations as prognostic factors of the aforementioned pregnancy disorders. Until now, although different placental biomarkers have been associated with pregnancy syndromes, no biomarker has been effectively used in clinical practice to diagnose and predict such diseases.
Low birthweight is a risk factor for later adverse health. Here the impact of placentally-mediated prenatal growth-restriction followed by postnatal nutrient abundance on growth, glucose metabolism and body composition was assessed in both sexes at key stages from birth to mid-adult life. Singleton-bearing adolescent dams were fed control or high nutrient intakes to induce normal or growth-restricted pregnancies, respectively. Restricted lambs had ~40% reduced birthweight. Fractional growth rates were higher in restricted lambs of both sexes predominantly during suckling/juvenile phases. Thereafter, rates and patterns of growth differed by sex. Absolute catch-up was not achieved and restricted offspring had modestly reduced weight and stature at mid-adulthood necropsy (~109 weeks). Dual-energy X-ray absorptiometry revealed lower bone mineral density in restricted versus normal lambs at 11, 41, 64 and 107 weeks, with males>females from 41 weeks onwards. Body fat percentage was higher in females versus males throughout, in restricted versus normal lambs at weaning (both sexes), and in restricted versus normal females at mid-adulthood. Insulin secretion after glucose-challenge was greater in restricted versus normal of both sexes at 7 weeks, and in restricted-males at 32 weeks. In both sexes fasting glucose concentrations were greater in restricted offspring across the life-course, while glucose area-under-the-curve after challenge was higher in restricted offspring at 32, 60, 85 and 106 weeks, indicative of persistent glucose intolerance. Therefore prenatal growth-restriction has negative consequences for body composition and metabolism throughout the life-course with the effects modulated by sex differences in postnatal growth rates, fat deposition and bone mass accrual.
Breeding and management of pregnant females are essential components of livestock production. Improper gestational management creates maternal stressors which negatively affect prenatal and postnatal offspring development. We hypothesized that 1) using transabdominal ultrasound, pregnancy diagnosis would be accurate during early gestation in ewes and measure fetal growth patterns during mid-gestation, and 2) inflammation may be a mechanism contributing to suboptimal offspring performance when maternal nutrition is poor during gestation. To investigate, 99 ewes were scanned three times per wk between d26 and d40 of gestation. The sensitivity and specificity of pregnancy diagnoses were >90% from d33 onward, coinciding with visualization of fetal and placental development. This demonstrated that transabdominal ultrasound can be accurately integrated during early gestation for proactive flock management. Ewes determined to be pregnant (n=82) were randomly assigned to diets of 100% (CON), 60% (RES) or 140% (OVER) of NRC from d30 through parturition. Ultrasounds continued weekly between d45 and d90 to monitor growth of the fetal heart width (HW), umbilical diam., (UMB) and rib width (RW). At d45 and d90, ewes (n=20 or 21) were euthanized and fetuses were obtained for comparative gross measurements. As gestation advanced, measurement of the HW and UMB increased (PP<0.12). Interactions of maternal diet and litter size with gestation were observed for the RW; however, the effects were inconsistent and explained by Bland-Altman analysis that demonstrated measurement bias on ultrasound. At d45 ultrasound measurement underestimated RW by 7.7% but overestimated RW by 23.8% at d90. To determine how gestational diet affected the inflammatory status of dams (n=5 to 7 per diet) and offspring (n=6 per diet), RT-PCR arrays were utilized. RES and OVER promoted differing maternal systemic pro-inflammatory gene expression, with RES linked to increased NEFA concentrations. At birth, offspring systemic C-C motif chemokine ligand 8 increased in RES and OVER, and hepatic tumor necrosis factor increased in RES. Pro-inflammatory cytokines induced by maternal diet may antagonize offspring growth and performance. Future research may address anti-inflammatory interventions which can be implemented according to gestational information gained via ultrasound.
Compromised placental function can result in fetal growth restriction which is associated with greater risk of neonatal morbidity and mortality. Large increases in transplacental nutrient and waste exchange, which support the exponential increase in fetal growth during the last half of gestation, are dependent primarily on the rapid growth and vascularization of the uteroplacenta. The amplitude of melatonin secretion has been associated with improved oxidative status and altered cardiovascular function in several mammalian species; however, melatonin mediated alterations of uteroplacental capacity in sheep and cattle are lacking. Therefore, our laboratories are examining uteroplacental blood flow and fetal development during maternal melatonin supplementation. Using a mid- to late-gestation ovine model of intrauterine growth restriction, we examined uteroplacental blood flow and fetal growth during supplementation with 5 mg/d of dietary melatonin. Maternal nutrient restriction decreased uterine arterial blood flow, while melatonin supplementation increased umbilical arterial blood flow compared with non-supplemented controls. Although melatonin treatment did not rescue fetal weight in nutrient restricted ewes; we observed disproportionate fetal size and fetal organ development. Elevated fetal concentrations of melatonin may result in altered blood flow distribution during important time points of development. These melatonin specific responses on umbilical arterial hemodynamics and fetal development may be partially mediated through vascular melatonin receptors. Recently, we examined the effects of supplementing Holstein heifers with 20 mg/d of dietary melatonin during the last third of gestation. Uterine arterial blood flow was increased by 25% and total serum antioxidant capacity was increased by 43% in melatonin supplemented heifers vs. non-supplemented controls. In addition, peripheral concentrations of progesterone were decreased in melatonin supplemented heifers vs. non-supplemented controls. Using an in vitro model, melatonin treatment increased the activity of cyto-chrome P450 2C, a progesterone inactivating enzyme, which was blocked by treatment with the melatonin receptor antagonist, luzindole. Elucidating the consequences of specific hormonal supplements on the continual plasticity of placental function will allow us to determine important endogenous mediators of offspring growth and development. © 2017 American Society of Animal Science. All rights reserved.
In the space of one generation major changes have begun to take place in the field of human reproduction. A rapid increase in the control of fertility and the understanding and treatment of sexual health issues have been accompanied by an emerging threat to reproductive function linked to increasing environmental pollution and dramatic changes in lifestyle. Organised around four key themes, this book provides a valuable review of some of the most important recent findings in human reproductive ecology. Major topics include the impact of the environment on reproduction, the role of physical activity and energetics in regulating reproduction, sexual maturation and ovulation assessment and demographic, health and family planning issues. Both theoretical and practical issues are covered, including the evolution and importance of the menopause and the various statistical methods by which researchers can analyse characteristics of the menstrual cycle in field studies.
Birth weight is a robust predictor of health and well-being immediately after delivery and throughout the life course. Maternal body composition at conception and gestational intake thereafter impacts prenatal growth velocity and birth weight irrespective of maternal age, but the most pronounced risk of poor outcome is when pregnancy coincides with adolescence and continued or incomplete growth of the mother. Experimental ovine paradigms have helped define the impact of nutrition in mediating pregnancy outcome in young adolescents. Low maternal nutrient status at conception has a modestly negative influence on placental growth and birth weight, but it is gestational intake after conception, particularly during the first third of pregnancy, which has the most profound influence on fetal development. Relative to optimally nourished controls, age-matched adolescents overnourished throughout pregnancy exhibit rapid maternal growth and increasing adiposity at the expense of the conceptus. Placental growth and vascular development, uteroplacental blood flows and fetal nutrient supply are compromised, and premature delivery of low birthweight lambs with a 45 % incidence of marked intrauterine growth restriction (IUGR) ensues. A more modest effect on fetal growth is evident in undernourished mothers (17 % incidence of IUGR). Here preventing maternal growth gradually depletes maternal body reserves and directly lowers nutrient availability in the maternal circulation independent of any change in placental size or gestation length. The maternal and placental adaptations to these diverse gestational intakes and the consequences for the fetus are presented together with the translational implications for detecting and avoiding birthweight extremes in human pregnancy.
