SemOpenAlex |

SemOpenAlex

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2534782676> ?p ?o ?g. }

Showing items 1 to 100 of ±129 with 100 items per page.

W2534782676 endingPage "35" @default.
W2534782676 startingPage "25" @default.
W2534782676 abstract "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 (O2) 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 O2 and nutrients to the foetus. As the interface between the mother and foetus, the placenta has multiple functions important to the successful outcome of pregnancy. It transports O2, nutrients, ions and key micronutrients from mother to foetus as well as wastes, such as carbon dioxide (CO2) and urea, in the opposite direction (Sibley, Glazier, & D'Souza, 1997). The placenta also converts nutrients that it receives to other forms to provide alternative substrates for foeto-placental metabolism and growth (Fig. 1). In addition, the placenta produces hormones and growth factors that are released into the maternal and foetal circulations (Burton & Fowden, 2012). These have key roles in the maintenance of uterine quiescence and the maternal physiological adaptations to pregnancy that are essential for meeting the increasing nutrient demands of the growing foetus. Finally, the placenta acts as a barrier restricting access of maternal hormones and xenobiotics to the foetus by enzymatic inactivation or transporting them back into the maternal circulation. Consequently, the placenta is a metabolically active organ with significant nutrient and energy requirements. The placenta uses a range of substrates to meet its energy needs and has a higher rate of oxygen (O2) consumption than either the adult or the foetus (Hay, 1991). Placental metabolism varies with species and alters in response to the foetal nutrient demands for growth with increasing gestational age (Fowden, 1997; Pere, 2003). It is also responsive to homoeostatic challenges that evoke stress responses in both the mother and foetus (Sferruzzi-Perri & Camm, 2016; Vaughan, Sferruzzi-Perri, Coan, & Fowden, 2012). The mother signals adverse changes in the general environment, such as scarcity or excess of nutrients, low oxygen availability or extremes of temperature, as well as physiological changes in the individual, like the availability of fuel reserves and the degree of glycaemic control and physical activity (Fowden, Ward, Wooding, & Forhead, 2010; Fowden, Forhead, Sferruzzi-Perri, Burton, & Vaughan, 2015; Gaccioli, Lager, Powell, & Jansson, 2013;: Sferruzzi-Perri & Camm, 2016). The foetus signals mismatches between its supply and demand for nutrients in relation to its mass, genotype and degree of maturation (Burton & Fowden, 2012; Vaughan et al., 2012). In many circumstances, the signalling is via stress and other metabolic hormones, like the glucocorticoids, catecholamines, leptin and insulin (Fowden et al., 2015). The stresses experienced during pregnancy may be chronic or acute depending on their origin. Chronic stress induced early in pregnancy often reduces foeto-placental growth, whereas more acute stresses tend to alter availability of specific nutrients and hormones transiently without major effects on intrauterine growth (Fowden, Ward, Wooding, Forhead, & Constancia, 2006). In farm animals and other species, there are also changes in placental morphology and nutrient transport capacity in response to stressful conditions including undernutrition, hypoxia and manipulations of dietary composition, maternal adiposity, glucose availability and glucocorticoid concentrations (Fowden et al., 2010, 2015; Gaccioli et al., 2013). However, much less is known about the effects of these stresses on placental metabolism per se. This review, therefore, examines placental metabolism and its response to stresses common during pregnancy with particular emphasis on farm animals like the sheep. It also discusses the consequences of changes in placental metabolism for the supply of O2 and nutrients to the foetus. It does not consider the effects of stressful conditions on placental growth and development as these topics have been reviewed recently (Fowden et al., 2015; Gaccioli et al., 2013; Sferruzzi-Perri & Camm, 2016). Like most tissues, aerobic respiration is the main source of placental ATP during normal conditions. In the farm animals studied to date, the respiratory rate of the combined uteroplacental tissues is higher per kg total tissue than that seen per kg of foetus (Fowden, Forhead, Silver, & Macdonald, 1997). As most of this O2 consumption is placental rather than myometrial (Hay, 1991), rates of O2 consumption per kg placenta are at least three- to fourfold higher than those per kg of foetus as a whole (Table 1) and similar to that of the foetal brain (Hay, 2006). Oxygen consumption rates calculated per kg placenta are of the same order of magnitude in different species with an epitheliochorial placenta and similar to those of the haemochorial human placenta (Table 1; Hay, 2006). Of the O2 consumed by the ovine placenta, approximately 70–75% is used to generate ATP by mitochondrial oxidative phosphorylation using a variety of substrates including carbohydrates, amino acids, probably certain volatile fatty acids (VFA) and possibly also some free fatty acids (Fig. 1). The majority of this ATP is used for protein synthesis and active transport processes (Carter, 2000). Oxygen is also used in placental mitochondria without generating ATP through