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Maternal-fetal resource allocation: Co-operation and conflict
Placenta 33 (2012) e11ee15
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Maternal-fetal resource allocation: Co-operation and conflict A.L. Fowden a, *, T. Moore b a b
Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK Department of Biochemistry, Biosciences Institute, University College Cork, College Road, Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 7 May 2012
Pregnancy is generally a co-operative interaction between mother and fetus in which the evolutionary genetic interests of both benefit from production of healthy offspring. While this view is largely supported by empirical data, Kinship Theory predicts that mother and fetus will disagree over the optimum level of maternal investment that maximises their respective fitnesses. This conflict will be more evident with polyandrous than monogamous mating systems, when resources are scarce and in late gestation when the fetus is growing maximally, particularly if conceptus mass is large relative to maternal mass. As the site of nutrient transfer, the placenta is pivotal in the tug-of-war between mother and fetus over resource allocation. It responds to both fetal signals of nutrient demand and maternal signals of nutrient availability and, by adapting its phenotype, regulates the distribution of available resources. These adaptations involve changes in placental size, morphology, transport characteristics, metabolism and hormone bioavailability. They are mediated by key growth regulatory, endocrine and nutrient supply genes responsive to mismatches between nutrient availability and the fetal genetic drive for growth. Indeed, evolution of genomic imprinting and placental secretion of hormones are believed to have been driven by maternal-fetal conflict over resource allocation. Although many of the specific mechanisms involved still have to be identified, the placenta confers optimal fitness on the offspring for its developmental environment by balancing conflict and cooperation in the allocation of resources through generation of nutrient transport phenotypes specific to the prevailing nutritional conditions and/or fetal genotype. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Placental nutrient transfer Imprinted genes Fetal growth Nutrition
1. Introduction In eutherian mammals, pregnancy is an apparently highly cooperative interaction between the mother and fetus which, at best, leads to delivery of viable offspring with little detriment to the future health or fecundity of the mother [1]. Through a variety of morphological and physiological adaptations, the fetus demands resources from the mother that support its growth in utero, and generally, a larger well-resourced fetus is more likely to survive at birth and onto reproductive age. The mother benefits from the investment in her offspring because it contributes to the transmission of her genes to future generations [2]. However, inevitably, maternal investment in the current fetus will leave fewer resources for future reproduction. Because the fetus inherits only half of its genes from its mother and shares, at most, half of its genes with its mother’s future offspring, there is a conflict between the mother and fetus because the fetus will demand more resources from the
* Corresponding author. Tel.: þ44 (0) 1223 333855; fax: þ44 (0) 1223 333840. E-mail address: [email protected] (A.L. Fowden). 0143-4004/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.placenta.2012.05.002
mother than may be in her long term reproductive interests to supply [1]. Several lines of evidence suggest that interactions between maternal and fetal genes can occur in determining the level of maternal investment in individual pregnancies. Inter- and intra-specific crosses between breeds of several species show that the mother can constrain the fetal genetic drive for growth and that, conversely, the fetal genome can influence the mother with consequences for fetal growth and pregnancy outcome [3e6]. Similarly, more direct manipulation of the fetal genome by gene deletion or disruption is known to alter the metabolic and endocrine adaptations of the mouse dam to pregnancy [7e9]. However, much less is known about the nature of the interactions between maternal and fetal genes in the context of normal pregnancy. If, as predicted by Kinship Theory, maternal-fetal conflict over the level of maternal investment in the fetus is the norm, it is likely to be particularly relevant in late gestation when the fetus is growing most rapidly in absolute terms or when resources are scarce, for example, due to undernutrition during pregnancy or to a low pre-pregnancy body mass index (BMI) of the mother [10,11]. Similarly, the importance of conflict will vary with the mating system of the species, particularly the degree of polyandry, and
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perhaps the size of the conceptus(es) in relation to maternal mass [1,10]. There are wide inter-species differences in fetal growth rates and in the proportion of maternal weight that is accounted for by the gravid uterus in late gestation (Table 1). Therefore, conflict in nutrient allocation during pregnancy may be more significant in rodents and other species in which total conceptus mass accounts for 20% or more of maternal weight than in higher order primates, in which the gravid uterus is only 6e9% of maternal mass at term (Table 1). Increased litter size leading to direct inter-sibling rivalry and an increased total fetal demand for nutrients may also heighten potential conflict between mother and fetuses in determining nutrient allocation ([5,6,11] and Table 1). With strict monogamy which occurs rarely in mammals [12], the mother and current offspring are equally related to her future offspring and this provides a constraint on the magnitude of maternal-fetal conflict. From Hamilton’s rule (Fig. 1), the current offspring will demand resources from the mother as long as the fitness benefit to itself is twice the fitness cost to future offspring [1]. However, in the more common polyandrous mating systems where females mate with more than one male during their reproductive life, conflict is potentially more intense as the differing paternal contributions to the fetal genomes of half-sibs will be less constrained in demanding resources from the mother to the detriment of half-sibs (Fig. 1). Maternal-fetal conflict under polyandry results in differential selection on maternally and paternally inherited alleles in the fetus, with paternal alleles promoting increased maternal investment in the fetus and maternal alleles evolving expression patterns that counteract the effects of ‘greedy’ paternal alleles [2]. The resulting biased expression pattern of the parental alleles is manifested as genomic imprinting [13]. 