Are epigenetic changes in the intrauterine environment related to newborn neurobehavior?

Abstract

Advances in the developmental origins of chronic diseases suggest that there are multiple environmental influences linked to normal variations in fetoplacental development [1]. The mechanism of this plasticity is thought to be through fetal programming involving epigenetic processes that alter gene expression and permanently set pathways linked to disease. A key question in the burgeoning field of human behavioral epigenetics is whether similar mechanisms can explain the development of behavioral ‘diseases’, in particular, mental health disorders [2]. However, the study of how variations in the intrauterine environment trigger epigenetic modifications that alter behavioral development is virtually uncharted territory. A good place to start is the neurobehavior of the newborn infant. It is well known that the postnatal environment has a substantial influence on child development [3,4]. By focusing on newborn neurobehavioral phenotypes, we have an opportunity to hone in on the role of the prenatal period before postnatal environmental factors come into play. In addition, newborn neurobehavior may predict long-term developmental outcome, allowing the identification of individual infants most likely to suffer mental illness and the pursuit of interventions to prevent or ameliorate later deficits. Focusing on the epigenetics of newborn neurobehavior could provide the molecular context for individual differences in neurobehavior as well as an understanding of children’s responses to the postnatal environment – that is, why some infants are more vulnerable or susceptible to poor developmental outcome than others. Newborn neurobehavior can be quantified with the NNNS (NICU Network Neurobehavioral Scale), a well-established evaluation that includes neurological and behavioral measures and indicators of stress [5] and has been shown to predict behavior problems, school readiness, and IQ through 4.5 years [6]. Here, we describe a series of studies relating epigenetic changes in placental genes and the NNNS in a sample of several hundred term, healthy infants who vary in physical growth, born to mothers with uncomplicated medical histories [7]. The placenta provides an ideal fetal record of the intrauterine environment and alterations to its function through epigenetic processes that could affect newborn neurobehavior [8]. The placenta modulates the fetal environment and has been described as a ‘third brain’ that links the developing fetal brain and the mature maternal brain, and is thus a sensitive functional tissue to understand the prenatal environment’s effects on neurobehavior [9]. The neuroendocrine system, in particular, programming of the HPA axis is a good model for the exploration of epigenetic effects on placental genes and newborn neurobehavior. This is a well-studied system that includes an extensive literature on cortisol reactivity and the development of mental health disorders [10] and is known to be an active system within placental tissue [11]. In the placenta, 11β-HSD-2 is responsible for the inactivation of maternal cortisol. Increased DNA methylation of 11β-HSD-2 Barry M Lester