proton leak and superoxide production along the electron transport system and for synthesis of progesterone or other steroids (Fig. 1). These processes account for another 15–20% of the O2 consumed by the ovine placenta, while the remaining 10–15% is non-mitochondrial due to cellular oxidative reactions unrelated to energy production (Carter, 2000). Oxygen consumption by the combined uteroplacental tissues increases by 25–50% between mid-gestation and late gestation in sheep and horses but not in pigs when expressed per kg wet weight (Bell, Kennaugh, Battaglia, Makowski, & Meschia, 1986; Fowden, Forhead, White, & Taylor, 2000; Fowden, Taylor, White, & Forhead, 2000; Molina, Meschia, Battaglia, & Hay, 1991; Reynolds, Ford, & Ferrell, 1985). In contrast, when values are calculated per gram dry weight of placenta alone, there is little change in placental O2 consumption during the second-half of gestation in sheep (Vatnick & Bell, 1992). However, growth rates of the placenta and foetus differ over this period of gestation and also show wide species variation (Wooding & Burton, 2008). Consequently, the amount of O2 consumed by the uteroplacental tissues as a proportion of the total uterine O2 uptake alters with gestational age depending on the species. For instance, in sheep, the percentage of uterine O2 uptake used by the uteroplacental tissues decreases from 80% to 40–45% between mid-gestation and late gestation, whereas, in horses and pigs, this percentage remains at 55% and 65%, respectively, throughout the second-half of gestation (Bell et al., 1986; Fowden, Forhead et al., 2000; Fowden, Taylor et al. 2000; Molina et al., 1991; Reynolds et al., 1985). Absolute rates of uteroplacental O2 consumption vary with placental weight and are often reduced in response to chronic stresses such as hyperthermia and hypoglycaemia that compromise placental growth from early in development (Carter, 2000; Carver & Hay, 1995; Thureen, Trembler, Meschia, Makowski, & Wilkening, 1992). However, when all the data available for pregnant sheep in late gestation are summarized, rates of O2 consumption calculated per kg of placenta are relatively unaffected by the range of acute and chronic stresses studied to date (Fig. 2). It is only when placental growth is severely compromised by carunclectomy before pregnancy that O2 consumption per kg placenta is reduced (Fig. 2). Even when uterine O2 delivery is reduced by 50% by maternal anaemia, uteroplacental O2 consumption is maintained by increasing O2 extraction (Delpapa, Edelstone, Milley, & Balsan, 1992). Normal rates of uteroplacental consumption and umbilical uptake of O2 are also sustained in a similar manner when uterine O2 delivery is reduced for 24 h by restricting uterine blood flow (Carter, 2000; Hooper, Walker, & Harding, 1995). In contrast, when O2 availability is reduced chronically by pregnancy at high altitude, O2 consumption per unit weight of human placenta appears to decline relative to sea-level values (Illsley Caniggia, & Zamudio, 2010). Collectively, these findings suggest that the rate of placental respiration varies little with nutritional stresses but may adapt when the O2 supply is restricted chronically by hypoxia or low uterine blood flow. To date, little is known about placental energetics or mitochondrial function during stressful conditions in farm animals. In the human and rodent placenta, both nutritional and hypoxic stresses alter mitochondrial function. More specifically, there are changes in mitochondrial biogenesis, morphology, apoptosis and abundance of electron transport complexes and uncoupling proteins during common pregnancy stresses including maternal diabetes, obesity, pre-eclampsia, calorie restriction, protein deprivation and high-altitude hypoxia (Belkacemi, Desai, Nelson Michael, & Ross Michael, 2011; Chiaratti et al., 2015; Colleoni et al., 2013; Hastie & Lappas, 2014; Hercules, Esquisatto, Moraes, Amaral, & Catisti, 2013; Mando et al., 2014; Mayeur et al., 2013). Increased abundance of uncoupling protein-2 has also been observed in the ovine placenta at mid-gestation and late gestation of ewes undernourished during early pregnancy (Gnanalingham et al., 2007). These mitochondrial changes are likely to affect the efficiency of ATP production and superoxide generation with wider implications for placental function (Fig. 1). Certainly in humans and mice, nutritional and hypoxic stimuli alter placental ATP content (Chiaratti et al., 2015; Tissot van Patot et al., 2010). Consequently, even though placental O2 consumption is maintained during many stressful conditions (Fig. 2), there may be changes in placental energetics and consumption of oxidative substrates that affect foetal delivery of nutrients and O2. Indeed, rates of umbilical O2 uptake per kg sheep foetus vary little in response to acute and chronic stresses, which indicates that the foetus grows primarily in relation to its overall O2 availability (Fig. 2). In all farm animals studied to date, the main carbohydrate used by the uteroplacental tissues is glucose (Fig. 1). Its primary source in normal conditions is the mother. Glucose crosses the placenta by facilitated diffusion down a materno-foetal glucose concentration gradient using glucose transporters (GLUTs). However, when this gradient is abolished experimentally in sheep, uteroplacental glucose consumption remains at 80% of normal values by deriving glucose from the foetal circulation (Simmons, Battaglia, & Meschia, 1979). Two GLUT isoforms, GLUT1 and GLUT3, have been detected in ruminant and equine placenta and are used sequentially in transplacental glucose transfer (Wooding & Burton, 2008). GLUT 8 has also been identified in the ovine placenta and may be involved in transporting glucose across the foetal facing membranes (Limesand, Regnault, & Hay, 2005). In late gestation, foetal and placental rates of glucose consumption calculated by kg tissue vary between species but are consistently five- to 10-fold higher in the placenta than foetus (Table 1). Consistent with the lower rates of foetal glucose uptake in sheep and cows in late gestation (Table 1), the cotyledonary epitheliochorial placenta of these ruminants appears to use a greater proportion of the glucose taken up from the uterine circulation (55–85%) than the diffuse epitheliochorial placenta of horses and pigs (25–50%, Fowden, 1997). Glucose consumption per kg of combined uteroplacental tissues increases between mid-gestation and late gestation in sheep but decrease over the last-third of gestation in the horse, although, in both species, the percentage of total uterine glucose uptake used by the uteroplacental tissues is less near term than earlier in gestation (Bell et al., 1986; Fowden, Forhead et al., 2000; Fowden, Taylor et al. 2000; Molina et al., 1991). In sheep, the glucose consumed by the uteroplacental tissues is known to be used for oxidative phosphorylation and synthesis of polyols, other sugars and carbohydrates (Fig. 1). Measurements made with tracer glucose indicate that, of the glucose used by the uteroplacental tissues, 15–20% is oxidized to CO2, approximately 30% is converted to lactate via glycolysis and 5–10% is metabolized to fructose via sorbitol (Aldoretta & Hay, 1999). The remaining 40–50% of the glucose carbon is unaccounted for but may contribute to the short-term turnover of amino acids, glycerol and keto acids and/or to the synthesis of substances with longer turnover times such as glycosaminoglycans, proteins and lipids (Aldoretta & Hay, 1999; Kim, Song, Wu, & Bazer, 2012). Some of the lactate and fructose produced by the ovine placenta may also be used oxidatively for ATP generation, which, together with glucose, could account for up to 50% of the normal rate of uteroplacental O2 consumption (Meznarich, Hay, Sparks, Meschia, & Battagla, 1987; Sparks, Hay, Bonds, Meschia, & Battaglia, 1982). However, the majority of the lactate and fructose produced by the ovine placenta in late gestation appears to be transported into either the umbilical and/or uterine circulations (Fig. 1). GLUT8 may be responsible for fructose transport but little is known about placental expression of the monocarboxylate transporters (MCTs) that transport lactate in any farm animal (Limesand et al., 2005). Two MCT isoforms, MCT1 and MCT4, have been identified in human and mouse placenta with species-specific polarized expression on maternal and foetal facing membranes indicative of different transport kinetics at the two surfaces (Nagai, Takebe, Nio-Kobayashi, Takahashi-Iwanaga, & Iwanaga, 2010; Settle et al., 2004). Fructose is also detected in high concentrations in foetal pigs, cows and horses but whether the placenta produces fructose and releases it into the foetal circulation in late gestation in these species remains unclear (Silver, 1984). Porcine trophectoderm cells can use fructose in vitro to synthesize glycosaminoglycans such as hyaluronic acid and the ovine placenta uses small amounts of fructose oxidatively and to produce lactate in vivo, although little is known about these metabolic processes in other species (Kim et al., 2012; Meznarich et al., 1987). In contrast, lactate production by the uteroplacental tissues has also been observed in pigs, horses and cows (Table 1). In the ovine and bovine placenta, net production of lactate appears to be derived solely from glucose and varies directly with the rate of uteroplacental glucose consumption in normal conditions (Aldoretta, Carver, & Hay, 1994; Aldoretta & Hay, 1999; Comline & Silver, 1976). Uteroplacental lactate production per unit weight of total tissue increases between mid-gestation and late gestation in sheep and horses in association with changes in its relative distribution between the uterine and umbilical circulations (Bell et al., 1986; Fowden, Forhead et al., 2000; Fowden, Taylor et al. 2000; Sparks et al., 1982). In sheep at mid-gestation, uteroplacental lactate production is low and distributed almost entirely into the uterine circulation, whereas, by late gestation, production is three- to fourfold higher per unit weight and distributed equally into the foetal and maternal circulations (Bell et al., 1986; Fig. 1). In horses, uteroplacental lactate production is undetectable at mid-gestation while near term, it occurs at a significant rate and is distributed solely to the foetus (Fowden, Forhead et al., 2000; Fowden, Taylor et al. 2000). Similarly, in cows near term, the majority of lactate produced by the uteroplacental tissues is released into the umbilical circulation, although absolute rates of production vary with breed (Comline & Silver, 1976; Ferrell, 1991). Like cows, uteroplacental lactate production in pigs appears to be delivered primarily to the foetus near term and makes a greater contribution to the daily foetal carbon requirement in pigs than other farm animals (Fowden Forhead, Silver & Macdonald 1997). The mechanisms involved in these ontogenic changes in uteroplacental production and distribution of lactate remain unknown but may involve alterations in cell types or cellular O2 availability within the placental tissues and, possibly, a switch from oxidative to more glycolytic metabolism of glucose towards term. However, as lactate and fructose can both be utilized by foeto-placental tissues (Meznarich et al., 1987; Sparks et al., 1982), their placental production provides alternative sources of carbon for foetal metabolism and growth, which may be beneficial in stressful conditions. During nutritional stresses, uteroplacental consumption and umbilical uptake of glucose alter largely in line with the changes in maternal glycaemia and the transplacental glucose concentration gradient (Hay, 2006). In sheep, stresses which produce maternal hypoglycaemia, therefore, tend to reduce glucose consumption calculated per kg placenta while, conversely, maternal hyperglycaemia increases these rates (Fig. 2). During maternal hypoglycaemia lasting two to seven days, percentage distribution of uterine glucose uptake between ovine uteroplacental and foetal tissues does not alter and both share equally in the reduced glucose availability (Fowden & Forhead, 2011; Hay, Molina, DiGiacomo, & Meschia, 1990; Hay, Sparks, Wilkening, Battaglia, & Meschia, 1983). However, as maternal hypoglycaemia becomes prolonged, the uteroplacental tissues appear to use proportionally more of the uterine glucose uptake than in normoglycaemic conditions (Carver & Hay, 1995; Hay et al., 1983). The relationship between uteroplacental glucose consumption and maternal glucose levels is, therefore, more complex during stressful than normal conditions. Particularly in late gestation, foetal sheep can activate glucogenesis when hypoglycaemic or hypercortisolaemic, which raises their glucose levels independently of the maternal concentrations (DiGiacomo & Hay, 1990; Houin et al., 2015; Ward, Wooding, & Fowden, 2004). This has consequences for the transplacental glucose concentration gradient and carbon fluxes from the placenta to foetus and vice versa (DiGiacomo & Hay, 1990). Indeed, net uteroplacental glucose consumption varies directly with the foetal glucose concentration when foetal glucose levels are manipulated experimentally independently of the mother (Hay et al., 1990; Thureen et al., 1992; Ward et al., 2004). Chronic stresses that reduce placental growth such as hyperthermia and hypoglycaemia alter the glucose transport capacity of the ovine placenta at any given transplacental gradient, which suggests that other morphological and/or functional factors are influencing placental fluxes and consumption of glucose in these circumstances (Fowden et al., 2010). Certainly, placental GLUT expression is affected by longer term variations in maternal glycaemia with decreases in GLUT1 abundance in hypoglycaemia and hyperthermic conditions, and in both GLUT1 and GLUT 3 abundance in response to maternal hyperglycaemia in ewes (Das, He, Ehrhardt, Hay, & Devaskar, 2000; Das, Sadiq, Soares, Hay, & Devaskar, 1998; Ma et al., 2011; Zhu, Ma, Long, Du, & Ford, 2010). Similar changes in the glucose transport capacity associated with altered GLUT expression are observed in the small placenta of carunclectomized ewes and in the mouse placenta after maternal undernutrition and other dietary manipulations (Owens, Falconer, & Robinson, 1987b; Vaughan et al., 2012). During uterine artery constriction, ovine uteroplacental tissues use less glucose, which sustains umbilical glucose uptake in the face of the reduced uterine glucose delivery (Hooper et al., 1995). As placental O2 consumption is maintained in these and other stressful conditions in which placental glucose consumption is reduced (Fig. 2), the ovine placenta must switch from glucose to other oxidative substrates to maintain its respiratory rate (Fig. 1). In contrast, when O2 availability is reduced at high altitude, the human placenta uses 60% more glucose and 20% less O2 than at sea level (Illsley & Caniggia, 2010). The hypoxic human placenta, therefore, appears to switch from oxidative phosphorylation of glucose to a greater dependence on glycolysis to meet its ATP requirements, thereby sparing O2 but reducing glucose availability for foetal delivery. In sheep, placental production and umbilical uptake of lactate appear to parallel placental glucose consumption during most stressful conditions (Fig. 2). However, in the small placenta of carunclectomized ewes, uteroplacental lactate production exceeds the rate of uteroplacental glucose consumption, so there must be other carbon sources for lactate synthesis and/or oxidative phosphorylation in these animals (Owens et al., 1987b). Similarly, when either maternal or foetal cortisol levels are raised, placental lactate production appears to vary independently of placental glucose consumption (Fig. 2). With cortisol overexposure from the foetus, uteroplacental lactate production is unaffected despite increased uteroplacental glucose consumption, whereas, when cortisol is infused maternally, uteroplacental lactate production increases without a significant rise in uteroplacental glucose consumption (Vaughan, Davies, Ward, De Blasio, & Fowden, 2016; Ward et al., 2004). Thus, lactate production by ovine uteroplacental tissues is regulated dynamically and is responsive to foetal and maternal environmental