A study was conducted to evaluate late gestation maternal nutrient restriction (NR) with or without protein supplementation on endocrine regulation in newborn beef calves. This study utilized multiparous cows (4 and 5 y of age, n = 57) randomly assigned to one of three treatments for the last 100 d of gestation. The control (n = 19) cows were fed to increase BCS while the NR (n = 19) and NR with protein supplement (NRS, n = 19) cows were fed to lose 1.2 ± 0.2 body condition score units during the last 100 d of gestation. Control cows were allowed ad libitum access to tall fescue/crabgrass paddock and, when grazing became insufficient, ad libitum hay was provided along with 1.3 kg of corn gluten feed 5 day/wk. Tall fescue paddocks were strip grazed to limit forage availability for NR and NRS. The NRS treated dams were individually penned and fed 0.45 kg of soybean meal 3 day/wk. As forage became limited the nutrient restricted paddocks received limited fescue hay. After parturition cow/calf pairs were moved to a common pasture and received ad libitum silage and high concentrate feed. Maternal NR regardless of supplementation reduced cow plasma glucose and insulin concentrations during late gestation (P<0.0001 and P=0.0051 respectively). Calves from NR dams weighed less at birth than control calves (P=0.04), while NRS calves were intermediate (33.4 ± 1.2, 35.0 ± 1.3 and 37.2 ± 1.3 kg NR, NRS and Control respectively). Plasma glucose concentrations of unsuckled calves at birth were reduced (P=0.037) in NR and NRS calves compared to control (67.7 ± 6.5 and 60.1 ± 6.9 vs. 83.7 ± 6.1 mg/dl respectively). At birth, Control and NRS calves had increased (P=0.0037) plasma leptin concentrations compared to NR calves, while calf plasma cortisol concentrations were greater for the nutrient restricted groups than the control group (treatment x day P=0.0135). Plasma IgG concentrations from calves at 5 days of age were similar (P=0.701) between maternal late gestation treatments. This research demonstrates that late gestation NR reduces postnatal calf birth weight, plasma glucose and leads to reduced plasma leptin. Maternal protein supplementation appears to partially alleviate the effects of late gestation nutrient restriction on reducing plasma leptin, birth weight and growth rate from day 30 of age to weaning.
Glucose is the principal blood sugar of the human foetus and its main energy source. Not surprisingly, therefore, its supply to these tissues is regulated by a relatively complex set of mechanisms that tend to keep its metabolism relatively constant. The first point in this regulation is the maintenance of maternal glucose concentration by increasing rates of maternal glucose production and development of relative maternal glucose intolerance and insulin resistance. The second point is the transfer of maternal glucose to the fetus by the placenta, which is buffered by placental glucose utilization. The third point is the production of insulin by the developing foetal pancreas, which enhances glucose utilization among the insulin-sensitive tissues (skeletal muscle, liver, heart, adipose tissue) that increase in mass and thus glucose need during late gestation. Glucose uptake into foetal tissues is regulated by glucose transporters that increase or decrease in response to both acute and chronic changes in foetal glucose concentration and conditions of intrauterine growth restriction (IUGR). At the same time, signal transduction protein regulators of amino acid synthesis into protein are down-regulated, emphasizing that IUGR presents a mixed phenotype, with increased propensity to take up energy substrates, such as glucose, and diminished capacity for protein synthesis and growth.
Aspects of placental protein and energy metabolism were examined in pregnant ewes subjected to either thermoneutral (TN, 18 to 20 degrees C, 30% humidity, n = 7) or hot (H, 30 to 40 degrees C, 40% humidity, n = 5) temperatures through mid and late gestation. Fetal and placental weights and total content of protein, RNA, and DNA were reduced (P less than .001) in H ewes. Placental protein and RNA concentrations (mg/g) were not different, and DNA concentrations were slightly greater (P less than .1), in H vs TN ewes. Thus, heat seemed to greatly reduce total cell number and placentome size and only slightly decrease cell size. Ratios of RNA to DNA indicated a reduced capacity for protein synthesis in H placenta. However, in vitro fractional rates of protein synthesis in tissue slices from the fetal and maternal placenta and from the myoendometrium were not different between TN and H ewes. The H ewes had greater placental protein concentrations of hydroxyproline and glycine, perhaps suggesting a greater collagen content. In vitro oxygen consumption of fetal placenta, but not of maternal placenta or myoendometrium, was lower in H than in TN ewes. This lower oxygen consumption was partially due to a lower Na+,K+ ATPase-dependent oxygen consumption.
Ditocous Dorset ewes were fed to predicted requirements and kept in environmental chambers at 21 degrees C (n = 6) or 40 degrees C (n = 5) between days 50 and 75 of gestation. Ewes were slaughtered and the pregnant uterus was dissected for measurement of conceptus weights and in vitro estimations of placental mitotic activity. Heat caused a 19% reduction in placental weight but did not affect fetal weight. Placental DNA and protein concentrations and protein/DNA were similar in both groups. Total placental DNA content was significantly reduced in the heated ewes, suggesting a reduction in cell number; however, DNA synthetic rate tended to be higher. These results are consistent with the hypothesis that fetal growth retardation in chronically heat-stressed ewes occurs in late pregnancy as a consequence of a primary reduction in placental growth in early gestation.
Pregnant ewes were exposed continuously to high ambient temperature (38-40 degrees C for 9 h, 30-32 degrees C for 15 h daily, relative humidity 40-50%) between about 45 days and 120 days of gestation and studied at 132-137 days. Results were compared with those of ewes of similar gestational age which were not exposed to heat at any stage of pregnancy. Heat exposure did not depress appetite but caused variable reductions in placental weight. Fetal weight was reduced to a lesser extent and correlated with placental weight. Uterine and umbilical blood flows and placental glucose transfer capacity were all significantly reduced and highly correlated with placental weight. These effects were accompanied by an enlargement of the PO2 difference between uterine and umbilical venous blood, a decrease in the PO2 and oxygen saturation of fetal arterial blood, and fetal hypoglycemia. Uteroplacental rates of oxygen and glucose utilization and the concentration of fructose in fetal blood were each significantly correlated with placental weight. It is suggested that reduced placental growth is a primary effect of chronic maternal heat stress and that the associated retardation of fetal growth represents a fetal adaptation to a decreased placental ability to supply oxygen and nutrients.
To explore the molecular basis for the gestational increase in glucose transport capacity of the sheep placenta in vivo, placentas from twin-pregnant ewes at days 75, 110, and 140 postcoitus (n = 6/group) were analyzed for glucose transporter (GT) concentration. Concentration (pmol/mg protein) of D-glucose-inhibitable binding sites, measured by [3H]cytochalasin B binding analysis, increased 3.4 times from mid- to late pregnancy. Concurrently, abundance of GLUT-1 and GLUT-3 protein, measured by immunoblotting with specific polyclonal antibodies, increased 2.3 and 2.9 times, respectively, while abundance of GLUT-1 and GLUT-3 mRNA, measured by Northern blotting, increased 1.8 and 3.9 times, respectively. GLUT-4 protein was undetectable at all stages of pregnancy. Quantitative immunoblotting indicated that GLUT-1 accounted for 86.8 +/- 1.6% at day 75 and 56.1 +/- 4.1% at day 140 of total cytochalasin B binding sites. Thus increases in GT concentration explain much of the gestational increase in glucose transfer capacity observed in vivo. The gestational decline in relative contribution of GLUT-1 to cytochalasin binding, together with the greater developmental increases in GLUT-3 mRNA and protein, further suggests that the relative importance of GLUT-3 increases with gestational age.
Pregnancy is associated with a significant increase in uteroplacental blood flow (UBF), which is responsible for delivering adequate nutrients and oxygen for fetal and placental growth. The present study was designed to determine the effects of vascular insufficiency on fetal and placental growth. Thirty-nine late-term pregnant ewes were instrumented to investigate the effects of chronic UBF reduction. Animals were split into three groups based on uterine blood flow, and all animals were killed on gestational day 138. UBF, which began at 851 +/- 74 ml/min (n = 39), increased in controls (C) to 1,409 +/- 98 ml/min (day 138 of gestation) and in the moderately restricted (R(M)) group to 986 +/- 69 ml/min. In the severely restricted (R(S)) group, UBF was only 779 +/- 79 ml/min on gestational day 138. This reduction in UBF significantly affected fetal body weight with R(M) fetuses weighing 3,685 +/- 178 g and R(S) fetuses weighing 2,920 +/- 164 g compared with C fetal weights of 4,318 +/- 208 g. Fetal brain weight was not affected, whereas ponderal index was significantly reduced in R(M) (2.94 +/- 0.09) and R(S) fetuses (2.49 +/- 0.08) compared with the value of the C fetuses (3.31 +/- 0.08). Placental weight was also significantly reduced in the R(M) group, being 302 +/- 24 g, whereas the R(S) group placenta weighed 274 +/- 61 g compared with the C values of 414 +/- 57 g. Fetal heart, liver, lung, and thymus were all significantly smaller in the R(S) group. Thus the present study shows a clear relationship between the level of UBF and both fetal and placental size. Furthermore, the observation that fetal brain weight was not affected, whereas fetal body weight was significantly reduced suggests that this experimental preparation may provide a useful model in which to study asymmetric fetal growth restriction.