2. The placenta and maternal-fetal nutrient allocation As the site of nutrient transfer, the placenta is pivotal in the tugof-war between mother and fetus over resource allocation [14]. It is the interface where cooperation and conflict coexist and responds to both fetal signals of nutrient demand and maternal signals of nutrient availability in optimising the distribution of available nutrients. To achieve this, the placenta adapts its phenotype in response to a wide range of environmental conditions by changing its surface area for nutrient transfer, the thickness of its
Table 1 Maternal and offspring body weight at term and fetal growth rate in different species during late gestation (85% gestation). Data from Ref. [6,10,12,18]. Species
Maternal weight kg
Offspring birthweight kg
Placental-fetal wt% maternal wt
Growth g/kg fetal wet wt/day
Mouse Rat Guinea pig Monkey Pig Sheep Welsh Mountain Suffolk Singleton Twins Triplets Primate Human Chimpanzee Macaque Marmoset Twins Triplets Horse
0.037 0.450 1.2 6.0 180
0.0012 0.006 0.090 0.500 1.200
30 25 30 8 17
450 300 68 44 33
45
3.000
9
36
60 68 75
5.000 4.500 3.250
9 14 15
e e e
72 40 5.5
3.500 1.850 0.500
6 5 11
15 e 11
0.380 0.425 550
0.060 0.082 52.000
19 22 10
e e 9
interhaemel barrier separating the maternal and fetal circulations, its abundance of nutrient transporters, metabolic rate and blood flow as well as its synthesis and metabolism of specific hormones [15,16]. These factors also change with gestational age to meet the increasing nutritional demands of the growing fetus in late gestation [14]. For instance, between mid and late gestation in several species, placental surface area increases and barrier thickness decreases along with increases in the weight specific rate of placental blood flow [16,17]. Maternal nutrient allocation to the fetus can, therefore, be manipulated either, directly, by morphological and functional changes to the placenta per se or, indirectly, by systemic changes in nutrient availability that alter the transplacental concentration gradients for nutrient diffusion. These mechanisms are used by both mother and fetus to alter nutrient distribution. 2.1. Placental growth and morphology From the maternal perspective, placental growth needs to reflect both the available nutrient stores at the time of conception and the current nutritional state. Indeed, in several species including humans, placental weight at term is directly related to pre-pregnancy BMI or body condition score and is reduced if there is gestational weight loss or undernutrition during late gestation when fetal nutrient demands are normally at their highest [15,18e21]. Thus, mothers do not operate solely to constrain nutrient allocation to their fetuses but will permit a greater transplacental nutrient flow if their nutritional status can support the extra investment. From the fetal perspective, the larger the placenta, the greater the potential supply of nutrients [10,14]. Increases in placental size or in the surface area for transport are observed in response to maternal undernutrition during the period of placental development but are not always sustained to term, particularly if undernutrition persists [14]. This is consistent with a fetal drive to maximise nutrient provision that is tempered by maternal constraint when the nutrient requirements of the rapidly growing fetus exceed nutrient availability in late gestation. The nature of the nutritional signals controlling placental growth and morphology remains unknown, particularly at the earliest stages of development. At the blastocyst stage, differentiation of the trophectoderm from the inner cell mass may be affected by the nutrient and growth factor content of the uterine secretions providing histiotrophic nutrition [22]. Later, maternal endocrine signals of nutritional status, such as growth hormone (GH) and insulin-like growth factor (IGF)-I concentrations, may influence placental growth either directly or indirectly through their actions on maternal metabolism [23e25]. However, the specific effects of these hormones appear to depend on the anabolic status of the mother as they direct maternal nutrients away from utero-placental growth in young growing adolescents but towards fetal growth in fully grown animals [25e27]. In contrast, maternal endocrine signals of adversity like the glucocorticoids reduce placental and fetal growth in several species including humans and rodents [28]. 2.2. Placental nutrient transfer Nutrient allocation can be altered independently of any change in placental size or morphology by changing the abundance of nutrient transporters or the transplacental concentration gradients used to drive simple and facilitated diffusion [14]. As gestation proceeds in several species, the fetus lowers its glucose concentrations to maximize the gradient and increase the transplacental glucose supply. In some species, there are also gestational increases in placental abundance of the glucose transporters used for
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Fig. 1. Schematic diagram showing the genetic relatedness coefficients (r) between maternally (rmat) and paternally (rpat) inherited haploid genomes of offspring under theoretical strictly monogamous and polyandrous mating systems (See Ref. [1] for detailed explanation).