cues. Indeed, the ovine placenta can switch rapidly from net production to net consumption of lactate during exercise and from releasing lactate into the foetus to clearing it from the foetal circulation within 4 hr of uterine artery restriction (Chandler, Leury, Bird, & Bell, 1985; Hooper et al., 1995). The placenta transports, utilizes, produces and interconverts amino acids. The ovine placenta has a high rate of protein synthesis and, given the changes that occur in placental morphology over the second-half of gestation, its rate of protein turnover is also likely to be high (Bell & Ehrhardt, 2002; Vatnick & Bell, 1992; Wooding & Burton, 2008). In sheep, all nine essential amino acids that cannot be synthesized de novo and most of the other amino acids needed for protein synthesis are taken up from the uterine circulation against their concentration gradients using energy-dependent active transport (Bell & Ehrhardt, 2002). In late gestation, foetal concentrations of most amino acids are also higher than those of the mother in cows and pigs although not consistently in the horse (Ashworth, Nwagwu, & McArdle, 2013; Silver, Fowden, Taylor, Knox, & Hill, 1994; Zicker, Vivrette, & Rogers, 1994). There are also breed differences in foetal and maternal amino acid profiles and in foetal to maternal concentration ratios for specific amino acids in sheep, pigs and horses, which may relate, in some instances, to differences in nutrition (Ashworth, Dwyer, McIlvaney, Wekman, & Rooke, 2011; Ashworth et al., 2013; Jobgen et al., 2008; Kwon et al., 2004; Silver et al., 1994; Wu, Pond, Ott, & Bazer, 1998; Zicker et al., 1994). In addition, foetal to maternal concentration amino acid ratios may change with increasing gestational age in pigs and horses (Ashworth et al., 2013; Silver et al., 1994; Wu et al., 1998; Zicker et al., 1994). Although net amino acid transport is from mother to foetus for most amino acids, significant bidirectional fluxes have been observed across ovine placental membranes using labelled amino acid tracers (Battaglia, 2002). For three amino acids (glutamate, aspartate and serine), there is no net uteroplacental uptake from the ovine uterine circulation (Regnault, de Vrijer, & Battaglia, 2002). Instead, the uteroplacental tissues derive these amino acids from the foetal circulation. Multiple amino acid transporter systems have been identified in the ovine placenta, which differ in their amino acid specificity, sodium dependence and localization within the placental barrier (Regnault et al., 2002; Wooding & Burton, 2008). Amino acid specificity of the transporter systems overlaps for some amino acids, so there is competition between these amino acids for uteroplacental uptake and transplacental transport, which depends on their concentrations in the maternal circulation (Regnault et al., 2002). The ovine placenta is a net consumer of glutamate, serine and three branched-chain amino acids (BCAA), valine, leucine and isoleucine, and also releases glutamine, methionine and glycine into the foetus in excess of the uterine uptakes (Chung, Teng, Timmerman, Meschia, & Battaglia, 1988). Thus, significant catabolism and/or transamination of amino acids occurs within the ovine placenta, which leads to the production of ammonia and α-keto acids (Fig. 1). The ammonia is released primarily into the uterine circulation but can also be used to synthesis other amino acids such as glutamate (Liechty, Kelley, & Lemons, 1991). The α-keto derivatives may be oxidized to produce ATP, released into the foetal circulation or metabolized into amino acids and other substances, such as fatty acids, proteins and peptides that are, in turn, metabolized or secreted by the placenta (Fig. 1). Placental mitochondria have been shown to use several amino acids for oxidative phosphorylation in vitro and glutamate is oxidized at high rates by the ovine placenta in vivo in late gestation (Moores et al., 1994; : Battaglia, 2002). Given its large placental uptake and synthesis in utero from BCAA (Battaglia & Regnault, 2001), glutamate is likely to be quantitatively the most important fuel amongst the amino acids. If complete, its oxidation would account for 10% of the uteroplacental O2 consumption and provide NADPH for placental steroidogenesis, lipogenesis and nucleoside production. In addition to oxidation, 6% of the glutamate taken up by the ovine placenta is converted to glutamine, which is then released into the foetal circulation in amounts exceeding its uterine uptake (Moores et al., 1994). Glutamine is also synthesized from BCAA and glutamate by the porcine and equine placenta (Manso Filho, Costa, Wu, McKeever, & Watford, 2009; Self et al., 2004). It is used for foeto-placental synthesis of protein and glycosaminoglycans and is re-converted back to glutamate by foetal ovine liver (Battaglia, 2000; Kim et al., 2012). There is also significant metabolic interconversion of alanine, pyruvate and lactate in the ovine placenta without net uteroplacental alanine consumption (Timmerman et al., 1998). Alanine derived from the maternal circulation is, therefore, exchanged for endogenously produced alanine with the result that net umbilical uptake of alanine is derived from placental transamination and protein turnover with only a small fraction coming from direct transplacental flux (Timmerman et al., 1998). Similarly, serine taken up from both circulations is metabolized to glycine in the ovine