Abstract and Introduction
Abstract
The developmental origins of disease or fetal programming model predict that early exposures to threat or adverse conditions have lifelong consequences that result in harmful outcomes for health. The maternal endocrine 'fight or flight' system is a source of programming information for the human fetus to detect threats and adjust their developmental trajectory for survival. Fetal exposures to intrauterine conditions including elevated stress hormones increase the risk for a spectrum of health outcomes depending on the timing of exposure, the timetable of organogenesis and the developmental milestones assessed. Recent prospective studies, reviewed here, have documented the neurodevelopmental consequences of fetal exposures to the trajectory of stress hormones over the course of gestation. These studies have shown that fetal exposures to biological markers of adversity have significant and largely negative consequences for fetal, infant and child emotional and cognitive regulation and reduced volume in specific brain structures.
Introduction
The developmental origins of disease or fetal programming model predicts that early exposures to threat or adverse conditions have lifelong consequences that result in poor health outcomes.[1] The fetal period in the life cycle is unmatched by any other in growth and development, and it is the period in the human lifespan that is most vulnerable to both organizing and disorganizing influences. The human fetal brain is a primary target for programming influences because it is undergoing dramatic growth over a prolonged period of time. From 8 to 16 weeks gestational age (GA), neurons migrate to form the subplate zone and await connections from afferent neurons originating in the thalamus, basal forebrain and brainstem. At the same time, cells collect in the outer cerebral wall to form the cortical plate, which eventually will become the cerebral cortex. By gestational week 20, axons form synapses with the cortical plate, and by gestational week 24, cortical circuits are organized.[2,3] The growth of the nervous system is distinguished by the proliferation of neurons. Remarkably, by gestational week 28, the number of neurons in the human fetal brain is 40% greater than that in the adult.[3–6] The rate of synaptogenesis reaches an astonishing peak so that at gestational week 34 to 24 months postpartum, there is an increase of 40,000 synapses per second.[7] Thus, prenatal life is a time of enormous neurological change and because of that the fetal nervous system is principally susceptible to programming influences.
The basic assumption of the fetal programming model of disease is that developing organisms, including the human fetus, play a dynamic role in their own construction.[8] One example of this is the adjustment made by the tadpole in response to stress.[9–11] The desert-dwelling Western spadefoot toad lays its eggs in desert rainwater. If the developing tadpoles detect that the conditions for normal development and survival are unfavorable (e.g., rapid evaporation of the pool), stress hormones including corticotrophin-releasing hormone (CRH) and corticosterone (glucocorticoids) are released. These hormones influence metabolism and accelerate metamorphosis, so that the tadpole can escape the desiccating environment and avoid impending peril. If the biological stress response is blocked during this life-threatening stress, the rate of development is arrested, and the tadpole's survival is compromised. There are penalties for the tadpole that survives under these conditions, however, because it is smaller at maturity and is at a disadvantage when competing with a normally developing toad foraging for food or reproducing.
Variations of this remarkable surveillance and response system are conserved so that many species, including the human fetus, can detect threats and adjust their development.[10,12,13] The human placenta is both a sensory and effector organ that incorporates and transduces information from its maternal host environment into the fetal developmental program. Early detection by the fetal/placental unit of stress signals from the maternal environment 'informs' the fetus that there is a threat to survival. The placental/fetal unit responds to this information in an unusual but adaptive way. In contrast to the inhibitory influence on the promoter region of the CRH gene in the hypothalamus (i.e., negative feedback), maternal stress signals (glucocorticoids) activate the CRH promoter region in the placenta, stimulate its synthesis, and advance the placental clock, resulting in myometrial activation and fetal escape (premature birth) from a malignant environment.[14,15] In parallel, the fetus adjusts its developmental trajectory and modifies its nervous system to ensure survival in a potentially hostile postpartum environment. Survival under these circumstances, as described below, is associated with compromised motor, cognitive and emotional function[16,17] and reduced brain gray matter volume.[18–20]
Expert Rev Endocrinol Metab. 2012;7(4):445-459. © 2012 Expert Reviews Ltd.