We immunolocalized the GLUT-3 glucose transporter isoform versus GLUT-1 in the late-gestation epitheliochorial ovine placenta, and we examined the effect of chronic maternal hyperglycemia and hypoglycemia on placental GLUT-3 concentrations. GLUT-3 was limited to the apical surface of the trophoectoderm, whereas GLUT-1 was on the basolateral and apical surfaces of this cell layer and in the epithelial cells lining the placental uterine glands. GLUT-3 concentrations declined at 17–20 days of chronic hyperglycemia ( P < 0.05), associated with increased uterine and uteroplacental net glucose uptake rate, but a normal fetal glucose uptake rate was observed. Chronic hypoglycemia did not change GLUT-3 concentrations, although uterine, uteroplacental, and fetal net glucose uptake rates were decreased. Thus maternal hyperglycemia causes a time-dependent decline in the entire placental glucose transporter pool (GLUT-1 and GLUT-3). In contrast, maternal hypoglycemia decreases GLUT-1 but not GLUT-3, resulting in a relatively increased GLUT-3 contribution to the placental glucose transporter pool, which could maintain glucose delivery to the placenta relative to the fetus when maternal glucose is low.
Rectal temperatures of a flock of 151 Merino ewes from the semi-arid tropics of northern Australia were measured in March 1991 (Year 1). Two sub-groups of ewes, with different abilities to thermoregulate body temperature, were then classified according to rectal temperature at 16:00 h on 3 consecutive hot summer days: low body temperature status (LBT) ewes had a rectal temperature of ≤39.8 °C on each of the 3 days, and high body temperature status (HBT) ewes had a rectal temperature of ≥39.9 °C. These ewes were mated 20 months later and exposed to a hot summer gestation under typical field conditions. In February 1993 (Year 3) rectal temperatures of ewes were measured again to confirm body temperature status, and on the following day, at 107 ± 0.3 days of gestation, placental and fetal weights were determined at post mortem. Weight (20%, P < 0.01), DNA content (14%, P < 0.05) and protein content (15%, P < 0.05) of the placenta of LBT ewes were greater than for HBT ewes, whereas there was no significant difference in DNA or protein concentrations (mg per g tissue) or DNA:protein ratio. Fetal thoracic girth and fetal heart weight of HBT ewes were lower (P < 0.05) than for LBT ewes, but there was no significant difference in fetal body weight or fetal crown-rump length. We conclude that placental growth is restricted in sheep which do not thermoregulate well (i.e. HBT) when exposed to a hot environment. The ability of flock managers to identify HBT ewes, which will subsequently experience restricted placental growth, can be used to identify low producing individuals early in their commercial life.
In the investigation described, we have observed a t monthly intervals throughout gestation the changes taking place in a series of similar ewes, in lamb to the same ram, and each receiving the same standard diet.In following the live-weight growth curves of the ewes it was found that on a constant level of feeding the weight gains became greater during each succeeding month of pregnancy, and at corresponding stages were larger for ditocous than for monotocous ewes. This was found to be due to the fact that, although on our diet the ewes did gain slightly in actual body weight, the main increases in live weight resulted from the growth of the gravid uterus itself, and this increases in weight far more rapidly in the later stages of gestation, and is also heavier where twins are carried.
In four series of experiments Merino ewes were exposed to ambient temperatures of about 44 °C and water vapour pressure of 33 mmHg for 9 h daily, and to 32 °C and 18 mmHg for the remaining 15 h daily, during the middle third, the final third or the final two-thirds of pregnancy. Birth weight and the weight of the placenta were considerably reduced by the treatments and the reductions were considerably more than could be accounted for by the partial loss of appetite produced by heating.
There was a close inverse relationship between birth weight and the elevated rectal temperature of heated ewes in several series; but the absence of foetal dwarfing in ewes with elevated rectal temperatures due to daily heating for only 9 h at 44 °C indicates that the elevated rectal temperature of the ewe is not the main cause of dwarfing.
Contrary to previous suggestions, the dwarfed lambs were not proportional miniatures, for the head components, the body lengths, the kidneys and adrenal glands were disproportionately large in heated lambs, while the liver, thyroid and thymus glands and the biceps femoris muscle were disproportionately small, and the ratio of secondary to primary wool fibres was very much reduced. There were cavities in the white matter of the cerebral hemispheres of heat-dwarfed lambs.
The hypothesis that foetal dwarfing is due to stunting of the placenta was examined, but conflicting evidence was obtained in the different series. However, it appears that under some circumstances a heat-stunted placenta is capable of considerable growth in the absence of heating during the final third of pregnancy, when the placenta is normally shrinking, and that placental shrinkage in late pregnancy may be greatly accelerated by the application of heat.
Neither thyroxine nor a preparation of ovine growth hormone, injected into heated ewes, prevented foetal dwarfing; the injections of growth hormone appeared to increase foetal mortality.
Subjectively assessed body condition scores, determined on the live animal, were related to the percentages of chemical fat in the fleece-free empty bodies of 30 adult Scottish Blackface ewes. The results show that body condition scores can provide an acceptable and useful estimate of the proportion of fat in the live animal, and that the level of prediction is superior to that afforded by live weight.
This paper deals with some aspects of ovine biology which are relevant to the use of the sheep as a model for fetal and paediatric research.Birth weight in sheep covers the same range as that in man, and neonatal mortality in both species is high at the weight extremes, particularly the lower extreme. Despite the absence of a prematurity problem in sheep, their neonatal mortality is some 15%, compared with 3% in man.The birth weight of lambs is sensitive to a variety of expected influences (maternal disease, number in litter, sex, parental breeds, maternal age, size and parity), but lamb birth weight, particularly of multiples, is also very sensitive to the level of maternal prenatal nutrition. Chronic exposure of pregnant ewes to heat will also produce lambs weighing as little as 1 kg, compared with a minimum of 2 kg that can be produced by nutritional restriction. It is also possible to produce 1 kg lambs by surgical removal (before mating) of many of the discrete sites for placental attachment (caruncles); despite compensatory placental growth, placental size and hence lamb size is reduced.The peculiarities of digestion and metabolism in ruminants make it difficult for the pregnant ewe to provide adequate glucose for fetal requirements; and it seems reasonable to explain all these influences on birth weight as acting, at least in part, through restriction of the nutrient supply to the fetus.It is not known whether lambs small for different reasons have different rates of mortality, but small lambs are at a great thermal disadvantage because of the high surface area: weight ratio and retarded coat development. Lambs from nutritionally deprived ewes have poor vigour, and small lambs in general have reduced energy resources (fat and glycogen) which are probably affected by the supply of nutrients near term. Reduced birth weight is also associated with altered body proportions, but virtually independently of the mode of reduction. Muscle, spleen, liver, thymus and thyroid weights tend to be disproportionately small in small lambs. Chronic maternal hyperthermia tends to produce microcephaly and cavitation of the white matter of the cerebral hemispheres.Finally, a plea is made for medical research workers who study sheep to familiarize themselves with ovine biology.