placenta, which results in significant umbilical glycine uptake without net uterine uptake (Geddie et al., 1996; Regnault et al., 2002). In addition, the methylenetetrahydrofolate produced by conversion of serine to glycine can be used in purine synthesis or for remethylation of homocysteine to methionine. If homocysteine is taken up from the uterine circulation, this metabolic pathway may also account for the umbilical uptake of methionine in the sheep foetus. Placental amino acid metabolism is, therefore, complex and involves metabolic cycling between the maternal, placental and foetal compartments with important consequences for the amounts and composition of the amino acids delivered to the foetus. In farm animals, foetal and maternal amino acid concentrations are affected by a wide range of stressful conditions including heat stress, undernutrition, hypoglycaemia, protein deprivation and glucocorticoid administration (Ashworth et al., 2011, 2013; Kwon et al., 2004; Regnault et al., 2013; Schaefer, Krishnamurti, Heindze, & Gopinath, 1984; Silver et al., 1994; Timmerman et al., 2000; Wu et al., 1998). For instance, maternal undernutrition influences maternal and foetal amino acid profiles, reduces specific amino acid concentrations and alters the foetal to maternal concentration ratios for specific amino acids in sheep, pigs and horses, which suggests that placental amino acid transport or competition amongst the amino acids for the transporters and/or foeto-placental amino acid metabolism are altered in these circumstances (Ashworth et al., 2011; Kwon et al., 2004; Schaefer et al., 1984; Silver et al., 1994). In sheep, these changes persist after restoration of normal nutrition which indicates that foeto-placental amino acid metabolism may be permanently altered by nutritional stress earlier in gestation (Kwon et al., 2004). Certainly, undernutrition of pregnant ewes for seven days leads to increased placental BCAA utilization and ammonia production, indicative of increased placental amino acid deamination (Liechty et al., 1991). There are also reductions in the umbilical uptake, transplacental flux and foeto-placental back flux of leucine and threonine after heat stress, even when the lower placental weight is taken into account (Anderson, Fennessey, Meschia, Wilkening, & Battaglia, 1997; Ross, Fennessey, Wilkening, Battaglia, & Meschia, 1996). Similarly, umbilical leucine uptake per kg foetus is less during prolonged maternal hypoglycaemia and coupled with a trend for greater percentage utilization of the uterine uptake by the uteroplacental tissues (Carver et al., 1997). In addition, both maternal undernutrition and foetal dexamethasone administration reduce foetal glutamate concentrations and placental glutamate uptake from the foetal circulation, which indicates that ovine placental–foetal amino acid cycling is also responsive to environmental conditions during late gestation (Houin et al., 2015; Liechty et al., 1991; Schaefer et al., 1984; Timmerman et al., 2000). Reduced placental uptake and metabolism of glutamate may also lower NADPH availability consistent with the decrease in progesterone synthesis seen when foetal glucocorticoids rise in late gestation (Silver, 1984; Timmerman et al., 2000). Similar changes in amino acid cycling between the foetal and placental compartments are also seen in response to manipulation of other foetal hormone concentrations (Teng, Battaglia, Meschia, Narkewicz, & Wilkening, 2001). When availability of single amino acids is increased experimentally in pregnant ewes, their umbilical uptake and placental utilization is increased significantly, probably at the expense of other amino acids using the same transporters (Battaglia, 2002; Thureen, Baron, Fennessey, & Hay, 2002; Timmerman et al., 1998). Similarly, maternal BCAA infusion increases their umbilical uptake and uteroplacental utilization by deamination as indicated by the increased uteroplacental production of ammonia (Jozwik, Teng, Battaglia, & Meschia, 1999; Jozwik et al., 2001). However, when mixtures of amino acids are infused, umbilical uptake may increase, decrease or be unaffected depending on the specific amino acid due to competitive inhibition by the other amino acids for the different transporter systems in the ovine placenta (Battaglia, 2002). Collectively, these findings suggest that placental amino acid metabolism and transport adapt to environmental stresses in farm animals with implications for foetal growth as seen in humans and rodents (Day et al., 2015; Gaccioli et al., 2013; Lewis et al., 2013; Vaughan et al., 2012). Although lipids and free fatty acids (FFA) are required for growth and development of foeto-placental tissues, the epitheliochorial placenta of ruminants, pigs and horses appears to be relatively impermeable to these substances compared to the human and rodent haemochorial placenta (Herrera & Ortega-Senovilla, 2014). Both the uterine arterio-venous and the umbilical venous-arterial concentration differences in fatty acids are negligible in sheep, cows and horses during late gestation (Elphick, Hull, & Broughton Pipkin, 1979; James, Meschia, & Battaglia, 1971; Stammers, Silver, & Fowden, 1988). There is also little evidence for transfer of labelled short- or long-chain fatty acids across the ovine placenta, despite the presence of fatty acid transporters in the placentomes at mid-gestation and late gestation (Elphick et al., 1979; Leat & Harrison, 