facilitated diffusion [10,29]. The mother counteracts by lowering her fasting glucose concentrations but not to the same extent as the fetus [29,30]. However, maternal glucose concentrations do vary with nutritional state and, thereby, alter fetal glucose delivery in relation to maternal resource availability. Transplacental provision of amino acids for growth is an active process requiring amino acid transporters which increase in placental abundance concomitantly with the rapid phase of fetal growth in late gestation [31]. Often, in poor nutritional conditions, there is up-regulation of placental amino acid transporters expression and of amino acid transport, which helps to maintain fetal growth, even when the placenta is small [14,15]. With more extreme under- or mal-nutrition, amino acid transport and transporter abundance may be down-regulated in association with fetal growth restriction [31,32]. These ontogenic and nutritionallyinduced changes in placental nutrient transport are likely to be the result of complex interactions between maternal and fetal systemic signals arising from the mismatch between the fetal genetic drive for growth and nutrient availability on both sides of the placenta [14,16,31e33]. A range of nutritionally sensitive hormones including GH, IGF-I, leptin and the glucocorticoids have been shown to alter placental nutrient transfer both in vitro in human cultured trophoblast and in vivo in several species including sheep, guinea pigs and rodents [24,34e36]. Endocrine signals of nutrient abundance like leptin and IGF-I increase amino acid transport by cultured human trophoblast [19,32,34]. Similarly, GH increases glucose transfer across human placental villous fragments [34]. Maternal GH and IGF-I also increase nutrient partitioning to fetal sheep by actions on the diffusion capacity and carbohydrate metabolism of the placenta [35,36]. On the other hand, glucocorticoids, which signal nutrient insufficiency and other adverse environmental conditions, tend to reduce weight specific transplacental transfer of glucose and amino acids in vivo, irrespective of whether maternal or fetal glucocorticoid concentrations are raised [28,36,37]. Since glucocorticoids inhibit fetal growth directly, these placental adaptations ensure that the nutrient supply of the compromised fetus is commensurate with its reduced drive for growth [36]. In part, these systemic effects on placental nutrient transfer are mediated through changes in placental expression of key growth regulatory and nutrient transport genes [28,36]. 2.3. Placental endocrine function The placenta produces a variety of hormones which are essential for the success of pregnancy. In fitness terms, some of these are
acting co-operatively to maintain pregnancy while others are acting as demand signals to the mother in the potential conflict over resource allocation [2,38]. The high level of synthesis of many placental hormones, underpinned by expansion of their gene families, is consistent with a co-evolutionary arms race between fetal production of demand signals and maternal counteracting mechanisms [1,2]. Thus, inadequate placental production of hormones is often associated with pregnancy failure, poor placentation or fetal growth restriction depending on the type and timing of the endocrine deficiency [38e40]. Conversely, maternal concentrations of placental hormones are higher when placental mass is increased in multiple pregnancies where total fetal demand for nutrients is greater too [41]. The junctional zone (Jz) of the mouse placenta is primarily responsible for hormone secretion and its size appears to be related to fetal body weight in mid gestation in different strains and genetic mutants when there is little, if any, difference in the size of the labyrinthine zone responsible for nutrient transport [40,42,43]. Placental hormones, such as the placental lactogens, placental GH, prolactin and the prolactin-like proteins, are sensitive to nutritional state and other endocrine signals like the glucocorticoids [43]. They have a wide range of functions relevant to maternal-fetal nutrient allocation, probably the most important of which is their anti-insulin effect on maternal metabolism [44e46]. Although the mother counteracts by b cell proliferation and increased insulin secretion [26,29,30], maternal insulin resistance develops in most species during mid to late gestation, which diverts glucose from maternal to fetal use, particularly after meals when maternal glucose levels are high [29,30]. Indeed, maternal insulin resistance is higher the greater the placental mass in sheep with multiple pregnancies [45]. Similarly, mouse dams appear more insulin resistant in late pregnancy when the endocrine zone of placenta is enlarged by genetic manipulation [8]. The prolactin gene family is one of the most rapidly evolving classes of genes in the mature rodent placenta, which suggests that these placental hormones are involved in an evolutionary conflict between mother and fetus in late but not early gestation in these species [44e46]. However, the duplication and divergence of the human homologues of some rodent genes encoding placental hormones is not as extensive [47], consistent with the suggestion that conflict over nutrient allocation may be more pronounced when feto-placental mass is relatively large at term. Any co-evolutionary arms races over maternal-fetal nutrient allocation may involve hormone metabolism as well as hormone synthesis. In most species studied to date, glucocorticoids are higher in concentration in the mother than fetus and, hence, they
