DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

Abstract

Background Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored. Methods We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations (G1,G2), including 50 G1 individuals hospitalized during the first year of life for moderate to severe protein energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study. Attention deficits and cognitive performance were evaluated with Connors Adult Attention Rating Scale (CAARS) and Wechsler Abbreviated Scale of Intelligence (WASI). Expression of nutrition-sensitive genes was explored by qRT-PCR in rat prefrontal cortex. Results We identified altogether 134 nutrition-sensitive differentially methylated genomic regions (DMR), with the overwhelming majority (87%) specific for G1. Multiple neuropsychiatric risk genes, including COMT, IFNG, MIR200B, SYNGAP1 and VIP2R showed associations of specific methyl-CpGs with attention and IQ. Interferon Gamma (IFNG) expression was decreased in prefrontal cortex of rats showing attention deficits after developmental malnutrition. Conclusions Early childhood malnutrition entails long lasting epigenetic signatures associated with liability for attention and cognition, and limited potential for intergenerational transmission.

Annual Research Review: DNA methylation as a mediator in the association between risk exposure and child and adolescent psychopathology

“…In turn, these changes associated with relevant developmental outcomes, including birth weight and low-density lipoprotein cholesterol levels. Using data from the multigenerational Barbados Nutrition Study, Peter et al (2016) examined whole blood from adults in their fifth decade of life (n = 94), including a group (n = 44) who had been hospitalised in early infancy due to severe protein-energy malnutrition. Epigenome-wide DNAm analyses identified 134 nutritionsensitive, differentially methylated genomic regions, including loci annotated to a number of neuropsychiatric risk genes (e.g.…”

Hippocampal mechanisms in impaired spatial learning and memory in male offspring of rats fed a low‐protein isocaloric diet in pregnancy and/or lactation

“…Developmental programming is defined as “The response to a specific challenge to the mammalian organism during a critical developmental time window that alters the trajectory of development with resulting effects on health that persist throughout life” (Zambrano & Nathanielsz, ). Fetal and neonatal exposure to various maternal challenges, such as hypoxia (Giussani & Davidge, ), suboptimal maternal nutrition (Langley‐Evans, ), and maternal obesity and over nutrition (Nathanielsz et al, ; Rodriguez‐Gonzalez et al, ; Santos et al, ; Taylor, Samuelsson, & Poston, ; Vega et al, ; Zambrano & Nathanielsz, ) alter offspring phenotype as a result of epigenetic gene/environment interactions (Hanson & Gluckman, ; Peter et al, ). Reduced maternal nutrition is the most extensively studied programming challenge of phenotypic plasticity (Cripps et al, ; Fernandez‐Twinn et al, ; Pinheiro, Salvucci, Aguila, & Mandarim‐de‐Lacerda, ; Qasem, Li, Tang, Pontiggia, & D'mello, ; Rodriguez‐Gonzalez et al, ; Vega et al, ).…”

System biology approach intersecting diet and cell metabolism with pathogenesis of brain disorders

“…The quality of maternal care may “program” the genome through epigenetic mechanisms to modulate the stress response in the offspring (Weaver et al, 2004). Through epigenetic modifications, acquired traits such as maternal and paternal conditions (Champagne, 2016; Peter et al, 2016) (Ng et al, 2010), hormonal (Stolzenberg and Champagne, 2016) may be transmitted to offspring. In support of a link between cell metabolism and epigenetics, it has been shown that chronic consumption of a caloric diet can program pancreatic ß-cell dysfunction, impaired insulin secretion and glucose tolerance in the female rat offspring (Ng et al, 2010).…”