Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms

Abstract

"Barker's hypothesis" emerged almost 25 years ago from epidemiological studies of birth and death records that revealed a high geographic correlation between rates of infant mortality and certain classes of later adult deaths as well as an association between birthweight and rates of adult death from ischemic heart disease. These observations led to a theory that undernutrition during gestation was an important early origin of adult cardiac and metabolic disorders due to fetal programming that permanently shaped the body's structure, function, and metabolism and contributed to adult disease. This theory stimulated interest in the fetal origins of adult disorders, which expanded and coalesced approximately 5 years ago with the formation of an international society for developmental origins of health and disease (DOHaD). Here we review a few examples of the many emergent themes of the DOHaD approach, including theoretical advances related to predictive adaptive responses of the fetus to a broad range of environmental cues, empirical observations of effects of overnutrition and stress during pregnancy on outcomes in childhood and adulthood, and potential epigenetic mechanisms that may underlie these observations and theory. Next, we discuss the relevance of the DOHaD approach to reproductive medicine. Finally, we consider the next steps that might be taken to apply, evaluate, and extend the DOHaD approach.

Figure 1

Regulation of gene expression through epigenetic processes. Epigenetic modification of histones or of DNA itself controls access of transcription factors (TFs) to the DNA sequence, thereby modulating the rate of transcription to messenger RNA (mRNA). Transcriptionally active chromatin (top) characterized by the presence of acetyl groups (Ac) on specific lysine residues of core histones in the nucleosome, which decreases their binding to DNA and results in a more open chromatin structure that permits access of transcription factors. In addition, cytidine-guanosine (CpG) sequences in the promoter regions (P) of actively transcribed genes are generally unmethylated, allowing for the binding of transcription factors. Transcriptionally inactive chromatin (bottom) is characterized by histone deacetylation, promoter CpG methylation (as indicated by methyl groups [Me]), and decreased binding of transcription factors. (For simplicity, other histone modifications [such as methylation] and additional regulatory factors [such as methyl-CpG binding proteins] are not shown.) A further level of epigenetic control is provided by microRNA molecules (19 to 22 nucleotides in length), which bind to complementary sequences in the 3′ end of mRNA and reduce the rate of protein synthesis. From Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 2008;359(1):61–73.

Figure 2

(A) Methylation reprogramming in the germ line. Primordial germ cells (PGCs) in the mouse become demethylated early in development. Remethylation begins in prospermatogonia on E16 in male germ cells and after birth in growing oocytes. Some stages of germ cell development are shown (modified from 73). (B) Methylation reprogramming in preimplantation embryos. The paternal genome (blue) is demethylated by an active mechanism immediately after fertilization. The maternal genome (red) is demethylated by a passive mechanism that depends on DNA replication. Both are remethylated around the time of implantation to different extents in embryonic (EM) and extraembryonic (EX) lineages. Methylated-imprinted genes and some repeat sequences (dashed line) do not become demethylated. Unmethylated imprinted genes (dashed line) do not become methylated. From Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science 2001;293(5532):1089–1093.