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enter feto-placental tissues down the concentration gradient to restrict fetal growth both directly and indirectly by inhibiting placental development and nutrient transport [28,48]. The trophoblast, therefore, contains the enzyme 11b-hydroxysteroid dehydrogenase (11bHSD2), normally found in kidneys, which metabolises the active glucocorticoid to its inactive metabolite [48]. Amongst species, placental 11bHSD2 activity is related to the magnitude of the transplacental glucocorticoid gradient and can be regulated from the fetal or maternal compartments by nutrition and glucocorticoid concentrations per se [49]. Thus, depending on the precise conditions, the mother can decrease her nutrient investment in fetal growth while the fetus can limit the detrimental effects of the maternal glucocorticoid signals of adversity by modifying placental 11bHSD2 activity reciprocally. Certainly, in human infants, birthweight is inversely correlated with placental 11bHSD2 activity at term [48]. 2.4. Placental metabolism Fetal nutrient delivery depends not only on maternal nutrient provision but also on the rate of nutrient utilisation by the metabolically active utero-placental tissues [14,49]. Partitioning of uterine nutrient uptake between the fetal and utero-placental tissues is known to be altered by undernutrition, hypoxia and glucocorticoid overexposure [14,49]. In most of these conditions, the utero-placental tissues consume a greater proportion of the available nutrients, even though the absolute supply may be reduced. This is consistent with the continued need for placental transport and hormone secretion to maintain pregnancy. Indeed, the fetus can supply nutrients to the placenta in extreme circumstances [50]. However, when maternal hypoxia and/or hypoglycaemia are more prolonged, offspring fitness is threatened more directly and there are changes in placental metabolism at the cellular and mitochondrial level that help conserve some oxygen and glucose for onward transfer to the fetus [51,52]. At this level, there might appear to be little conflict between the mother and fetus as both should benefit from maintaining a functional placenta. However, if pregnancy is severely compromised by adverse environmental or other factors, it may be in the mother’s interest to abort the fetus and conserve resources for herself rather than allocating them to offspring of potentially reduced fitness. 3. Imprinted genes in maternal-fetal nutrient allocation Imprinted genes, which are expressed in a parent-of-origin manner, have an important role in resource allocation across species and are believed to have evolved in mammals in response to the conflict between parental genomes in transplacental nutrient transfer [13,53]. These genes are expressed preferentially in the placenta and, in general, paternally expressed genes increase placental and fetal growth while maternally expressed genes have the reverse effects [13,33,53]. Indeed, key paternally and maternally expressed genes appear to be co-regulated in a network of imprinted genes in the control of conceptus growth [54]. In addition to controlling placental size, imprinted genes affect resource allocation by altering the morphology and transport characteristics of the placenta through changes in trophoblast differentiation, zonal organisation, vascularisation and transporter abundance [33]. Furthermore, they can act as environmental signals in the epigenetic regulation of placental phenotype and, hence, control nutrient allocation to fetal growth in a context-specific manner [33,55]. Consequently, imprinted genes are likely to be particularly important in maternal-fetal nutrient allocation in polyandrous species with a high relative conceptus mass. This may explain the apparently large number of imprinted genes in murine compared
Placental endocrine signals
Placental resource signals
Placenta Mother Nutrients Fuel reserves Glucocorticoids GH, IGF-I Leptin
Nutrients
Size Morphology Blood flow Transporters Metabolism Hormones Igf2/IGF-II mTOR 11βHSD2
Maternal resource signals
Fetus Fetal mass Nutrients Igf2/IGF-II Glucocorticoids
Fetal demand signals
Fig. 2. Schematic diagram showing some of the maternal, placental and fetal factors that influence transplacental resource allocation from mother to fetus(es). GH, growth hormone. IGF-I, Insulin-like growth factor-I. Igf2/IGF-II, Insulin-like growth factor-II. mTOR, mammalian target of rapamycin. 11bHSD2, 11b-hydoxysteroid dehydrogenase.
to human placenta [55], although ascertainment bias and rapid evolution of placental epigenetic control mechanisms must be considered as alternative explanations. One of the best characterised imprinted genes is Igf2. This gene is paternally expressed and encodes one of the most potent fetoplacental growth factors, IGF-II [23e25,53]. Comparison of the placental transport characteristics in mouse mutants under- or over-expressing the Igf2 gene suggests that IGF-II has an important role in resource allocation by signalling mismatches between fetal demand and placental supply of nutrients [56,57]. These studies also indicate that the placental specific transcript of the Igf2 gene, Igf2P0, is involved in regulating expression of glucose and System A amino acid transporters in the mouse placenta. Certainly, the placental adaptations that enhance the fetal amino acid supply during maternal undernutrition do not occur in Igf2P0 null mutants [9]. In addition, placental Igf2 gene expression is responsive to a wide range of environmental signals including maternal calorie intake, dietary composition and glucocorticoid concentrations [33]. 4. Conclusions Many aspects of gestation, including components of the control of maternal-fetal nutrient allocation, may be largely co-operative processes mutually beneficial to mother and fetus. It is in late gestation when the fetus begins to growth rapidly that conflict over maternal investment may become particularly intense. Especially when nutrients are scarce or conceptus mass is unusually high, some constraint on maternal investment is likely, even if only to ensure sufficient reserve for lactation and postnatal survival of the current offspring. As the site of nutrient transfer, the placenta is at the forefront of these maternal and offspring fitness-determining mechanisms. It integrates a wide range of nutritional and other signals of fetal, placental and maternal origin and, by acting as an environmental sensor, optimises the fate of the available nutrients (Fig. 2). The complexity and diversity of this signalling will increase as gestation advances in line with the greater potential for conflict over resource allocation. At a cellular level, the signals may converge through a single common pathway, like the mTOR pathway [58], or use multiple mechanisms to generate placental phenotypes specific to the environmental conditions and/or fetal genotype [31]. However, in conferring optimal fitness to the offspring for its developmental environment, these placental adaptations may programme adult phenotypes more prone to disease, albeit long after the acquired benefit of successful reproduction.
