Early Origins of Adult Disease: Approaches for Investigating the Programmable Epigenome in Humans, Nonhuman Primates, and Rodents

Abstract

According to the developmental origins of health and disease hypothesis, in utero experiences reprogram an individual for immediate adaptation to gestational perturbations, with the sequelae of later-in-life risk of metabolic disease. An altered gestational milieu with resultant adult metabolic disease has been observed in instances of both in utero constraint (e.g., from famine or uteroplacental insufficiency) and overt caloric abundance (e.g., from a maternal high-fat, caloric-dense diet). The commonality of the adult metabolic phenotype begs the question of how diverse in utero experiences (i.e., reprogramming events) converge on common metabolic pathways and how the memory of these events is maintained across the lifespan. We and others have investigated the molecular mechanisms underlying fetal programming and observed that epigenetic modifications to the fetal and placental epigenome accompany these reprogramming events. Based on several lines of emerging data in human and nonhuman primates, it is now felt that modified epigenetic signature--and the histone code in particular--underlies alterations in postnatal gene expression and metabolic pathways central to accurate functioning and maintenance of health. Because of the tissue lineage specificity of many of these modifications, nonhuman primates serve as an apt model system for the capacity to recapitulate human gene expression and regulation during development. This review summarizes recent epigenetic advances using rodent and primate (both human and nonhuman) models during in utero development and contributing to adult diseases later in life.

Essential nutrient supplementation prevents heritable metabolic disease in multigenerational intrauterine growth‐restricted rats

“…There is evidence of compromised kidney development and function and an altered intestinal morphology (32,65,66). Further, important molecules related to development and to a MetS phenotype, such as IGF-1, PGC-1, CPTI, and PDX1, have been shown to be epigenetically altered (33,34,67,68).…”

A study of the consequences of early gestational ethanol and/or nicotine exposure in the mouse

“…In this cohort, men who were exposed to famine during the first two trimesters of gestation were found to have increased levels of obesity at age 19, whereas men exposed during the final trimester and/or the first few months of life had reduced levels of obesity at age 19 when compared to control individuals not exposed to the famine (Ravelli et al, 1976). Subsequently, numerous other longitudinal cohort studies have been established, further strengthening the hypothesis that a range of early-life environments in humans is associated with long-term health (recently reviewed in Ganu et al, 2012;Hanson andGluckman, 2014, andHeindel et al, 2016). While these are striking correlations, human studies have many confounding variables (e.g., variable exposure severity and window, effects of socio-economic status, heterogeneous genetic background), and consequently, it can be difficult to claim that early-life environments have a causal relationship with adult health.…”

“…The potential for early-life environments to influence long-term health is well characterised in both humans and animal models (Ravelli et al, 1976;Barker and Osmond, 1986;Kwong et al, 2000;Holloway et al, 2005;Golan and Huleihel, 2006;Kaminen-Ahola et al, 2010b;Moritz et al, 2011;Ganu et al, 2012;Hanson and Gluckman, 2014;Heindel et al, 2016). However, comparatively little is known as to whether exposure to an adverse environment restricted to just early gestation can also impact future health.…”

A fejlődési rendellenesség fogalmának átértelmezése: a hibás perinatalis imprinting jelentősége

“…A hibás imprinting, ha a neuroendokrin rendszerben következik be, tehát nemcsak lokálisan okozhat problémát, hanem olyan általános zavarokhoz vezethet, mint az ellenálló képesség csökkené-se, ennek következtében metabolikus betegségek és daganatok kialakulása. Nem véletlen, hogy ezen betegségek okaként egyre inkább előtérbe kerül a perinatalis hiba, amely tartósan rejtve marad és más faktorokkal együtt-működve csak valamikor a felnőttkorban manifesztáló-dik, akár obesitasban, akár daganat vagy egyéb, például pszichiátriai kórkép formájában [42,43,44,45,46,47,48]. Ezen az alapon mind több kórkép kerülhet a fejlő-dési rendellenesség kategóriába.…”