Fetal origins of adult disease

Abstract

Dr. David Barker first popularized the concept of fetal origins of adult disease (FOAD). Since its inception, FOAD has received considerable attention. The FOAD hypothesis holds that events during early development have a profound impact on one's risk for development of future adult disease. Low birth weight, a surrogate marker of poor fetal growth and nutrition, is linked to coronary artery disease, hypertension, obesity, and insulin resistance. Clues originally arose from large 20th century, European birth registries. Today, large, diverse human cohorts and various animal models have extensively replicated these original observations. This review focuses on the pathogenesis related to FOAD and examines Dr. David Barker's landmark studies, along with additional human and animal model data. Implications of the FOAD extend beyond the low birth weight population and include babies exposed to stress, both nutritional and nonnutritional, during different critical periods of development, which ultimately result in a disease state. By understanding FOAD, health care professionals and policy makers will make this issue a high health care priority and implement preventive measures and treatment for those at higher risk for chronic diseases.

Figure 1

Standardized mortality ratio by gender based on birth weight in pounds. (Reprinted with permission from Barker DJ, Sultan HY. Fetal programming of human disease. In: Hanson M, et al, editors. Fetus and neonate physiology and clinical applications: growth. Vol. 3. Cambridge: Cambridge University Press; 1995.)

Figure 2

The “thrifty hypothesis.” Schematic representation of risk of disease based on the “mismatch concept,” which focuses on the degree of disparity between the intra- and extrauterine environment. During the period of developmental plasticity, epigenetic processes are thought to alter gene expression in the fetus based on maternal environmental cues to produce phenotypes in the offspring best suited for the environment. Greater mismatch between pre- and post birth environments results in greater risk of disease (e.g., development in a poor environment followed by transition to an affluent Western lifestyle with unpredicted excessive richness of high calorically dense food with sedentary lifestyle as seen in A versus B). (Reprinted with permission from Godfrey KM, et al. Epigenetic mechanisms and the mismatch concept of the developmental origins of the health and disease, Pediatr Res 61:5R, 2007).

Figure 3

Schematic representing the pathogenesis of Fetal Origins of Adult Disease (FOAD.) In-utero malnutrition results in neuroendocrine, pancreatic, skeletal muscle, and adipose tissue dysfunction, and increased food intake and decreased energy expenditure. This leads to increased adiposity and insulin resistance, and ultimately future adult disease.

Figure 4

Simplistic scheme showing methylation (CH₃) of CpG islands achieved by DNA methyltransferases (Dnmts) and S-adenosyl-L-methionione. Methylated DNA attracts methylated CpG binding protein (MeCP2), which recruits histone deacetylases and histone methylases, resulting in histone deacetylation and methylation. This process occuring in a gene promoter causes heterochromatin formation, resulting in failure of gene expression, which further is stabilized by the binding of the heterochromatin protein (HPI). In contrast, hypomethylation of DNA attracts histone actetylases and demethylases, which results in the oppositie effect with increased euchromatin formation, transcription factor binding, and the activation of gene transcription adenosine triphosphate (ATP). (Reprinted with permission from Devaskar SU, Thamotharan M. Metabolic programming in the pathogenesis of insulin resistance. Rev Endocr Metab Disord 2007; 8:105).