Experimental intrauterine growth retardation was studied in sheep. Endometrial caruncles (anlagen of maternal cotyledon) were removed before pregnancy and at a second operation, catheters were implanted into the ewe and fetus at 105-135 days of pregnancy. Three groups of fetuses were defined: low birthweight-for-dates (small-caruncle), normal birthweight-for-dates (normal-sized-caruncle) from ewes which had endometrial caruncles removed and the controls. The mean placental weights in these groups were 139 plus or minus 5 g, 283 plus or minus 46 g, 334 plus or minus 22 g respectively. The brains, kidneys and adrenals of the small-caruncle-fetuses were significantly greater in proportion to body weight than in the controls and the appearance of ossification centres was delayed. Arterial oxygen tension was lower and packed cell volume higher in the small-caruncle-fetuses (PaO2 15 plus or minus 0.6 mmHg; packed cell volume 37.3 plus or minus 1.6%) and normal sized caruncles (PaO2 20.7 plus or minus 1.2 mmHg; packed cell volume 35.2 plus or minus 0.7%) than in the controls (PaO2 23.2 plus or minus 0.7 mmHg; packed cell volume 29.8 plus or minus 0.7%). Plasma concentrations of glucose (0.65 plus or minus 0.12 micromol/ml), lactate (0.9 plus or minus 0.1 micromol/ml) and pyruvate (0.08 plus or minus 0.025 micromol/ml) were lower in small-caruncle fetuses than in the control fetuses (glucose 1.05 plus or minus 0.06 micromol/ml, lactate 1.83 plus or minus 0.7 micromol/ml, pyruvate 0.21 plus or minus 0.06 micromol/ml). The corresponding values for the normal-sized-caruncle fetuses were glucose 0.71 plus or minus 0.12, lactate 1.18 plus or minus 0.7 and pyruvate 0.12 plus or minus 0.03 micromol/ml. The plasma concentration of alanine in the small-caruncle-fetuses (0.25 plus or minus 0.09 micromol/ml) was higher than in the normal-sized-caruncle (0.073 plus or minus 0.009 micromol/ml) or control fetuses (0.12 plus or minus 0.013 micromol/ml). The results indicate that fetal growth retardation due to restriction of placental growth after removal of endometrial caruncles is associated with chronic hypoxaemia, polycythaemia and hypoglycaemia. The restriction of nutrient supply probably accounts for the altered pattern of fetal growth but the relative importance of the changes observed remains uncertain.
The cerebral uptakes of glucose, oxygen, lactate, pyruvate, acetoacetate and beta-hydroxybutyrate were compared in the adult, the fetal, and the newborn sheep. Beginning 1-2 days after surgery, we withdrew samples simultaneously from an artery and from the sagittal sinus for up to 2 wk. At all ages glucose was the only substrate taken up in significant quantity relative to oxygen. The glucose-oxygen quotients were 0.98 less than 1.03 less than 1.08 in adults; 0.92 less than 0.99 less than 1.06 in lambs; 0.92 less than 0.98 less than 1.03 in fetuses. These quotients were not significantly different. There was a significant (P less than .05) arteriovenous difference for lactate in the adult (-0.031 mM), but not in the lamb or fetus. A significant (P less than .05) arteriovenous difference pyruvate was found in the adult (-0.013 mM) and in the fetus (-0.020 mM). The findings of a glucose-oxygen quotient of approximately 1 and the lack of significant lactate production in fetal sheep brain are consistent with the hypothesis that anerobic glycolysis is unimportant to the steady-state cerebral metabolism of the fetal sheep.
In six ewes heat stressed from 39 to 125 days gestation and studied in a normothermic environment at 135 days, fetal and placental masses were less than in control sheep (1,645 vs. 3,112 and 149 vs. 356 g, respectively, P less than 0.01). Umbilical glucose uptakes (Rf,UP) were measured keeping maternal arterial plasma glucose at 70 mg/dl at spontaneously occurring fetal plasma glucose values (state A) and at two additional fetal glucose levels, to determine the transplacental glucose difference (delta) vs. Rf,UP relation. At normal delta of 49.2 mg/dl, Rf,UP was less in the experimental group (3.2 vs. 5.6 mg.min-1.kg fetus-1, P less than 0.05). Differences in placental perfusion and glucose consumption could not account for this result, thus indicating a reduced placental glucose transport capacity. In state A, fetal hypoglycemia enlarged significantly (P less than 0.01) the delta to 56.7 mg/dl and increased Rf,UP approximately 50% over the Rf,UP at a normal delta. In heat-induced fetal growth retardation, fetal hypoglycemia increases the flux of maternal glucose across a placenta with reduced glucose transport capacity.
We have described the properties of glucose transporters expressed in several mammalian tissues and have summarized some of the adaptations that take place involving these molecules in various normal and abnormal states. With the exception of a few cell types, such as adipocytes and skeletal muscle, glucose transport is not a rate-limiting step in cellular glucose metabolism, and other substrates may be equally important for cellular metabolism. Nevertheless, an understanding of the mechanisms behind the regulation of glucose transport in individual tissues may facilitate an understanding of in vivo glucose utilization and clearance processes as they relate to normal and disease states. Although adult studies provide an impetus toward a mechanistic approach in preventing and treating various disease states involving derangements in glucose homeostasis, there remains a need for similar studies in the fetus and newborn. These developmental studies should help unravel the fetal/neonatal responses to normal and abnormal hormonal and substrate milieu.
Interactions between protein supply and the anabolic response to exogenous bovine (b) GH have been examined in two experiments using 28–35 kg lambs sustained entirely by intragastric infusion of volatile fatty acids (700 kJ/kg W 0·75 per day) into the rumen and the casein (600 mg (low protein; LP) or 1200 mg (high protein; HP)/kg W 0·75 per day) into the abomasum. Sheep received continuous i.v. infusions of bGH for 6 days in experiment 1 and for 18 days in experiment 2. Nitrogen balances were determined daily throughout both experiments and blood samples, from indwelling catheters, were assayed for GH, insulin-like growth factor-I (IGF-I), insulin and glucose.
Infusion of bGH increased plasma GH concentration by five- to sixfold in all animals. There was an increase in N retention in both HP and LP animals over the first 2–3 days of GH administration. HP animals sustained higher N retentions (31%; P < 0·05) throughout the GH administration but LP animals did not. In contrast, plasma IGF-I concentrations increased progressively over the first 72 to 96 h of GH administration in all sheep and thereafter remained significantly ( P < 0·05) elevated until termination of the GH infusion. In lambs which received both HP and LP infusions in experiment 1 the increase in IGF-I concentration by day 6 of GH administration was significantly ( P < 0·05) greater when they received the higher protein intake. Plasma insulin concentrations increased rapidly ( P < 0·05) with the onset of GH administration to levels which were 2·5 (LP)- and 4·8 (HP)-fold greater than those observed in the pre-and post-GH periods. Glucose concentration also increased during GH administration ( P < 0·05), by 35% in LP animals and by 58% in HP animals.
High protein availability appeared necessary to sustain a protein anabolic response where lambs received exogenous GH infusions, even though plasma IGF-I concentrations were elevated on both high and low protein treatments.
Journal of Endocrinology (1991) 130, 53–61
In early ovine fetal development, the placenta grows more rapidly than the fetus so that at mid-gestation the aggregate weight of placental cotyledons exceeds fetal weight. The purpose of this study was to compare two separate methods of measuring uterine blood flow and glucose and oxygen uptakes in seven mid-gestation ewes, each carrying a single fetus. Uterine blood flow to both uterine horns was measured by microsphere and by tritiated water steady-state diffusion methodology. Calculations of tritiated water blood flows and oxygen and glucose uptakes were based on measurements of arteriovenous concentration differences across each uterine horn. The distribution of blood flow and oxygen uptake between the two uterine horns was strongly correlated with placental mass distribution. The two methods gave comparable results for uterine blood flow (457 +/- 35 vs 476 +/- 35 ml/min), oxygen uptake (457 +/- 35 vs 476 +/- 35 mumol/min), and glucose uptake (63 +/- 8 vs 64 +/- 6 mumol/min). Uterine blood flow was approximately 38% of the late gestation value and 56.1 +/- 1 times higher than umbilical blood flow. Uteroplacental oxygen consumption was about 58% of late gestation measurements and 3.9 +/- 0.5 times higher than fetal oxygen uptake. We confirm that the large placental mass of mid-gestation is associated with high levels of maternal placental blood flow and placental oxidative metabolism.
Net ovine uteroplacental glucose consumption (Ro,up) and transfer rates to the fetus (Rf,up) were measured at different concentrations of maternal (GA) and fetal (Ga) arterial plasma glucose that were set and maintained independently by a glucose clamp procedure. Five GA/Ga combinations were studied: 70/15, 70/20, 70/30, 50/14, and 50/24 mg/dl. Rf,up was inversely related to Ga both at GA = 70 and GA = 50. Linear regression analysis of Rf,up vs. Ga for the GA = 70 and GA = 50 groups of observations revealed similar slopes (-0.286 +/- 0.012 vs. -0.217 +/- 0.028 dl.min-1.kg fetus-1) but a significantly higher intercept for the GA = 70 group (10.3 +/- 0.12 vs. 5.5 +/- 0.47 mg.min-1.kg fetus-1). In contrast, Ro,up increased significantly in response to an increase of Ga and had no significant dependence on GA. These results indicate that uteroplacental glucose metabolism occurs primarily in tissues that have direct access to glucose molecules carried by the umbilical circulation and that the glucose transport capacity of the placental barrier is greater on its fetal than its maternal surface. Uteroplacental glucose metabolic rate and its dependence on fetal glucose concentration are major factors that determine the magnitude and variability of the glucose concentration gradient (and thus the rate of net glucose transfer) between maternal and fetal plasma.
