Embryos respond to their environment in vitro or in vivo in diverse ways that can influence their future growth and health. As discussed above, developmental plasticity, evident in epigenetic, metabolic, and proliferative states can lead to changes in fetal development through changes in imprinted gene expression, nutrient, and stress-related signaling pathways or cell cycling and apoptotic rates. Last, we consider the interaction between the embryo-centric phenotype changes and the maternal environment during subsequent gestation.
The search for basic mechanisms underlying the intrauterine programming of fetal and postnatal growth, cardiovascular, and metabolic physiology and ultimately the enhanced risk of adult-onset disease has indicated a complex network of interactions with a central role for maternal-fetal neuroendocrine signaling [reviewed in 140–142]. Maternal undernutrition during gestation alters maternal steroid hormone levels, including elevation of glucocorticoids (GC; corticosterone, cortisol), the stress hormones, which can profoundly influence the physiological condition of the conceptus [143]. Fetal protection against maternal GC is enzymatically regulated by placental 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which converts GC to an inactive form [144]. Placental 11ß-HSD2 expression and activity are reduced by maternal undernutrition, resulting in increased GC exposure to the fetus [145–147]. This exposure can alter the setting of the fetal hypothalamus-pituitary-adrenal (HPA) axis, leading to elevated fetal GC activity which, through the nuclear GC receptors, can modify the expression of many downstream genes controlling growth and metabolism, including cardiovascular and renal physiology [140–142]. Vascular function and setting of resting blood pressure can be further modified via the renin-angiotensin system and kidney nephrogenesis in response to HPA modulation [141, 148].
How important are these neuroendocrinal pathways in initiating fetal and postnatal alteration in growth, metabolic, and cardiovascular phenotype following environmental manipulation during preimplantation development? The effect of restricted periconceptional nutrition (70% control feed allowance) before mating and for 7 days after mating, prior to control feed provision for the duration of gestation, has been investigated on the development of the fetal HPA axis in sheep [30, 31]. Periconceptional undernutrition resulted in higher fetal plasma concentrations of pituitary adrenocorticotropic hormone (ACTH) between 110 and 145 days of gestation, a significantly greater cortisol response to corticotropin-releasing hormone and an increase in fetal blood pressure in twin fetuses in late gestation [30, 31]. A change in the setting of the fetal HPA axis following periconceptional undernutrition may derive from reduced trophectoderm development and a change in the secretion of placental hormones such as prostaglandin E2, which is thought to control ACTH secretion in late gestation [30, 149].
The consequences of early embryo environment on future development may also be mediated through disturbance in the balance of placental-fetal growth and function derived from i) nonequivalent epigenetic changes to imprinted genes expressed in fetal or placental pathways and/ or ii) inappropriate allocation of cells during early lineage specification [15, 44, 46]. The influence of placental function and placental/fetal exchange on fetal programming has been reviewed recently [150]. Many imprinted genes contribute to placental function and nutrient exchange [38, 46] and may therefore amplify early epigenetic effects in embryos caused by environmental conditions with physiological impairment to growth due to reduced nutrient supply. Thus, deletion of the mouse Igf2 isoform Igf2P0, which is expressed exclusively in the labyrinthine trophoblast of the placenta, results in reduced placental growth and transport capacity and subsequently retardation in fetal growth [44]. Abnormal allantoic development and defective placentation resulting from in vitro culture of ruminant embryos and leading to fetal pathology has been proposed as a mechanistic basis for LOS [16, 151, 152].
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