Journal Article
Louiza Belkacemi,
3Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, and David Geffen School of Medicine at UCLA, Torrance, California
2Correspondence: Louiza Belkacemi, Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, and David Geffen School of Medicine at UCLA, Torrance, CA 90502. FAX: 310 222 4131;
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D. Michael Nelson,4Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri
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Mina Desai,3Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, and David Geffen School of Medicine at UCLA, Torrance, California
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Michael G. Ross3Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, and David Geffen School of Medicine at UCLA, Torrance, California
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Supported by a Los Angeles Biomedical Research Institute Seed Grant.
Author Notes
Revision received:
28 March 2010
Published:
01 September 2010
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Louiza Belkacemi, D. Michael Nelson, Mina Desai, Michael G. Ross, Maternal Undernutrition Influences Placental-Fetal Development, Biology of Reproduction, Volume 83, Issue 3, 1 September 2010, Pages 325–331, //doi.org/10.1095/biolreprod.110.084517
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Abstract
Maternal nutrition during pregnancy has a pivotal role in the regulation of placental-fetal development and thereby affects the lifelong health and productivity of offspring. Suboptimal maternal nutrition yields low birth weight, with substantial effect on the short-term morbidity of the newborn. The placenta is the organ through which gases, nutrients, and wastes are exchanged between the maternal-fetal circulations. The size, morphology, and nutrient transfer capacity of the placenta determine the prenatal growth trajectory of the fetus to influence birth weight. Transplacental exchange depends on uterine, placental, and umbilical blood flow. Most important, maternal nutrition influences factors associated not only with placental homeostasis but also with optimal fetal development. This review associates fetal growth with maternal nutrition during pregnancy, placental growth and vascular development, and placental nutrient transport.
Introduction
An optimal maternal nutrient supply has a critical role in placental-fetal growth and development. Maternal suboptimal nutrition during pregnancy results in intrauterine growth restriction (IUGR) and newborns with low birth weight. Intrauterine growth restriction is associated with increased perinatal morbidity and mortality, and newborns with low birth weight have increased risk for development of adult metabolic syndrome [1, 2]. Adverse effects of maternal undernutrition (MUN) have generally focused on the reduced maternal nutrient supply to the fetus. Few studies [3–8] highlight the crucial role of the placenta on the ensuing phenotype.
The placenta forms the interface between the maternal-fetal circulations and as such is critical for fetal nutrition and oxygenation. In turn, the placental supply of nutrients to the fetus depends on its size, morphology, blood supply, and transporter abundance. During normal pregnancy, the placenta undergoes a variety of physiological changes, regulated by angiogenic factors, hormones, and nutrient-related genes, to maximize efficiency for an ever-increasing demand for nutrients. Perturbations in the maternal environment following MUN may adversely alter these changes.
This review discusses the influence of MUN during pregnancy on placental development and nutrient transfer. It also describes the subsequent effects on fetal development.
MUN and Placental Development
The placenta of mammals is a highly efficient multifunctional organ that integrates signals from both mother and fetus to match fetal demand with the maternal substrate supply of nutrients and gases, while ensuring that fetal waste products are transferred back to the mother. Altered placental structure and function (reflected by weight, morphology, vascular development, and transport function for amino acids, glucose, and fatty acids) may contribute to altered nutrient supply.
Effects on Placental Weight
Placental weight is correlated with dietary intake in mammalian pregnancies. Although the effect of global MUN on placental weight is unequivocal, the timing, duration, and etiology of nutritional restriction can each differently affect placental mass. A frequently cited example of this premise is the effect of timing and duration of limited nutrient intake during the Dutch Famine of 1944–1945 [9]. Women subjected to starvation in their third trimester of pregnancy had light placentas and newborns with low birth weight but an unaltered placental weight:birth weight ratio compared with nonstarved women. In contrast, exposure to famine only during the first trimester of pregnancy enhanced placental weight at delivery, although without any effect on newborn weight compared with control women. These results suggest that human placental adaptation in early pregnancy can overcome environmental stressors so that fetal nutrition is maintained in late gestation.