The effect of restricting placental growth on glucose metabolism in pregnant sheep in late gestation was determined by primed constant infusions of D-[U-14C]- and D-[2-3H]glucose and antipyrine into fetuses of six control sheep and six sheep from which endometrial caruncles had been removed before pregnancy (caruncle sheep). In the latter, placental and fetal weights were reduced, as was the concentration of glucose in fetal arterial blood. Fetal glucose turnover in caruncle sheep was only 52-59% of that in controls, largely because of lower umbilical loss of glucose back to the placenta (38-39% of control) and lower fetal glucose utilization (61-74% of control). However, fetal glucose utilization on a weight-specific basis was similar in control and caruncle sheep. Significant endogenous glucose production occurred in control and caruncle fetal sheep. Maternal glucose production and partition of glucose between the gravid uterus and other maternal tissues were similar in control and caruncle sheep. In conclusion, when placental and fetal growth are restricted, fetal glucose utilization is maintained by reduced loss of glucose back to the placenta and mother and by maintaining endogenous glucose production.
We studied ten normoglycemic [maternal glucose (GA) = 70 mg/dL] and six insulin-induced hypoglycemic (GA = 22 mg/dL) pregnant sheep to test the hypothesis that development of fetal glucose production (GPR) could help maintain fetal glucose concentration, limit uteroplacental-fetal glucose transfer (UPGT), and sustain uteroplacental glucose consumption (UPGC). Compared with the normoglycemic group, the hypoglycemic group demonstrated the following values: fetal glucose concentration (Ga) was 9.8 +/- 0.8 mg/dL (51% lower, p less than 0.01), uterine glucose uptake (UtGU) was 16.7 +/- 1.4 mg/min (54% lower, p less than 0.01), UPGT was 3.1 +/- 0.6 mg/min (81% lower, p less than 0.001), and UPGC was 13.6 +/- 1.4 mg/min (30% lower, p less than 0.05). The reduction in UPGC was significantly less (p less than 0.05) than the reductions in UPGT and UtGU. Fetal glucose utilization rate (GUR) was decreased 20% (p less than 0.05) to 3.99 +/- 0.35 mg/min/kg. A further decrease in GUR was prevented by the appearance of fetal GPR of 2.82 +/- 0.32 mg/min/kg (p less than 0.05) compared with negligible GPR in the normoglycemic group. UPGT and UPGC in both groups were not influenced by maternal or fetal insulin infusions as long as Ga did not change; however, fetal glucose infusion that increased Ga increased UPGC in both groups. We conclude that, during chronic maternal hypoglycemia, increased fetal GPR limits the simultaneous decrease in fetal GUR and glucose concentration. By sustaining Ga fetal GPR limits UPGT to a significantly greater extent than UtGU, diverting UtGU to UPGC. Thus, fetal GPR promotes placental as well as fetal metabolic autonomy when the maternal supply of glucose is reduced.
The effect of restriction of placental growth on the supply of glucose to the gravid uterus and fetus and on fetal and utero-placental metabolism of glucose and lactate was examined in this study. Endometrial caruncles were removed from 13 sheep (caruncle sheep) prior to mating, which restricted placental growth in the subsequent pregnancy. Half the fetuses of caruncle sheep were small or growth retarded, with the remainder normal in size. After insertion of vascular catheters at 110 days gestation, the caruncle sheep, together with 16 control sheep, were studied between 121 and 130 days of gestation. Glucose delivery to and consumption by the gravid uterus and its contents, both as a total and per kg of tissue mass, was significantly lower in caruncle ewes with small fetuses, although glucose extraction was similar to that in controls. Utero-placental glucose consumption was significantly lower in caruncle ewes carrying small fetuses compared to that in control ewes, both as a total and per kg of placenta. Small caruncle fetuses were hypoxaemic and hypoglycaemic and the lactate concentration in the common umbilical vein was significantly higher than in control sheep. Glucose delivery to and consumption by the fetus was significantly lower in normal-sized and in small caruncle fetuses compared to controls. Fetal glucose consumption per kg of fetus was similar in control and caruncle sheep. Fetal glucose extraction increased as fetal weight decreased. Utero-placental production of lactate was similar in control and caruncle ewes. However, uterine output of lactate decreased as placental weight fell. Utero-placental production of lactate per kg of placenta was significantly higher in caruncle ewes compared to controls and increased as oxygen content in blood from the fetal femoral artery decreased. Fetal lactate consumption per kg of fetus increased as the concentration of lactate in blood from the common umbilical vein increased. It is concluded that intrauterine growth retardation due to restriction of placental growth is associated with a reduced supply of glucose to both the pregnant uterus and fetus and a redistribution of glucose therein to the fetus, both directly as glucose and indirectly as lactate. This reflects the disproportionate maintenance of fetal weight relative to that of the placenta, reduced utero-placental consumption of glucose per kg of placenta, conversion of a greater proportion of that glucose or other substrate(s) to lactate by the placenta and an increase in the fraction of the lactate produced by utero-placental tissues that is secreted into the fetal circulation.
• Young maternal age has been associated with adverse neonatal outcome, particularly an increased incidence of low birth weight (<2500 g) and neonatal mortality. Very young adolescents (<15 years old) and multiparous adolescents are at particularly high risk. Very young maternal age is probably a marker for one for more other maternal risk factors known to adversely affect neonatal outcome. Current studies do not provide adequate data to determine which risk factors account for the less-than-optimal outcome of the neonates of very young adolescents. Risk conditions that are potentially treatable include poor nutrition, substance use, and genital infections.
(AJDC 1987;141:1053-1059)
When placental growth is restricted, fetal growth is reduced but the fetal to placental weight ratio increases, suggesting that the efficiency of placental transfer may have increased. Therefore, placental transfer of antipyrine, 3-O-methyl-D-glucose and urea was measured in control pregnant sheep and in sheep with restricted placental growth (pre-pregnancy excision of endometrial caruncles). Clearance of each decreased with placental weight but clearance of antipyrine and of 3-O-methyl-D-glucose per kg of placenta increased as placental weight decreased. The small placenta exhibited increased efficiency of flow-determined transfer of antipyrine and of facilitated-diffusion transfer of glucose but not of passive transfer of the hydrophilic substance, urea. These compensatory changes should help to maintain oxygen and glucose to the fetus when the growth of the placenta has been limited by reduction of the number of placental attachment sites.
Endometrial caruncles were excised from sheep (caruncle sheep) before pregnancy. The effect of this on umbilical and uterine blood flows in a subsequent pregnancy was examined. Thirteen caruncle and twelve control sheep with indwelling vascular catheters were studied at 121 and 130 days pregnancy. In caruncle sheep, fetal, placental, and total uterine content weights were significantly lower than in control sheep. Six caruncle sheep carried normal-sized fetuses (weight within +/- 2 SD of mean weight for control fetuses) and seven carried small fetuses (weight greater than +/- 2 SD below mean weight for control fetuses). Mean weights of placentas in these groups were 0.290 +/- 0.067 and 0.156 +/- 0.069 kg, respectively, compared with 0.459 +/- 0.157 kg in control sheep. In small caruncle fetuses, umbilical and uterine blood flows and placental antipyrine clearance were significantly lower than in controls at 121 and 130 days gestation. Only umbilical blood flow was reduced in normal-sized caruncle fetuses. Umbilical blood flow and placental antipyrine clearance increased with gestational age in control sheep but not in sheep with normal-sized or small caruncle fetuses. In all sheep, umbilical and uterine blood flows and antipyrine clearance correlated with placental weight. Umbilical blood flow per kilogram of placenta but not uterine blood flow per kilogram of placenta correlated inversely with placental weight. Fetal weight at 130 days generally correlated with placental weight, umbilical and uterine blood flows, and antipyrine clearance in a curvilinear fashion such that fetal weight was not greatly restricted until these variables were less than or equal to 65% of control values.
