Sex-specific associations between placental leptin promoter DNA methylation and infant neurobehavior
Introduction
The developmental origins of health and disease (DOHaD) hypothesis (Gluckman et al., 2005) postulates that environmental influences during intrauterine and early life can affect adult metabolic disease risk. Importantly, this concept has been extended to non-metabolic chronic diseases including mental health outcomes such as childhood cognitive and behavioral problems, personality disorders and schizophrenia (Lester et al., 2012, Schlotz and Phillips, 2009). The DOHaD paradigm entails the existence of early life plasticity that programs the organism to adapt to the intrauterine environment (Gluckman et al., 2005). Increasing evidence has suggested that epigenetic marks could mediate such plasticity (Low et al., 2012). Epigenetic modifications are heritable changes in gene expression without DNA sequence alterations; the principal mechanisms of epigenetic regulation are DNA methylation, histone modifications and noncoding RNAs (Bird, 2002). DNA methylation involves the addition of a methyl group to a cytosine within CpG dinucleotides, which usually occur in CpG islands in gene promoters and is frequently associated with gene silencing (Deaton and Bird, 2011). DNA methylation is particularly interesting in the context of fetal programming because these marks are reset during development and their reestablishment occurs in a tissue-specific fashion (Godfrey et al., 2007). Moreover, studies have shown that DNA methylation, although stable during adult life, can be altered by environmental cues (Christensen and Marsit, 2011, Jirtle and Skinner, 2007, Novakovic and Saffery, 2013). Hence, is plausible that some of the adaptive mechanisms involved in fetal programming are mediated through altered DNA methylation during intrauterine life. A common and critical feature of epigenetic regulation, including DNA methylation, is its tissue specificity, thus defining the appropriate tissue for examination of the role of DNA methylation in mediating the intrauterine environment's role in long-term child health is critical.
The placenta is the key regulator of the intrauterine environment mediating maternal-fetal interactions, such as nutrient and gas exchange and endocrine regulation. Maternal physiological or pathological signals are translated into the placenta and can affect fetal programming (Jansson and Powell, 2007). For instance, maternal insults such as infection and malnutrition increase placental pathology susceptibility like intrauterine growth retardation (IUGR), that itself is associated with psychopathologies such as schizophrenia and autism (Hsiao and Patterson, 2012) and other fetal outcomes. Hence, the placenta can serve as an ideal fetal record of intrauterine life, as well as a functional tissue in which to study how alterations in epigenetic regulation of key genes and pathways in this tissue impact fetal development and future child health (Maccani and Marsit, 2009, Novakovic and Saffery, 2012).
Leptin is a peptide hormone initially shown to be involved in energy homeostasis through actions in the hypothalamus, but has more recently been related to neuroendocrine, immune, and reproductive functions in normal and gravid physiology (Alexe et al., 2006). Leptin has also been implicated in fetal growth and development, including brain development (Bouret, 2010, Udagawa et al., 2007). Evidence from rodent studies have shown that leptin has an array of neurodevelopmental activities, that at the cellular level impact neurogenesis, axon growth, dendrite proliferation, and synapse formation and that environmental cues during development can alter these activities through alterations of leptin levels (Bouret, 2010). Functionally, leptin has been involved in energy homeostasis, motivation, learning and memory, cognition and neuroprotection (Morrison, 2009). During pregnancy, this peptide is produced by the placenta and by maternal and fetal adipose tissue (Moschos et al., 2002). In human placental tissue, both leptin and its receptor have been identified, and this adipokine has autocrine and paracrine functions involved in proliferation and survival of trophoblast cells (Maymo et al., 2011). DNA methylation of the leptin promoter (LEP) has been shown to regulate placental leptin gene expression and has been linked to pregnancy pathology (Bouchard et al., 2010). More recently, we observed differences in placental LEP by infant sex (Lesseur et al., 2013). In summary, leptin is an important placental signal, epigenetically regulated by DNA methylation that exhibits differences between male and female placentas, has been linked to brain development and may be related to newborn neurobehavior. Hence, in this study we aimed to explore: first, possible associations between placental LEP methylation and profiles of newborn neurobehavior, which we can assess using the NICU Network Neurobehavioral Scales (NNNS). And, secondly to examine if infant sex can modified these associations.
Section snippets
Study population
Study participants are part of the ongoing Rhode Island Child Health Study (RICHS), which enrolls mother-infant dyads following delivery at Women and Infants Hospital of Rhode Island. Term infants born small for gestational age (SGA, <10th percentile), or large for gestational age (LGA, >90th percentile), based on birth weight and gestational age calculated from the Fenton growth chart (Fenton, 2003), are selected; infants appropriate for gestational age (AGA, ≥10th percentile and ≤90th
Characteristics of the study population
The clinical and socio-demographic characteristics of the study population (n = 444) are presented in Table 1. Consistent with the RICHS study design, our population is overrepresented for LGA (26%) and SGA (21%) infants with similar distribution of males and females. Maternal age ranged from 18 to 40 years old and more than 70% of mothers reported Caucasian race. Only 5% of participants reported smoking during pregnancy.
NNNS profiles
The distribution of the NNNS summary scores within each neurobehavioral
Discussion
The intrauterine environment is hypothesized to impact fetal development and adult life disease risk. The placenta plays an important role in regulating this environment effects on lifelong health. In this study, we found that LEP methylation was associated with distinct profiles of infant neurobehavior based on the NNNS assessment at birth in a population study of healthy infants in Rhode Island. More specifically, we demonstrated that LEP methylation amongst male infants was associated with
Role of funding source
This work was funded by the National Institute of Health (NIH) through the following grants: R01MH094609 (NIH-NIMH), P01 ES022832 (NIH-NIEHS), and P30CA23108 (NIH-NCI). Its contents are the responsibility of the authors and do not necessarily represent the official views of the funding institutions.
Conflicts of interest
The authors have no conflicts of interest to declare.
Contributors
CL designed the study, collected and analyzed the data, and wrote the manuscript. DAA helped with sample processing and contributed to reviewed/edited the manuscript, AGP contributed to discussion and reviewed/edited the manuscript, MAM, AAA and DCK contributed to data analysis, discussion and reviewed/edited the manuscript, BML contributed to discussion and reviewed/edited the manuscript, CJM designed the study, contributed to data analyses, discussion and reviewed/edited the manuscript.
Acknowledgements
Thanks to Joyce Lee for her hard work in recruitment of subjects into this study, the support of the staff of the Brown Center for the Study of Children at Risk for their efforts and the RICHS cohort participants for their collaboration.
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