Similar to humans, global MUN during early to mid pregnancy in sheep increased the placental weight:fetal weight ratio by enhancing placental weight at term without altering fetal weight [10]. Conversely, a 50% MUN during the second half of rat pregnancy yielded a decrease in the placental weight:fetal weight ratio [11], implying that MUN irreversibly affects placental weight when nutrient deprivation coincides with the time when fetal nutrient demand is maximal.
An important question is whether global MUN or deprivation of a selected nutrient component is the insult that induces the change in growth trajectories of the placenta and fetus. Notably, selective protein deprivation is a key factor in the dietary alteration of placental weight:fetal weight ratios. Protein restriction with 9% vs. 18% casein in the diet throughout pregnancy in the rat yielded heavier placentas and reduced fetal growth in late gestation [12]. The placental overgrowth compensates for the reduced protein availability in early gestation to maintain normal fetal weight in earlier gestation, but such compensation is insufficient to maintain fetal growth near parturition. Normal or even excess fetal growth occurs in rats exposed to protein deprivation in early gestation, with midgestation restoration of normal nutrition [4]. Collectively, these data suggest that an adaptive response in the placenta enhances transfer of substrates from mother to fetus, improves efficiency of substrate utilization, or both when the supply of amino acids is limited. The placenta compensates to minimize fetal growth restriction. However, placental function is not always improved with increases in weight because the histomorphology of the placenta ultimately determines placental function.
Changes in Histomorphology
The histomorphology and ultrastructure of the placenta change throughout normal gestation and in response to maternal nutritional manipulations [13]. In mammals, the placenta develops a large surface:volume ratio, forming highly branched structures with advancing pregnancy. Trophoblast provides the covering surface and is positioned to mediate critical steps in hormone production and immune protection of the fetus. Invasive trophoblasts also facilitate an increase in maternal vascular blood flow into the placenta [14]. In primates, the zone of exchange is represented by a single layer of syncytial trophoblast and an underlying layer of mononucleated cytotrophoblasts [15]. In rodents, this zone (labyrinth zone) is formed by a mononucleated trophoblast layer with two syncytiotrophoblast layers that serve as the structural basis of the placental barrier between the maternal-fetal blood. In ruminants, placental mononucleate trophoblasts form the majority of the interface and are primarily involved in nutrient exchange [16]. In pig, the labyrinth zone contains fetal capillaries and maternal blood sinuses and provides the means for exchange between the two circulations, as well as an interlobium that is composed of syncytiotrophoblast and maternal blood sinuses and is the site where much of the metabolic activity occurs [17].
Alterations of exchange surface area, barrier thickness, and cell composition of the different gestational ages of the placenta may all affect placental transport capacity [18]. Notably, MUN that results in human IUGR generates placentas with a reduced surface area for exchange in villi and a lower-volume density of trophoblasts [19]. These structural alterations in the placenta are mirrored in the guinea pig that is exposed to global MUN compared with control diets. The nutrient-deprived gestations exhibited placentas with surface area for exchange that were diminished by up to 70% due to reduced development of the labyrinth, while barrier thickness was increased by 40% in late gestation [20]. These histopathological changes predispose to reduced nutrient transfer to the fetus. Our work in which rats were exposed to MUN demonstrated enhanced apoptosis occurring in both the junctional and labyrinthine zones of the placenta [11]. Moreover, MUN affected to a greater degree the placenta located in the midhorn compared with proximal uterine horn positions. The marked effect of MUN on midhorn placentas may indicate a potential compounding effect of reduced maternal vascularity, decreased oxygen supply, or other factors that are regionally distributed along the uterine horn. Reflecting the complexity of the phenotype that results from exogenous insults, these findings suggest that two insults may interact in the same animal to accentuate the morbidity associated with growth restriction.
Alterations in Vasculogenesis and Angiogenesis
Vasculogenesis is de novo formation of blood vessels from mesoderm precursor cells, and angiogenesis is creation of new vessels from a preexisting blood supply. Both processes are critical to the maternal-fetal exchange. Vascular endothelial growth factor (VEGF) and angiopoietin proteins [21, 22] are critical to these processes. Angiopoietin proteins contribute to the formation of mature blood vessels, but their role in MUN placentas is unknown to date.