In 30 experiments performed on 5 pregnant sheep, the rate of glucose transfer from the placenta to fetus via the umbilical circulation was measured while varying uterine blood flow by means of a cuff-type occluder and while maintaining a constant maternal glucose concentration by means of a 'glucose clamp'. Over the range of uterine blood flows obtained, there was no significant effect on the simultaneously measured umbilical blood flow. Fetal glucose uptake and arterial glucose concentration remained normal as the uterine blood flow rate decreased from 600 to 300 ml per min per kg of fetus. At blood flow rates less than 300 ml.min-1.kg-1, the fetal glucose uptake decreased and became negative in one instance while the arterial glucose concentration became variable and markedly increased in 2 animals. This increase in fetal glucose concentration was associated with a decrease in the uterine oxygen delivery rate, a decrease in fetal oxygen content and a decrease in fetal oxygen uptake. These observations support the concept that fetal glucose metabolism is altered by severe hypoxia and demonstrate that there is little effect of uterine blood flow on fetal glucose uptake in the normal physiological range.
Fetal and placental growth rate in sheep has been manipulated by removal of endometrial caruncles prior to conception. This produced two groups of fetuses, one in which prenatal growth rate was similar to normal and a second group in which the fetuses were about half of the normal size. The mortality in the latter group was high, particularly after catheterisation, and there was evidence of early intra-uterine death and fetal reabsorption. Prior to 125 days the relationship between fetal and placental size was poor, but after 126 days a close correlation between the two was apparent. The small fetuses had comparably small placentas and in all cases there was a close relationship between fetal and placental weight. The experimental growth retardation was associated with hypoglycaemia, hypoxia and hypoinsulinaemia. Plasma T3, T4 and particularly prolactin were very low in the small fetuses whilst levels of cortisol and alanine were high. In contrast to the controls these fetuses showed little evidence of net glucose, alanine or lactate consumption. Infusion of 50% glucose into the pregnant ewe, sufficient to elevate maternal plasma glucose concentrations 2 to 3 fold, caused a comparable increase in the plasma concentrations of normal fetuses but only a 50% rise in the concentration in small fetuses. In contrast administration of 50% O2 to the ewes sufficient to cause a 2 to 3-fold increase in maternal PO2 caused only a small increase of arterial PO2 of normal fetuses but doubled that to normal levels in small fetuses. The results are discussed in relation to the effect of reduced placental size causing a fall in placental and transport and transport capacity and significance of this to the associated fetal growth retardation.
Extract: In the pregnant ewe in the fed state, higher maternal protein intake does not lead to increased protein catabolism by the fetus. Total maternal starvation results in a prompt fall in fetal glucose concentrations (by 35%) to a stable plateau by 48 hr of starvation. Transplacental glucose uptakes during prolonged starvation are less than 40% of normal fed state values. Fetal urea production rates (a reflection of amino acid catabolism) increase to a level twice the fed state values by the 4th day of starvation and then return to base-line values by the 7th day of starvation. Fetal glucose concentrations remain stable throughout prolonged starvation, even after urea production rates have returned to base-line values.
Previous studies have demonstrated the presence of insulin receptors on the maternal surface of the placenta in several species and the specific binding of insulin to the placenta in sheep. However, both in-vitro and in-vivo studies have produced conflicting evidence concerning the effect of insulin on placental glucose uptake. To clarify this problem, we measured maternal hindlimb, uterine and fetal glucose and oxygen extractions and glucose/oxygen quotients in chronically catheterized, non-stressed, late-gestation pregnant sheep over 1 h at a constant concentration of arterial plasma glucose, and again during the next 2 h at the same glucose level but at a higher insulin concentration using glucose 'clamp' methodology. Insulin produced a 4·9-fold increase in glucose extraction and a 3·5-fold increase in glucose/oxygen quotient across the hindlimb; in contrast, insulin did not significantly affect uterine or fetal glucose extraction or glucose/oxygen quotient. We conclude that in contrast to other tissues of the pregnant ewe, placental glucose uptake and transfer are insensitive to variations in maternal insulin concentration.
J. Endocr. (1984) 100 , 119–124
Knowledge of CO2 kinetics in the fetus is important for the design and interpretation of fetal metabolic studies that use carbon-labelled tracers. To study fetal CO2 kinetics, four fetal sheep were infused at constant rate with NaH14CO3 to simulate a constant rate of fetal 14CO2 production from the metabolism of a 14C-labelled substrate. Uterine and umbilical blood flows, and concentrations of 14CO2 and total CO2 in umbilical arterial and venous blood and in uterine arterial and venous blood were measured. During steady state, the excretion of 14CO2 via the umbilical circulation was 99.6 +/- 1.0 (SEM)% of the NaH14CO3 infusion rate. The irreversible disposal rate of CO2 molecules from the fetal CO2 pool was approximately 5 times greater than the metabolic production of CO2 by the fetus. This evidence demonstrates that measurements of fetal 14CO2 excretion via the umbilical circulation can provide an accurate measurement of fetal 14CO2 production and that the exchange rate of CO2 molecules between placenta and fetal blood is much greater than the net rate of excretion of CO2 molecules from fetus to placenta.
The regional distribution of cerebral blood flow was assessed in eight control and eight morphometrically growth-retarded fetal lambs to determine whether perfusion patterns within the cerebral circulation are altered in this model of intrauterine growth retardation. Growth retardation was induced by repetitive embolization of the uterine circulation, and flow distribution was assessed by use of microspheres. Distribution to 22 separate areas, expressed as a flow/weight ratio, was virtually identical in the two groups. Cortical gray matter received 56% of total cerebral flow, and cortical white matter received 7%. However, flow X gm-1 in cortical white matter was 85% of that in cortical gray matter. We conclude that perfusion patterns within the cerebral circulation are not altered in this model of intrauterine growth retardation and that, compared to gray matter, cortical white matter has a high flow X gm-1 in fetal life.
Blood flow measurements were made using radioactive microspheres in 14 unstressed, conscious, pregnant guinea pigs with gestational age ranging between 34 and 67 days. Within each litter placental blood flow (PBF) was positively correlated to fetal weight (FW), even after correcting for placental weight differences. Although the largest littermate was, on the average, only 30% larger than the smallest, its material placental blood flow was 95% greater. The PBF vs. FW relationship could be described by the allometric equation: PBF = Ai FW2.89 where Ai is a litter-specific coefficient. This study demonstrates that the placenta of the largest littermate is "hyperperfused" compared with its smaller siblings.
The uptakes of oxygen, glucose, and amino acids by the pregnant uterus via the uterine circulation and by the fetus via the umbilical circulation have been measured in sheep during the last month of gestation. The umbilical uptakes of oxygen and glucose are approximately 55 and 28%, respectively, of the total uterine uptake. This discrepancy between uterine and umbilical uptakes is due primarily to a large utilization rate of oxygen and glucose by the placenta. Part of the placental utilization of glucose can be accounted for by placental lactate excretion into both maternal and fetal blood. In marked contrast to the pattern of glucose utilization, the comparison of uterine and umbilical amino acid uptakes shows that the bulk of the amino acids taken up by the pregnant uterus is transferred to the fetus. The placenta utilizes glutamate of fetal origin and produces ammonia, which is excreted primarily into the maternal circulation.