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Placenta journal homepage: www.elsevier.com/locate/placenta
Maternal-fetal resource allocation: Co-operation and conflict A.L. Fowden a, *, T. Moore b a b
Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK Department of Biochemistry, Biosciences Institute, University College Cork, College Road, Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 7 May 2012
Pregnancy is generally a co-operative interaction between mother and fetus in which the evolutionary genetic interests of both benefit from production of healthy offspring. While this view is largely supported by empirical data, Kinship Theory predicts that mother and fetus will disagree over the optimum level of maternal investment that maximises their respective fitnesses. This conflict will be more evident with polyandrous than monogamous mating systems, when resources are scarce and in late gestation when the fetus is growing maximally, particularly if conceptus mass is large relative to maternal mass. As the site of nutrient transfer, the placenta is pivotal in the tug-of-war between mother and fetus over resource allocation. It responds to both fetal signals of nutrient demand and maternal signals of nutrient availability and, by adapting its phenotype, regulates the distribution of available resources. These adaptations involve changes in placental size, morphology, transport characteristics, metabolism and hormone bioavailability. They are mediated by key growth regulatory, endocrine and nutrient supply genes responsive to mismatches between nutrient availability and the fetal genetic drive for growth. Indeed, evolution of genomic imprinting and placental secretion of hormones are believed to have been driven by maternal-fetal conflict over resource allocation. Although many of the specific mechanisms involved still have to be identified, the placenta confers optimal fitness on the offspring for its developmental environment by balancing conflict and cooperation in the allocation of resources through generation of nutrient transport phenotypes specific to the prevailing nutritional conditions and/or fetal genotype. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Placental nutrient transfer Imprinted genes Fetal growth Nutrition
1. Introduction In eutherian mammals, pregnancy is an apparently highly cooperative interaction between the mother and fetus which, at best, leads to delivery of viable offspring with little detriment to the future health or fecundity of the mother [1]. Through a variety of morphological and physiological adaptations, the fetus demands resources from the mother that support its growth in utero, and generally, a larger well-resourced fetus is more likely to survive at birth and onto reproductive age. The mother benefits from the investment in her offspring because it contributes to the transmission of her genes to future generations [2]. However, inevitably, maternal investment in the current fetus will leave fewer resources for future reproduction. Because the fetus inherits only half of its genes from its mother and shares, at most, half of its genes with its mother’s future offspring, there is a conflict between the mother and fetus because the fetus will demand more resources from the
* Corresponding author. Tel.: þ44 (0) 1223 333855; fax: þ44 (0) 1223 333840. E-mail address: [email protected] (A.L. Fowden). 0143-4004/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.placenta.2012.05.002
mother than may be in her long term reproductive interests to supply [1]. Several lines of evidence suggest that interactions between maternal and fetal genes can occur in determining the level of maternal investment in individual pregnancies. Inter- and intra-specific crosses between breeds of several species show that the mother can constrain the fetal genetic drive for growth and that, conversely, the fetal genome can influence the mother with consequences for fetal growth and pregnancy outcome [3e6]. Similarly, more direct manipulation of the fetal genome by gene deletion or disruption is known to alter the metabolic and endocrine adaptations of the mouse dam to pregnancy [7e9]. However, much less is known about the nature of the interactions between maternal and fetal genes in the context of normal pregnancy. If, as predicted by Kinship Theory, maternal-fetal conflict over the level of maternal investment in the fetus is the norm, it is likely to be particularly relevant in late gestation when the fetus is growing most rapidly in absolute terms or when resources are scarce, for example, due to undernutrition during pregnancy or to a low pre-pregnancy body mass index (BMI) of the mother [10,11]. Similarly, the importance of conflict will vary with the mating system of the species, particularly the degree of polyandry, and
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perhaps the size of the conceptus(es) in relation to maternal mass [1,10]. There are wide inter-species differences in fetal growth rates and in the proportion of maternal weight that is accounted for by the gravid uterus in late gestation (Table 1). Therefore, conflict in nutrient allocation during pregnancy may be more significant in rodents and other species in which total conceptus mass accounts for 20% or more of maternal weight than in higher order primates, in which the gravid uterus is only 6e9% of maternal mass at term (Table 1). Increased litter size leading to direct inter-sibling rivalry and an increased total fetal demand for nutrients may also heighten potential conflict between mother and fetuses in determining nutrient allocation ([5,6,11] and Table 1). With strict monogamy which occurs rarely in mammals [12], the mother and current offspring are equally related to her future offspring and this provides a constraint on the magnitude of maternal-fetal conflict. From Hamilton’s rule (Fig. 1), the current offspring will demand resources from the mother as long as the fitness benefit to itself is twice the fitness cost to future offspring [1]. However, in the more common polyandrous mating systems where females mate with more than one male during their reproductive life, conflict is potentially more intense as the differing paternal contributions to the fetal genomes of half-sibs will be less constrained in demanding resources from the mother to the detriment of half-sibs (Fig. 1). Maternal-fetal conflict under polyandry results in differential selection on maternally and paternally inherited alleles in the fetus, with paternal alleles promoting increased maternal investment in the fetus and maternal alleles evolving expression patterns that counteract the effects of ‘greedy’ paternal alleles [2]. The resulting biased expression pattern of the parental alleles is manifested as genomic imprinting [13]. 