Insult induces compromise in placental vasculogenesis and angiogenesis and impairs exchange between the maternal-fetal circulations [4, 23], ultimately resulting in IUGR fetuses. For example, ewes fed with 60% global nutrient intake beginning on Day 50 of gestation had increased placental vascularity, reduced VEGF receptor expression in placentomes, and nutrient transfer deficiency [24]. The greater placentome vascularity in the feed-restricted ewes had no effect on VEGF mRNA expression, suggesting that other factors were essential in the overall process of angiogenesis; for example, the angiopoietin proteins may have a role in modulating VEGF function [25].
Endothelium-derived nitric oxide (NO) is a mediator of angiogenesis and has a role in modulating vascular resistance [26]. VEGF stimulates the release of NO and upregulates the expression of NO synthetase. A critical role for NO during human pregnancy is suggested by investigations of fetuses with IUGR [27]. The importance of NO was also demonstrated in pigs fed a protein-restricted diet for up to 60 days of gestation. The animals showed decreased placental arginine (a common substrate for NO), less NO synthesis, and reduced NO synthetase activity compared with pigs fed a normal protein diet [28]. These changes are likely one mechanism for placental vascular dysfunction that results in reduced placental-fetal growth in the protein-deficient offspring.
Collectively, these results underscore that typical features of nutrient restriction models include some level of placental vascular and angiogenesis dysfunction during pregnancy. This is summarized in two studies [29, 30] of low dietary protein intake.
Modifications of Nutrient Transfer Capacity
Fetal nutrient availability results from several elements. These include the interrelationships of maternal food intake, availability of nutrients in the maternal circulation, and ability of the placenta to efficiently transport substrates to the fetal circulation.
Global maternal nutritional status affects transporters in the placenta, thereby influencing the rate of nutrient delivery through the placenta. For example, rats fed a 50% global MUN during the last week of gestation experienced decreased glucose levels in maternal plasma [31]. The maternal-fetal glucose concentration gradient (which drives facilitative glucose diffusion across the placenta) is also reduced, and glucose transporter 3 (solute carrier family 2 [facilitated glucose transporter] member 3 [SLC2A3, previously called GLUT3]) expression is substantially decreased, suggesting a mechanism for placental glucose transport dysfunction. Although glucose represents the principal metabolic fuel during gestation, specific effects of maternal dietary glucose restriction on placental-fetal development have not been extensively studied to date.
Placental transport of amino acids is pivotal for fetal development and is affected by the activity and location of amino acid transporter systems. In humans, reduced circulating concentrations of essential amino acids (such as leucine and lysine) are observed in growth-restricted human fetuses [32–34], implying that there is a global alteration of placental amino acid transport activity in IUGR. In animal models, rats fed a 6% casein low-protein diet from Day 5 of gestation showed 27% reduced transfer of nonmetabolizable amino acid C-α amino isobutyric acid from the maternal-fetal circulations compared with well-fed controls [35]. In addition, rats fed a 5% casein diet exhibited reduced placental system A transporter (Na+-dependent neutral amino acid uptake) activity for neutral amino acids at term compared with dams pair-fed a control 20% casein diet [36]. Maternal protein restriction in rats resulted in downregulated placental nutrient transport before the onset of fetal growth restriction, suggesting that a reduced placental supply of amino acids is a causal factor for IUGR and not simply a consequence of this malady [37].
Adequate placental transport of fatty acids to the fetus is crucial for normal fetal development and growth because fatty acids have multiple roles as cell membrane components, energy sources, and precursors to cellular signaling molecules. Intrauterine growth restriction placentas showed disrupted lipid metabolism and altered microvillous plasma membrane lipid hydrolase activities; both affected the flux of essential fatty acids and preformed long-chain polyunsaturated fatty acids to the human fetus [38]. Undernourished women exhibited a relative placental deficiency of essential fatty acids, and this suggests a lower source of placental membrane fluidity and subnormal content of essential fatty acids in their offspring [39]. Placentas from pregnancies with IUGR also have decreased levels of arachidonic acid and docosahexaenoic acid [40], and fetuses affected by IUGR exhibit proportions of both these fatty acids that are lower than control proportions relative to their linoleic acid (LA) and αLA precursors [41].
Taken together, these studies demonstrate the pivotal role of fetal nutrient availability. Adequate transplacental exchange of multiple nutrients is needed to sustain normal fetal growth.