A highly controlled model to investigate nutrient partitioning and the control of fetal growth in the rapidly growing adolescent sheep is described. Embryos recovered from superovulated adult ewes inseminated by a single sire were transferred in singleton to the uterus of prepubertal adolescent recipients induced to ovulate at 21 weeks of age (liveweight 44.4 +/- 0.38 kg). After embryo transfer, the adolescent recipients were individually offered a high (n = 28) or low (n = 20) quantity of a complete diet calculated to achieve rapid (RMG) or normal (NMG) maternal growth rates. After day 100 of gestation the feed intake of the NMG group was adjusted weekly to meet the increasing nutrient demands of the gravid uterus. The proportion of adolescent recipients initially conceiving was significantly (P < 0.01) influenced by maternal nutrient intake and was lower in the RMG (0.57) than in the NMG (0.85) group. For adolescent dams that maintained their pregnancies, liveweight gain during the first 95 days of gestation was significantly (P < 0.001) higher in the RMG compared with the NMG group (234 +/- 9.5 and 75 +/- 5.0 g day-1, respectively). Rapid maternal growth rates were associated with a significant reduction in both fetal and placental weights as determined when the animals were killed on day 95 of gestation (n = 3 per group) or at term. For the RMG (n = 8) and NMG (n = 11) groups, respectively, mean lamb birthweights at term were 2.74 +/- 0.25 and 4.34 +/- 0.27 kg (P < 0.001), while term placental weights were 263 +/- 16.8 and 438 +/- 44.6 g (P < 0.002). The number of fetal cotyledons per placenta and mean fetal cotyledon weight were significantly lower in RMG compared with NMG ewes (P < 0.05). Irrespective of treatment group, lamb birthweight was highly positively correlated with placental weight and both parameters were negatively correlated with maternal liveweight gain during the first 100 days of gestation. The incidence of non-infectious spontaneous abortion at 125 +/- 1.3 days of gestation was higher (P < 0.001) in the RMG (4 of 12) than in the NMG (1 of 12) group. Similarly, duration of gestation for those ewes delivering live young was shorter (P < 0.01) in the RMG compared with the NMG group (140 +/- 0.94 versus 143 +/- 0.28 days). Colostrum yield at parturition was positively related to placental weight and significantly lower (P < 0.001) in the RMG than in the NMG group (35 +/- 12.1 and 247 +/- 36.2 g, respectively). Neonatal survival rates at 72 h after parturition were reduced (P < 0.05) in the RMG (38%) compared with the NMG group (91%). These data suggest that in rapidly growing adolescent ewes, the established anabolic drive to maternal tissue synthesis is maintained at the expense of the gradually evolving nutrient requirements of the gravid uterus. This results in a major restriction in placental growth and a highly significant decrease in birthweight.
It has previously been reported that high nutrient intakes which promote rapid maternal growth throughout pregnancy are associated with poor pregnancy outcome when compared with normally growing adolescent animals. The present study examined the maternal plasma concentrations of a number of putative endocrine regulators of nutrient partitioning between the maternal and fetal compartments in relation to placental and fetal growth in this novel experimental paradigm. Embryos were recovered on day 4 after oestrus from superovulated adult ewes that had been inseminated using semen from a single sire and synchronously transferred, in singleton, to the uterus of peripubertal adolescent recipients (n = 38), which had been induced to ovulate at 32 weeks of age (live weight 47.4 +/- 0.4 kg). Post-transfer, the adolescent recipients were offered a high (n = 21) or moderate (n = 17) level of a complete diet calculated to achieve rapid (RMG) or normal (NMG) maternal growth rates. After day 100 of gestation, the feed intake of the NMG group was adjusted weekly to meet the increasing nutrient demands of the gravid uterus. Pregnancy rate following embryo transfer was higher (P < 0.05) in the RMG (90%) than in the NMG (59%) group. For ewes delivering live young at term, liveweight gain during the first 100 days of gestation was 294 +/- 12.9 and 84 +/- 4.7 g/day for the RMG (n = 16) and NMG (n = 10) groups respectively, and body condition score immediately prior to parturition was higher in RMG than in NMG ewes (2.9 +/- 0.04 vs 1.9 +/- 0.15 score units respectively, P < 0.001). For the RMG and NMG groups respectively, mean placental weight was 327 +/- 18.1 and 485 +/- 16.6 g with lamb birth weights of 3.49 +/- 0.13 and 4.82 +/- 0.21 kg (P < 0.001). The reduction in placental mass in the RMG group reflected a decrease in the number (P < 0.001) and size (P < 0.01) of the fetal cotyledons. The duration of gestation was shorter (P < 0.001) and colostrum yield at parturition lower (P < 0.001) in the RMG group. Maternal insulin concentrations, determined three times weekly, were higher (P < 0.001) throughout gestation in the RMG group and irrespective of treatment group were negatively correlated (P < 0.01) with placental weight and lamb birth weight. High glucose levels throughout gestation and a decreased response to an exogenous insulin challenge on day 95 of gestation implied a degree of insulin resistance in the RMG group but, in spite of these high maternal glucose concentrations, the reduced size of the placenta probably constrained fetal growth. Maternal IGF-I levels determined weekly, were elevated (P < 0.001) during the second and third trimester in RMG versus NMG groups and a sustained elevation in maternal tri-iodothyronine and thyroxine concentrations was evident in the RMG group from mid-gestation. In contrast, GH pulse frequency and mean GH concentrations, determined on day 68 and 122 of gestation, were lower (P < 0.05) in the RMG group, and irrespective of treatment group, were correlated negatively with feed intake and positively with placental weight and colostrum yield at parturition. Progesterone concentrations were lower in the RMG group during the second and third trimesters (P < 0.001) and, irrespective of treatment group, were positively associated (P < 0.001) with placental weight, gestation length and colostrum yield. These results suggest that in pregnant adolescent sheep on high dietary intakes, elevated insulin and IGF-I levels ensure that the anabolic drive to maternal tissue synthesis is established during early gestation at the expense of placental growth. The consequent restriction in placental transport capacity is the primary limitation to fetal growth and reduced GH and placental progesterone secretion may impair colostrum production.
Uterine and umbilical uptakes of plasma amino acids were measured simultaneously in eighteen singleton pregnant ewes at 130 +/- 1 days gestation for the purpose of establishing which amino acids are produced or used by the uteroplacenta under normal physiological conditions and at what rates. The branched-chain amino acids (BCAA) had uterine uptakes significantly greater than umbilical uptakes. Net uteroplacental BCAA utilization was 8.0 +/- 2.5 mumol.kg fetus-1.min-1 (P < 0.005) and represented 42% of the total BCAA utilization by fetus plus uteroplacenta. There was placental uptake of fetal glutamate (4.2 +/- 0.3 mumol.kg fetus-1.min-1, P < 0.001) and no uterine uptake of maternal glutamate. Umbilical uptake of glutamine was approximately 61% greater than uterine uptake, thus demonstrating net uteroplacental glutamine production of 2.2 +/- 0.9 mumol.kg fetus-1.min-1 (P < 0.021). In conjunction with other evidence, these data indicate rapid placental metabolism of glutamate, which is in part supplied by the fetus and in part produced locally via BCAA transamination. Most of the glutamate is oxidized, and some is used to synthesize glutamine, which is delivered to the fetus. There was net uteroplacental utilization of maternal serine and umbilical uptake of glycine produced by the placenta. Maternal serine utilization and glycine umbilical uptake were virtually equal (3.14 +/- 0.50 vs. 3.10 +/- 0.46 mumol.kg fetus-1.min-1). This evidence supports the conclusion that the ovine placenta converts large quantities of maternal serine into fetal glycine.
To examine the in vivo and in vitro time-dependent effects of glucose on placental glucose transporter (GLUT-1) protein levels, we employed Western blot analysis using placenta from the short-term streptozotocin-induced diabetic pregnancy (STZ-D), uterine artery ligation-intrauterine growth restriction (IUGR) rat models, pregnant sheep exposed to chronic maternal glucose and insulin infusions, and the HRP.1 rat trophoblastic cell line exposed to differing concentrations of glucose. In the rat, 6 days of STZ-D with maternal and fetal hyperglycemia caused no substantive change, whereas 72 h of IUGR with fetal hypoglycemia and ischemic hypoxia resulted in a 50% decline in placental GLUT-1 levels (P < 0.05). In late-gestation ewes, maternal and fetal hyperglycemia caused an initial threefold increase at 48 h (P < 0.05), with a persistent decline between 10 to 21 days, whereas maternal and fetal hypoglycemia led to a 30-50% decline in placental GLUT-1 levels (P < 0.05). Studies in vitro demonstrated no effect of 0 mM, whereas 100 mM glucose caused a 60% decline (P < 0.05; 48 h) in HRP.1 GLUT-1 levels compared with 5 mM of glucose. The added effect of hypoxia on 0 and 100 mM glucose concentrations appeared to increase GLUT-1 concentrations compared with normoxic cells (P < 0.05; 100 mM at 18 h). We conclude that abnormal glucose concentrations alter rodent and ovine placental GLUT-1 levels in a time- and concentration-dependent manner; hypoxia may upregulate this effect. The changes in placental GLUT-1 concentrations may contribute toward the process of altered maternoplacentofetal transport of glucose, thereby regulating placental and fetal growth.