2. The placenta and maternal-fetal nutrient allocation As the site of nutrient transfer, the placenta is pivotal in the tugof-war between mother and fetus over resource allocation [14]. It is the interface where cooperation and conflict coexist and responds to both fetal signals of nutrient demand and maternal signals of nutrient availability in optimising the distribution of available nutrients. To achieve this, the placenta adapts its phenotype in response to a wide range of environmental conditions by changing its surface area for nutrient transfer, the thickness of its
Table 1 Maternal and offspring body weight at term and fetal growth rate in different species during late gestation (85% gestation). Data from Ref. [6,10,12,18]. Species
Maternal weight kg
Offspring birthweight kg
Placental-fetal wt% maternal wt
Growth g/kg fetal wet wt/day
Mouse Rat Guinea pig Monkey Pig Sheep Welsh Mountain Suffolk Singleton Twins Triplets Primate Human Chimpanzee Macaque Marmoset Twins Triplets Horse
0.037 0.450 1.2 6.0 180
0.0012 0.006 0.090 0.500 1.200
30 25 30 8 17
450 300 68 44 33
45
3.000
9
36
60 68 75
5.000 4.500 3.250
9 14 15
e e e
72 40 5.5
3.500 1.850 0.500
6 5 11
15 e 11
0.380 0.425 550
0.060 0.082 52.000
19 22 10
e e 9
interhaemel barrier separating the maternal and fetal circulations, its abundance of nutrient transporters, metabolic rate and blood flow as well as its synthesis and metabolism of specific hormones [15,16]. These factors also change with gestational age to meet the increasing nutritional demands of the growing fetus in late gestation [14]. For instance, between mid and late gestation in several species, placental surface area increases and barrier thickness decreases along with increases in the weight specific rate of placental blood flow [16,17]. Maternal nutrient allocation to the fetus can, therefore, be manipulated either, directly, by morphological and functional changes to the placenta per se or, indirectly, by systemic changes in nutrient availability that alter the transplacental concentration gradients for nutrient diffusion. These mechanisms are used by both mother and fetus to alter nutrient distribution. 2.1. Placental growth and morphology From the maternal perspective, placental growth needs to reflect both the available nutrient stores at the time of conception and the current nutritional state. Indeed, in several species including humans, placental weight at term is directly related to pre-pregnancy BMI or body condition score and is reduced if there is gestational weight loss or undernutrition during late gestation when fetal nutrient demands are normally at their highest [15,18e21]. Thus, mothers do not operate solely to constrain nutrient allocation to their fetuses but will permit a greater transplacental nutrient flow if their nutritional status can support the extra investment. From the fetal perspective, the larger the placenta, the greater the potential supply of nutrients [10,14]. Increases in placental size or in the surface area for transport are observed in response to maternal undernutrition during the period of placental development but are not always sustained to term, particularly if undernutrition persists [14]. This is consistent with a fetal drive to maximise nutrient provision that is tempered by maternal constraint when the nutrient requirements of the rapidly growing fetus exceed nutrient availability in late gestation. The nature of the nutritional signals controlling placental growth and morphology remains unknown, particularly at the earliest stages of development. At the blastocyst stage, differentiation of the trophectoderm from the inner cell mass may be affected by the nutrient and growth factor content of the uterine secretions providing histiotrophic nutrition [22]. Later, maternal endocrine signals of nutritional status, such as growth hormone (GH) and insulin-like growth factor (IGF)-I concentrations, may influence placental growth either directly or indirectly through their actions on maternal metabolism [23e25]. However, the specific effects of these hormones appear to depend on the anabolic status of the mother as they direct maternal nutrients away from utero-placental growth in young growing adolescents but towards fetal growth in fully grown animals [25e27]. In contrast, maternal endocrine signals of adversity like the glucocorticoids reduce placental and fetal growth in several species including humans and rodents [28]. 2.2. Placental nutrient transfer Nutrient allocation can be altered independently of any change in placental size or morphology by changing the abundance of nutrient transporters or the transplacental concentration gradients used to drive simple and facilitated diffusion [14]. As gestation proceeds in several species, the fetus lowers its glucose concentrations to maximize the gradient and increase the transplacental glucose supply. In some species, there are also gestational increases in placental abundance of the glucose transporters used for
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Fig. 1. Schematic diagram showing the genetic relatedness coefficients (r) between maternally (rmat) and paternally (rpat) inherited haploid genomes of offspring under theoretical strictly monogamous and polyandrous mating systems (See Ref. [1] for detailed explanation).