A number of factors have a critical role in the regulation of placental nutrient transport to the fetus. These include NO, glucocorticoids, and imprinted genes.
Nitric oxide is an angiogenic factor [42]; as such, decreased concentrations of NO synthesis can impair placental-fetal blood flow [43] to limit transfer of nutrients. For example, sheep exposed to 50% global MUN between Embryonic Day (E) 28 and E78 of gestation had levels of NO that were lower than those of controls in maternal-fetal plasma when measured at E78 [44].
Glucocorticoids affect placental expression of glucose transporters (SLC2A1 and SLC2A3) in a dose- and time-dependent manner in both human [45] and rat [46] placentas. Therefore, a single injection of glucocorticoids at E16 reduced placental SLC2A1 and SLC2A3 abundance in rat and results in IUGR [45]. Long-term glucocorticoid exposure from E15 to term in the rat was also associated with IUGR, despite a doubling in placental expression of SLC2As in late gestation [46]. Concomitant downregulation of both SLC2A1 and SLC2A3 following a single injection of glucocorticoid may reflect an immediate attempt to increase fetal glucose supply to attenuate potential fetal hypoglycemia [46]. In contrast, upregulation of the SLC2As following long-term glucocorticoid exposure may be due to placental hypoxia [47] that stimulates SLC2A expression [48]. Interestingly, fetal cortisol infusion in sheep increased placental glucose consumption and reduced placental delivery of glucose to the fetus [49]. Glucocorticoid treatment changed placental handling and fetal delivery of lactate and selected amino acids [50]. Whether or not glucocorticoids affect amino acid transporters in the placenta is still not fully known. Based on an in vitro study [51] using BeWo cells, glucocorticoids can alter placental solute carrier family 38 member 2 (SLC38A2, previously called sodium-coupled neutral amino acid transporter 2 [SNAT2]) by altering the localization of SLC38A2 and changing protein and mRNA expression.
Imprinted placental genes, expressed in a manner that is parent-of-origin specific, can also regulate nutrient transport capacity of the placenta. For instance, mice exposed to restriction of dietary intake to 80% of controls from Day 3 of pregnancy showed a significant decrease in an imprinted placental Igf2 transcript [52]. Deletion of a placenta-specific transcript (P0) from the Igf2 gene, which is expressed only in the mouse labyrinthine trophoblast, decreased placental growth, limited nutrient transfer, and reduced fetal growth [53]. These data offer a mechanism by which the Igf2 gene may affect placental structure and function during maternal food restriction. It remains to be determined whether MUN, fetal nutrient demands, or other environmental signals act on the placental-specific promoter in the Igf2 gene to change its imprint status, promoter usage, or expression from the active allele.
In summary, suboptimal placental growth and development following MUN yields growth-restricted fetuses. As discussed in the next section, those fetuses have altered fetal physiology in utero, resulting in newborn abnormalities with increased long-term effects well into adulthood.
MUN and Fetal Development
Maternal diet affects fetal growth directly by determining the amount of nutrients available, indirectly by affecting the fetal endocrine system, and epigenetically by modulating gene activity. Nutritional insults during critical periods of gestation may thereby have a permanent effect on progeny throughout postnatal life and beyond.
Nutrient Levels and Fetal Growth
Reduction of nutrient availability during gestation decreases fetal growth in both humans and animals [4]. MUN in pregnant women may result from low intake of dietary nutrients due to a limited supply of food or because of severe nausea and vomiting that persists long after the usual first-trimester effects [54]. Short interpregnancy intervals also result in maternal nutritional depletion at the outset of pregnancy, whereas pregnant teenage mothers compete with their own fetuses for nutrients. Infants with low birth weight babies and preterm deliveries in adolescent pregnancies were more than twice as common as in adult pregnancies, and neonatal mortality in adolescent pregnancies was almost three times higher than that for adult pregnancies [55]. In pregnant rat dams, a 5% protein reduction yielded offspring that were significantly smaller than pups born to 20% protein-fed controls [36]. Although maternal serum amino acid levels were maintained in the rat dams fed low-protein diets, fetomaternal serum amino acid ratios were reduced, suggesting diminished nutrient transfer to the fetus. Therefore, maternal protein deprivation in rats decreases the activity of Na+-dependent neutral amino acid transport mediated by system A but not system alanine-serine-cysteine transporter [36]. A decrease in placental amino acid but not glucose transport precedes IUGR [36, 37], and this reduced amino acid supply likely contributes to the fetal growth reduction, rather than being a consequence of the disorder.