1980; Ma et al., 2011; Zhu et al., 2010). However, in sheep and horses, the placenta does appear to hydrolyse esterified lipids and to desaturate and elongate fatty acids, including the essential C18 fatty acids, which, together with placental synthesis of lipids from glucose and keto acids, may provide an adequate supply of essential lipids and fatty acids to the foeto-placental tissues (Bell & Ehrhardt, 2002; Stammers et al., 1988). In sheep and cows, rumen fermentation leads to significant amounts of acetate and other volatile fatty acids (VFA), such as β-hydroxybutyrate and acetoacetate, in the maternal circulation. Although these substances are taken up by the uterus in relatively small amounts compared to other nutrients, they are utilized by the uteroplacental tissues and transported to the foetus (Fig. 1). In both sheep and cows, rates of VFA consumption are higher per kg of placental than foetal tissues (Carver & Hay, 1995; Comline & Silver, 1976). In sheep, the β-hydroxybutyrate taken up from the uterine circulation is utilized almost entirely within the uteroplacental tissues with no significant onward transfer to foetus, whereas uterine acetoacetate uptake is distributed equally between the uteroplacental and foetal tissues, although the uterus takes up significantly less acetoacetate than β-hydroxybutyrate (Carver & Hay, 1995; Smeaton, Owens, Kind, & Robinson, 1989). In cows near term, there is significant uteroplacental consumption of acetate at rates eight- to 10-fold higher than those of the foetus when expressed per unit weight (Comline & Silver, 1976). The fate of the VFA used in utero remains unknown but may involve oxidative phosphorylation to generate ATP and/or synthesis into steroids and fatty acids (Christie & Noble, 1982; Dhand, Mk, Shepherd, Smith, & Varnam, 1970; Miodovnik et al., 1982). Compared to carbohydrates and amino acids, much less is known about the effects of adverse conditions on the placental metabolism and transport of lipids, FFA and VFA in farm animals. In sheep and horses, there are changes in the lipid and FFA profiles of foetal and maternal plasma in response to maternal undernutrition, which may be related, in part, to altered placental lipid metabolism (Stammers, Hull, Silver, & Fowden, 1995; Stammers et al., 1988). Certainly, in both these species, maternal hypoglycaemia induced by short-term fasting or insulin infusion is associated with increased uteroplacental synthesis and release of prostaglandins, which are hormones derived from arachidonic acid through phospholipid metabolism (Fowden & Silver, 1983; Silver & Fowden, 1982). This has led to the suggestion that the placenta may switch from glucose to a greater use of lipids as metabolic fuels when glucose availability is limited, thereby increasing the supply of precursors for prostaglandin synthesis (Fowden, Ralph, & Silver, 1994). This is consistent with the increase in fatty acid transporters seen in the ovine placenta during undernutrition (Ma et al., 2011). Similar increases in placental lipid metabolism are believed to occur in the human and rodent placenta during intrauterine growth restriction (Cetin & Alvino, 2009; Herrera & Ortega-Senovilla, 2014). Foetal VFA concentrations have been shown to vary naturally with maternal concentrations in sheep and cows but little is known about the factors regulating placental VFA metabolism and transport in adverse conditions (Comline & Silver, 1976). Infusion of β-hydroxybutyrate into pregnant ewes increases its foetal concentration and causes foetal lactacidaemia and hypoxaemia (Miodovnik et al., 1982). Prolonged maternal undernutrition also increases maternal concentrations and uterine uptake of β-hydroxybutyrate through increased maternal fat utilization, which may provide the placenta with alterative oxidative substrates to glucose (Chandler et al., 1985). In contrast, prolonged insulin-induced maternal hypoglycaemia leads to decreased uterine uptake and uteroplacental utilization of both β-hydroxybutyrate and acetoacetate in the absence of changes in the maternal or foetal concentrations (Carver & Hay, 1995). Taken together, these findings suggest that VFA metabolism by the ruminant placenta is responsive to environmental stresses but is determined largely by maternal nutrient availability. The placenta is a metabolically labile organ that is responsive to a range of interdependent nutritional and endocrine signals of adversity (Fig. 3). It integrates these multiple signals and adapts its metabolic phenotype accordingly to maintain pregnancy and maximize the chances of foetal survival in utero. The metabolic response of the placenta depends on the nature, severity and duration of the stressful challenge and also on whether signals of stress are maternal, placental or foetal in origin (Fig. 3). By diversifying the sources of carbon and nitrogen available to the foetus, the metabolic responsiveness of the placenta also helps to optimize offspring fitness for the prevailing environmental conditions and, thus, improves the likelihood of the offspring reaching reproductive age. The authors would like to thank the many members of the Centre for Trophoblast Research (CTR) and the Department of Physiology, Development and Neuroscience, who have helped with their own studies presented here. They are also grateful to the CTR and the Biotechnology and Biological Sciences Research Council for research funding." @default.