facilitated diffusion [10,29]. The mother counteracts by lowering her fasting glucose concentrations but not to the same extent as the fetus [29,30]. However, maternal glucose concentrations do vary with nutritional state and, thereby, alter fetal glucose delivery in relation to maternal resource availability. Transplacental provision of amino acids for growth is an active process requiring amino acid transporters which increase in placental abundance concomitantly with the rapid phase of fetal growth in late gestation [31]. Often, in poor nutritional conditions, there is up-regulation of placental amino acid transporters expression and of amino acid transport, which helps to maintain fetal growth, even when the placenta is small [14,15]. With more extreme under- or mal-nutrition, amino acid transport and transporter abundance may be down-regulated in association with fetal growth restriction [31,32]. These ontogenic and nutritionallyinduced changes in placental nutrient transport are likely to be the result of complex interactions between maternal and fetal systemic signals arising from the mismatch between the fetal genetic drive for growth and nutrient availability on both sides of the placenta [14,16,31e33]. A range of nutritionally sensitive hormones including GH, IGF-I, leptin and the glucocorticoids have been shown to alter placental nutrient transfer both in vitro in human cultured trophoblast and in vivo in several species including sheep, guinea pigs and rodents [24,34e36]. Endocrine signals of nutrient abundance like leptin and IGF-I increase amino acid transport by cultured human trophoblast [19,32,34]. Similarly, GH increases glucose transfer across human placental villous fragments [34]. Maternal GH and IGF-I also increase nutrient partitioning to fetal sheep by actions on the diffusion capacity and carbohydrate metabolism of the placenta [35,36]. On the other hand, glucocorticoids, which signal nutrient insufficiency and other adverse environmental conditions, tend to reduce weight specific transplacental transfer of glucose and amino acids in vivo, irrespective of whether maternal or fetal glucocorticoid concentrations are raised [28,36,37]. Since glucocorticoids inhibit fetal growth directly, these placental adaptations ensure that the nutrient supply of the compromised fetus is commensurate with its reduced drive for growth [36]. In part, these systemic effects on placental nutrient transfer are mediated through changes in placental expression of key growth regulatory and nutrient transport genes [28,36]. 2.3. Placental endocrine function The placenta produces a variety of hormones which are essential for the success of pregnancy. In fitness terms, some of these are
acting co-operatively to maintain pregnancy while others are acting as demand signals to the mother in the potential conflict over resource allocation [2,38]. The high level of synthesis of many placental hormones, underpinned by expansion of their gene families, is consistent with a co-evolutionary arms race between fetal production of demand signals and maternal counteracting mechanisms [1,2]. Thus, inadequate placental production of hormones is often associated with pregnancy failure, poor placentation or fetal growth restriction depending on the type and timing of the endocrine deficiency [38e40]. Conversely, maternal concentrations of placental hormones are higher when placental mass is increased in multiple pregnancies where total fetal demand for nutrients is greater too [41]. The junctional zone (Jz) of the mouse placenta is primarily responsible for hormone secretion and its size appears to be related to fetal body weight in mid gestation in different strains and genetic mutants when there is little, if any, difference in the size of the labyrinthine zone responsible for nutrient transport [40,42,43]. Placental hormones, such as the placental lactogens, placental GH, prolactin and the prolactin-like proteins, are sensitive to nutritional state and other endocrine signals like the glucocorticoids [43]. They have a wide range of functions relevant to maternal-fetal nutrient allocation, probably the most important of which is their anti-insulin effect on maternal metabolism [44e46]. Although the mother counteracts by b cell proliferation and increased insulin secretion [26,29,30], maternal insulin resistance develops in most species during mid to late gestation, which diverts glucose from maternal to fetal use, particularly after meals when maternal glucose levels are high [29,30]. Indeed, maternal insulin resistance is higher the greater the placental mass in sheep with multiple pregnancies [45]. Similarly, mouse dams appear more insulin resistant in late pregnancy when the endocrine zone of placenta is enlarged by genetic manipulation [8]. The prolactin gene family is one of the most rapidly evolving classes of genes in the mature rodent placenta, which suggests that these placental hormones are involved in an evolutionary conflict between mother and fetus in late but not early gestation in these species [44e46]. However, the duplication and divergence of the human homologues of some rodent genes encoding placental hormones is not as extensive [47], consistent with the suggestion that conflict over nutrient allocation may be more pronounced when feto-placental mass is relatively large at term. Any co-evolutionary arms races over maternal-fetal nutrient allocation may involve hormone metabolism as well as hormone synthesis. In most species studied to date, glucocorticoids are higher in concentration in the mother than fetus and, hence, they