Modulation of Hormone Secretion
Normal pregnancy entails substantial production of hormones in the maternal, placental, and fetal compartments. Secretion of these hormones can be affected by MUN and can thereby affect fetal development. Glucocorticoids, insulin-like growth factors (IGFs), and leptin have important regulatory roles in fetal development and homeostasis.
Glucocorticoids are essential for maturation of fetal tissues so that the organs they form can cope with extrauterine life [56, 57]. However, excessive exposure to endogenous glucocorticoids in utero reduced fetal growth and predisposed to anxiety disorders in adult rats [58]. Moreover, maternal global nutrient restriction during late gestation in rats induced overexposure to glucocorticoids in the fetus and disturbed the hypothalamopituitary adrenal axis in the newborn [59]. Consequently, the rat offspring has an altered “set point” for negative feedback, giving rise to higher basal secretion of adrenal corticosterone. The increase in basal corticosterone levels in the newborn rat accelerates the appearance of age-related neural and cognitive deficits, including atrophy of dendritic processes and cell death.
Insulin-like growth factors are a family of hormones acting in autocrine, paracrine, and endocrine fashions to modulate growth [60]. The IGF ligands (IGF1 and IGF2) are regulated by a family of proteins known as the IGF-binding proteins (IGFBPs), and these interactions control fetal growth. In pregnant women, the concentration of IGFBP1 was negatively correlated with birth weight [61]. In sheep, MUN during periconceptual and gestational periods altered the IGF system to reduce fetal insulin, IGF1, and IGFBP3 levels, while enhancing IGFBP2 [62]. Alterations in the IGF cascade have a role in compromised fetal growth [62] and in fetal programming (see Note Added in Proof). For example, a reduction in plasma IGF1 is caused by MUN in pigs, and this yielded altered proportions of muscle fibers in the offspring [63]. Conversely, in ovine gestation, an increase in IGF1 plasma concentrations was associated with increased muscle mass and myofiber hypertrophy [64]. In MUN pigs, maternal-circulating IGF2 levels were positively associated with fetal weight [65] and inversely correlated with fetal IGF2 compared with age-matched controls [66], suggesting a crucial role for IGF2 in fetal growth. Taken together, these studies imply that IGFs are important for development both before and after birth.
Leptin is a satiety factor that has a key role in the regulation of energy homeostasis in adults and likely has a role in fetuses as well. In humans, growth-restricted newborn plasma leptin concentrations are low; however, these concentrations increased in infants by age 1 year [67]. The enhanced plasma leptin in infants was correlated with weight gain and an increase in subcutaneous tissue [68]. Whether this increase in plasma leptin is related to changes in leptin transport, metabolism, or clearance is unknown to date. The low levels of leptin in the growth-restricted fetuses enhanced development of appetite stimulatory pathways (e.g., increased NPY mRNA expression) and suppressed development of anorexigenic inhibitory pathways [69]. Offspring born with IUGR among sheep [70–73] and rodents [74–76] showed resistance to the anorexigenic effects of leptin as adults, which suggests in utero programming as a source of obesity in adults. The findings among humans and in animal models indicate that undernutrition in utero programs leptin dysregulation to yield subsequent obesity.
Collectively, these studies suggest that alteration in fetal hormones following MUN emerges as a major contributor to suboptimal fetal growth and development. Programmed changes induced by altered fetal hormone activity in utero can thus affect newborns and eventually yield disordered responses in adults.