W2534782676 created "2016-10-28" @default.
W2534782676 creator A5050299817 @default.
W2534782676 creator A5050849649 @default.
W2534782676 date "2016-10-01" @default.
W2534782676 modified "2023-09-27" @default.
W2534782676 title "Placental metabolism: substrate requirements and the response to stress" @default.
W2534782676 cites W1519493617 @default.
W2534782676 cites W1561075140 @default.
W2534782676 cites W1693014831 @default.
W2534782676 cites W1864718927 @default.
W2534782676 cites W1903178581 @default.
W2534782676 cites W1915654475 @default.
W2534782676 cites W1953054569 @default.
W2534782676 cites W1964036070 @default.
W2534782676 cites W1964325745 @default.
W2534782676 cites W1974232929 @default.
W2534782676 cites W1976712816 @default.
W2534782676 cites W1977442555 @default.
W2534782676 cites W1979484401 @default.
W2534782676 cites W1980612945 @default.
W2534782676 cites W1982376272 @default.
W2534782676 cites W1985770387 @default.
W2534782676 cites W1988673888 @default.
W2534782676 cites W1992084466 @default.
W2534782676 cites W1992975965 @default.
W2534782676 cites W1993046726 @default.
W2534782676 cites W1993194232 @default.
W2534782676 cites W2002565283 @default.
W2534782676 cites W2006313660 @default.
W2534782676 cites W2008257914 @default.
W2534782676 cites W2013789234 @default.
W2534782676 cites W2015944729 @default.
W2534782676 cites W2018580834 @default.
W2534782676 cites W2024887680 @default.
W2534782676 cites W2024996129 @default.
W2534782676 cites W2026755092 @default.
W2534782676 cites W2029402131 @default.
W2534782676 cites W2030780318 @default.
W2534782676 cites W2032433838 @default.
W2534782676 cites W2037410689 @default.
W2534782676 cites W2040263076 @default.
W2534782676 cites W2041893906 @default.
W2534782676 cites W2044436820 @default.
W2534782676 cites W2046283539 @default.
W2534782676 cites W2047336940 @default.
W2534782676 cites W2056331401 @default.
W2534782676 cites W2057992778 @default.
W2534782676 cites W2060871509 @default.
W2534782676 cites W2069396506 @default.
W2534782676 cites W2069401275 @default.
W2534782676 cites W2071424202 @default.
W2534782676 cites W2071735067 @default.
W2534782676 cites W2075544588 @default.
W2534782676 cites W2077244432 @default.
W2534782676 cites W2077557033 @default.
W2534782676 cites W2081579726 @default.
W2534782676 cites W2086065789 @default.
W2534782676 cites W2090799028 @default.
W2534782676 cites W2094104040 @default.
W2534782676 cites W2105773602 @default.
W2534782676 cites W2108184608 @default.
W2534782676 cites W2114921504 @default.
W2534782676 cites W2127716115 @default.
W2534782676 cites W2139400931 @default.
W2534782676 cites W2151760498 @default.
W2534782676 cites W2156556141 @default.
W2534782676 cites W2164709834 @default.
W2534782676 cites W2167231581 @default.
W2534782676 cites W2168371658 @default.
W2534782676 cites W2170663158 @default.
W2534782676 cites W2207208374 @default.
W2534782676 cites W2308489670 @default.
W2534782676 cites W2419265946 @default.
W2534782676 cites W2443565599 @default.
W2534782676 cites W253153322 @default.
W2534782676 cites W4250565790 @default.
W2534782676 doi "https://doi.org/10.1111/rda.12797" @default.
W2534782676 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27762057" @default.
W2534782676 hasPublicationYear "2016" @default.
W2534782676 type Work @default.
W2534782676 sameAs 2534782676 @default.
W2534782676 citedByCount "46" @default.
W2534782676 countsByYear W25347826762017 @default.
W2534782676 countsByYear W25347826762018 @default.
W2534782676 countsByYear W25347826762019 @default.
W2534782676 countsByYear W25347826762020 @default.
W2534782676 countsByYear W25347826762021 @default.
W2534782676 countsByYear W25347826762022 @default.
W2534782676 countsByYear W25347826762023 @default.
W2534782676 crossrefType "journal-article" @default.
W2534782676 hasAuthorship W2534782676A5050299817 @default.
W2534782676 hasAuthorship W2534782676A5050849649 @default.
W2534782676 hasBestOaLocation W25347826762 @default.
W2534782676 hasConcept C185592680 @default.
W2534782676 hasConcept C18903297 @default.
W2534782676 hasConcept C2777289219 @default.
W2534782676 hasConcept C55493867 @default.