The aim was to investigate whether placental growth and hence pregnancy outcome could be altered by switching adolescent dams from a high to a moderate nutrient intake, and vice-versa, at the end of the first trimester. Embryos recovered from adult ewes inseminated by a single sire were transferred in singleton to peripubertal adolescents. After transfer, adolescent ewes were offered a high (H, n = 33) or moderate (M, n = 32) level of a diet calculated to promote rapid or moderate maternal growth rates, respectively. At Day 50 of gestation, half the ewes had their dietary intakes switched, yielding 4 treatment groups: HH, MM, HM, and MH. A subset of ewes were killed at Day 104 of gestation to determine maternal body composition in relation to growth of the products of conception. Maternal body composition measurements revealed that the higher live weight in the high-intake dams was predominantly due to an increase in body fat deposition, with a less pronounced increase in body protein. At Day 104, HH and MH groups (high intake during second trimester) compared with MM and HM groups (moderate intake during second trimester) had a lower (p < 0.002) total fetal cotyledon weight; but fetal weight, conformation, and individual organ weights were not significantly influenced by maternal dietary intake. In ewes delivering live young at term, a high plane of nutrition from the end of the first trimester (HH and MH groups) compared with moderate levels (MM and HM groups) was associated with a reduction in gestation length (p < 0.009), total placental weight (p < 0.002), total fetal cotyledon weight (p < 0.001), and mean fetal cotyledon weight per placenta (p < 0.001). Fetal cotyledon number was dependent on maternal dietary intake during the first trimester only and was lower (p < 0.007) in HH and HM ewes compared to MM and MH ewes. The inhibition of fetal cotyledon growth in HH and MH groups was associated with a major decrease (p < 0.001) in lamb birth weight at term relative to the MM and HM groups. Thus, reducing maternal dietary intake from a high to a moderate level at the end of the first trimester stimulates placental growth and enhances pregnancy outcome, and increasing maternal dietary intake at this time point has a deleterious effect on placental development and fetal growth.
The aim was to investigate the consequences of nutritionally-mediated placental growth restriction on fetal organ growth, conformation, body composition and endocrine status during late gestation. Embryos recovered from superovulated adult ewes inseminated by a single sire were transferred in singleton to the uterus of peripubertal adolescent recipients. Post-transfer, adolescent dams were offered a high (H) or moderate (M) level of a complete diet to promote rapid or moderate maternal growth rates, respectively (n=7 per group). After day 100 of gestation the feed intake of the M dams was adjusted weekly to maintain body condition score. Liveweight gain during the first 100 days of gestation was 301+/-24 and 90+/-4.6 g/day for the H and M groups, respectively. Maternal plasma concentrations of insulin, IGF-I and urea were significantly higher and non-esterified fatty acid concentrations significantly lower in H compared with M dams prior to slaughter on day 128 of gestation. At this stage of gestation, total placentome weight was 50 per cent lower in H compared with M groups (P< 0.001) and was associated with a 37 per cent reduction in fetal weight (P< 0.01). All variables of fetal conformation and absolute fetal organ weights, with the exception of the adrenal glands, were lower (P< 0. 05) in the fetuses from H intake dams. However, relative fetal organ weights expressed as g/kg fetal body weight, with the exception of the gut, were not influenced by maternal dietary intake. Furthermore, fetal weight but not maternal nutritional group were predictive of individual organ weight for all organs dissected. Together these results imply that growth restriction in the fetuses derived from H intake dams was largely symmetrical. Fetal plasma concentrations of insulin, IGF-I and glucose were attenuated (P< 0.05) in fetuses from H compared with M groups. The lower fetal body weight in the former group was associated with a reduction in absolute but not relative crude protein (P< 0.01) and fat content (P< 0.05). Total fetal liver glycogen content but not concentration was (P< 0.05) reduced in H versus M groups. The lower mass of both the placenta and fetal liver was due to a reduction in cell number rather than an alteration in cell size. Thus, over-nourishing adolescent sheep is associated with a major restriction in placental growth which mediates a gradual slowing of fetal growth during the final third of pregnancy.
Appropriate nutrient partitioning between the maternal body and gravid uterus is essential for optimum fetal growth and neonatal survival, and in adult sheep nutrient partitioning during pregnancy generally favours the conceptus at the expense of the dam. However, recent studies using an overnourished adolescent sheep model demonstrate that the hierarchy of nutrient partitioning during pregnancy can be dramatically altered in young growing females. Overnourishing the adolescent dams to promote rapid maternal growth throughout pregnancy results in a major restriction in placental mass and leads to a significant decrease in birth weight relative to moderately-fed adolescents of equivalent gynaecological age. High maternal feed intakes are also associated with an increased incidence of non-infectious spontaneous abortion, a reduction in gestation length and colostrum production, and a higher incidence of neonatal mortality. The present paper examines the putative role of a variety of endocrine regulators of nutrient partitioning in this unusual model system, where the dam is overnourished while the stunted placenta restricts nutrient supply to the fetus. The central role of nutritionally-mediated alterations in placental growth and development in setting the subsequent pattern of nutrient partitioning between the maternal body, placenta and fetus is examined, and critical periods of sensitivity to alterations in maternal nutritional status are defined. Finally, the consequences of this form of inappropriate nutrient partitioning on the growth and development of the fetus and neonate are described with particular emphasis on the reproductive axis.
We immunolocalized the GLUT-3 glucose transporter isoform versus GLUT-1 in the late-gestation epitheliochorial ovine placenta, and we examined the effect of chronic maternal hyperglycemia and hypoglycemia on placental GLUT-3 concentrations. GLUT-3 was limited to the apical surface of the trophoectoderm, whereas GLUT-1 was on the basolateral and apical surfaces of this cell layer and in the epithelial cells lining the placental uterine glands. GLUT-3 concentrations declined at 17-20 days of chronic hyperglycemia (P < 0.05), associated with increased uterine and uteroplacental net glucose uptake rate, but a normal fetal glucose uptake rate was observed. Chronic hypoglycemia did not change GLUT-3 concentrations, although uterine, uteroplacental, and fetal net glucose uptake rates were decreased. Thus maternal hyperglycemia causes a time-dependent decline in the entire placental glucose transporter pool (GLUT-1 and GLUT-3). In contrast, maternal hypoglycemia decreases GLUT-1 but not GLUT-3, resulting in a relatively increased GLUT-3 contribution to the placental glucose transporter pool, which could maintain glucose delivery to the placenta relative to the fetus when maternal glucose is low.
Human adolescent mothers have an increased risk of delivering low birth weight and premature infants with high mortality rates within the first year of life. Studies using a highly controlled adolescent sheep paradigm demonstrate that, in young growing females, the hierarchy of nutrient partitioning during pregnancy is altered to promote growth of the maternal body at the expense of the gradually evolving nutrient requirements of the gravid uterus and mammary gland. Thus, overnourishing adolescent dams throughout pregnancy results in a major restriction in placental mass, and leads to a significant decrease in birth weight relative to adolescent dams receiving a moderate nutrient intake. High maternal intakes are also associated with increased rates of spontaneous abortion in late gestation and, for ewes delivering live young, with a reduction in the duration of gestation and in the quality and quantity of colostrum accumulated prenatally. As the adolescent dams are of equivalent age at the time of conception, these studies indicate that nutritional status during pregnancy rather than biological immaturity predisposes the rapidly growing adolescents to adverse pregnancy outcome. Nutrient partitioning between the maternal body and gravid uterus is putatively orchestrated by a number of endocrine hormones and, in this review, the roles of both maternal and placental hormones in the regulation of placental and fetal growth in this intriguing adolescent paradigm are discussed. Impaired placental growth, particularly of the fetal component of the placenta, is the primary constraint to fetal growth during late gestation in the overnourished dams and nutritional switch-over studies indicate that high nutrient intakes during the second two-thirds of pregnancy are most detrimental to pregnancy outcome. In addition, it may be possible to alter the nutrient transport function of the growth-restricted placenta in that the imposition of a catabolic phase during the final third of pregnancy in previously rapidly growing dams results in a modest increase in lamb birth weight.
Restricted implantation increases the proportion of fetal villi, trophoblast tissue, and surface density in the sheep placenta (Abstract)
- S Chidzanja
- J S Robinson
- J A Owens
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Time-dependent physiological regulation of rodent and ovine placental glucose transporter (GLUT-1) protein
- U G Das
- H F Sadiq
- M J Soares
- W W Hay
- Devasker Su
Das UG, Sadiq HF, Soares MJ, Hay WW Jr, and Devasker
SU. Time-dependent physiological regulation of rodent and ovine
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Regulatory Integrative Comp Physiol 277: R339-R347, 1999.