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enter feto-placental tissues down the concentration gradient to restrict fetal growth both directly and indirectly by inhibiting placental development and nutrient transport [28,48]. The trophoblast, therefore, contains the enzyme 11b-hydroxysteroid dehydrogenase (11bHSD2), normally found in kidneys, which metabolises the active glucocorticoid to its inactive metabolite [48]. Amongst species, placental 11bHSD2 activity is related to the magnitude of the transplacental glucocorticoid gradient and can be regulated from the fetal or maternal compartments by nutrition and glucocorticoid concentrations per se [49]. Thus, depending on the precise conditions, the mother can decrease her nutrient investment in fetal growth while the fetus can limit the detrimental effects of the maternal glucocorticoid signals of adversity by modifying placental 11bHSD2 activity reciprocally. Certainly, in human infants, birthweight is inversely correlated with placental 11bHSD2 activity at term [48]. 2.4. Placental metabolism Fetal nutrient delivery depends not only on maternal nutrient provision but also on the rate of nutrient utilisation by the metabolically active utero-placental tissues [14,49]. Partitioning of uterine nutrient uptake between the fetal and utero-placental tissues is known to be altered by undernutrition, hypoxia and glucocorticoid overexposure [14,49]. In most of these conditions, the utero-placental tissues consume a greater proportion of the available nutrients, even though the absolute supply may be reduced. This is consistent with the continued need for placental transport and hormone secretion to maintain pregnancy. Indeed, the fetus can supply nutrients to the placenta in extreme circumstances [50]. However, when maternal hypoxia and/or hypoglycaemia are more prolonged, offspring fitness is threatened more directly and there are changes in placental metabolism at the cellular and mitochondrial level that help conserve some oxygen and glucose for onward transfer to the fetus [51,52]. At this level, there might appear to be little conflict between the mother and fetus as both should benefit from maintaining a functional placenta. However, if pregnancy is severely compromised by adverse environmental or other factors, it may be in the mother’s interest to abort the fetus and conserve resources for herself rather than allocating them to offspring of potentially reduced fitness. 3. Imprinted genes in maternal-fetal nutrient allocation Imprinted genes, which are expressed in a parent-of-origin manner, have an important role in resource allocation across species and are believed to have evolved in mammals in response to the conflict between parental genomes in transplacental nutrient transfer [13,53]. These genes are expressed preferentially in the placenta and, in general, paternally expressed genes increase placental and fetal growth while maternally expressed genes have the reverse effects [13,33,53]. Indeed, key paternally and maternally expressed genes appear to be co-regulated in a network of imprinted genes in the control of conceptus growth [54]. In addition to controlling placental size, imprinted genes affect resource allocation by altering the morphology and transport characteristics of the placenta through changes in trophoblast differentiation, zonal organisation, vascularisation and transporter abundance [33]. Furthermore, they can act as environmental signals in the epigenetic regulation of placental phenotype and, hence, control nutrient allocation to fetal growth in a context-specific manner [33,55]. Consequently, imprinted genes are likely to be particularly important in maternal-fetal nutrient allocation in polyandrous species with a high relative conceptus mass. This may explain the apparently large number of imprinted genes in murine compared
Placental endocrine signals
Placental resource signals
Placenta Mother Nutrients Fuel reserves Glucocorticoids GH, IGF-I Leptin
Nutrients
Size Morphology Blood flow Transporters Metabolism Hormones Igf2/IGF-II mTOR 11βHSD2
Maternal resource signals
Fetus Fetal mass Nutrients Igf2/IGF-II Glucocorticoids
Fetal demand signals
Fig. 2. Schematic diagram showing some of the maternal, placental and fetal factors that influence transplacental resource allocation from mother to fetus(es). GH, growth hormone. IGF-I, Insulin-like growth factor-I. Igf2/IGF-II, Insulin-like growth factor-II. mTOR, mammalian target of rapamycin. 11bHSD2, 11b-hydoxysteroid dehydrogenase.
to human placenta [55], although ascertainment bias and rapid evolution of placental epigenetic control mechanisms must be considered as alternative explanations. One of the best characterised imprinted genes is Igf2. This gene is paternally expressed and encodes one of the most potent fetoplacental growth factors, IGF-II [23e25,53]. Comparison of the placental transport characteristics in mouse mutants under- or over-expressing the Igf2 gene suggests that IGF-II has an important role in resource allocation by signalling mismatches between fetal demand and placental supply of nutrients [56,57]. These studies also indicate that the placental specific transcript of the Igf2 gene, Igf2P0, is involved in regulating expression of glucose and System A amino acid transporters in the mouse placenta. Certainly, the placental adaptations that enhance the fetal amino acid supply during maternal undernutrition do not occur in Igf2P0 null mutants [9]. In addition, placental Igf2 gene expression is responsive to a wide range of environmental signals including maternal calorie intake, dietary composition and glucocorticoid concentrations [33]. 4. Conclusions Many aspects of gestation, including components of the control of maternal-fetal nutrient allocation, may be largely co-operative processes mutually beneficial to mother and fetus. It is in late gestation when the fetus begins to growth rapidly that conflict over maternal investment may become particularly intense. Especially when nutrients are scarce or conceptus mass is unusually high, some constraint on maternal investment is likely, even if only to ensure sufficient reserve for lactation and postnatal survival of the current offspring. As the site of nutrient transfer, the placenta is at the forefront of these maternal and offspring fitness-determining mechanisms. It integrates a wide range of nutritional and other signals of fetal, placental and maternal origin and, by acting as an environmental sensor, optimises the fate of the available nutrients (Fig. 2). The complexity and diversity of this signalling will increase as gestation advances in line with the greater potential for conflict over resource allocation. At a cellular level, the signals may converge through a single common pathway, like the mTOR pathway [58], or use multiple mechanisms to generate placental phenotypes specific to the environmental conditions and/or fetal genotype [31]. However, in conferring optimal fitness to the offspring for its developmental environment, these placental adaptations may programme adult phenotypes more prone to disease, albeit long after the acquired benefit of successful reproduction.
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