Effects of Epigenetic Influences
Maternal nutrition during pregnancy can program adult disease susceptibility through epigenetic changes of the fetal genome [77] that affect the adult genotype and phenotype. The epigenetic changes result from mechanisms unrelated to the DNA sequence. Availability of amino acids and micronutrients may alter DNA methylation or modify histones. For example, a deficiency of amino acids in cultured mouse embryos resulted in reduced genomic DNA methylation and aberrant expression of the normally silent paternal H19 allele, an imprinted gene [78]. Moreover, rat dams fed a low-protein diet generally developed hypermethylation of cytosine and adenosine residues in DNA of the fetal liver [79]. However, rat dams fed low protein showed hypomethylation of the nuclear receptor peroxisome proliferator-activated receptor alpha (Ppara) and the glucocorticoid receptor (Nr3c1, previously called Gr) in the liver of their offspring [80]. These changes in the epigenetic regulation of hepatic Ppara and Nr3c1 expression may contribute to adult-onset hypertension and to impaired fat and carbohydrate metabolism. Therefore, epigenetic modifications represent a molecular mechanism by which maternal nutrition influences fetal programming, postnatal disease susceptibility, and genomic imprinting. Whether subsequent interventions can reverse in utero epigenetic effects remains to be discovered.
Impact of Intrauterine Programming on Offspring
Low birth weight is a major consequence of MUN in both humans and animals [81, 82]. Human newborns with low birth weight are more likely than newborns with average birth weight to develop insulin resistance, type 2 diabetes mellitus, and hypertension in adult life [2]. In addition, infants exposed to IUGR are at high risk for physical and mental impairments in later life [83]. MUN results in precocious maturation of the fetal hypothalamic pituitary axis, and these effects are associated with a delay, if not a permanent deficit, in cognitive processes [84] and school performance of affected children [85]. Adverse effects are similarly observed in undernourished newborn animals. Growth restriction in prenatally undernourished pigs was accompanied by increased adiposity of the newborn and maldevelopment of offspring skeletal muscle and liver. Moreover, IUGR newborns exhibited altered thermogenesis, glucose levels, and cholesterol homeostasis at birth, while insulin action was adversely affected later in life [86]. Rats exposed to 50% MUN in the last half of pregnancy had reduced fetal and newborn weights [11, 87, 88], with poor remodeling of vasculature, a contributing factor to subsequent hypertension [89]. The liver of IUGR rat offspring increased expression of peroxisome proliferator-activated receptor gamma coactivator 1, a regulator of mRNA expression for glucose-6-phosphatase and other gluconeogenic enzymes, suggesting that the alteration in hepatic glucose production resulted from changes in intracellular signaling. In adulthood, these rats developed obesity, with increased adipocyte differentiation, adipocyte hypertrophy, and upregulation of lipogenic genes. Moreover, the Pparg gene produces an adipogenic transcription factor that is significantly increased in both newborns and adults [90] and promotes adipocyte differentiation and lipid storage [91, 92]. Therefore, the abnormal activation of adipocytes in the IUGR may contribute to the development of subsequent obesity. Collectively, these studies show that suboptimal maternal nutrition not only affects fetal growth but also influences long-term outcomes of the affected offspring.
Summary
Maternal nutrition during pregnancy is an important determinant of optimal fetal development, pregnancy outcome, and (ultimately) lifelong health as an adult. Normal placental function facilitates the maternal-fetal transfer of nutrients that are critical for the development of a healthy fetus [93]. MUN reduces fetal growth in part by impairing placental development and function. Placental alterations vary with the nutritional setting and include decreases or increases in placental weight, altered vascular development, diminished angiogenic growth factor expression, and reduced placental glucose, amino acid, and lipid transport. The plasticity of the placenta allows this pivotal tissue to respond to exogenous insults and compensate for varying nutritional status of the mother. When this response is insufficient to maintain fetal growth, IUGR results, and suboptimal outcomes may appear in newborns and persist into adult life [15].
MUN can also affect fetal growth and organ development through effects on the endocrine system or imprinted gene expression. Such effects may program future generations through epigenetic effects on the placental genome, fetal genome, or both [44]. We expect in the future to achieve new strategies to prevent and treat suboptimal fetal development as more knowledge is gained about the mechanisms regulating normal and abnormal placental function and fetal growth.
Note Added in Proof
Additional information regarding fetal programming can be found in an article by Gallaher et al., 1998 [94].
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Author notes
1
Supported by a Los Angeles Biomedical Research Institute Seed Grant.
© 2010 by the Society for the Study of Reproduction, Inc.