Twenty-five years ago, Doll and Peto (1981) published their milestone epidemiological estimates of avoidable risks and prevention of the cancer burden in the United States. Since then, many environmental and lifestyle factors beyond tobacco, diet, and infections have been associated with additional emerging pathologies such as heart disease, stroke, obesity, diabetes, and hypertension.
Forty years earlier, Waddington (1942) defined epigenetics, which stresses that gene expression, not DNA sequence, is critical to advancing our understanding of genomic imprinting, which is evident in many aspects of the management of human health and disease This genomic imprinting is notable during critical or sensitive periods of development of the common diseases noted above. These periods include intrauterine life, the first 12 months of life, preschool through school age, and adolescence. However, the genetic influences do not discount the influence of other determinants during these periods, such as biological, environmental, and behavioral. In the pediatric population, for example, these represent periods of potential abnormal weight gain, which may lead to adolescent obesity.
There are many clinical disorders of imprinted genes, exemplified by the phenotypes of Prader-Willi syndrome, which is characterized by excessive appetite and lack of satiation during childhood. This condition presents progressive obesity and subsequent risks of heart disease, diabetes, and life-threatening illnesses. These kinds of genetic abnormalities are associated with uniparental disomy, which is the inheritance of two chromosomes from one parent and none from the other (see www.geneimprint.com).
Atherosclerotic cardiovascular disease, the leading cause of death in the U.S., has a long preclinical phase which reflects pathological changes during childhood and perhaps even during postnatal development. A composite or cluster of related risk factors, such as obesity, insulin resistance, dyslipidemia, and hypertension, contribute to this disease, which is now termed metabolic syndrome. Genetic predisposition, nutrition programming, and environmental influences are the primary mechanisms through which the phenotypes of cardiovascular disease and metabolic syndrome are demonstrated.
The notion that nutritional perturbations during early critical periods of development may cause long-term changes in the development and adverse outcomes during the adult years was originally advanced by Barker et al. (1989). This debate between the fetal-origins hypothesis and the developmental model of adult disease focuses on fetal growth and birth weight. During these critical periods of prenatal and postnatal growth, a variety of genotypes for insulin and insulin-like growth factor—IGF-1 expressed by the infant or IGF-2 expressed maternally—may predispose infants to insulin resistance, diabetes, obesity, and cardiovascular disease in later life. In addition, the extent to which maternal nutrition affects the fetal-origins hypothesis deserves further assessment.
Caloric restriction, inadequate micronutrients and trace elements, therapeutic drugs, utero-placental circulation, and pre-implantation are other perturbations that influence the development of health and adult disease. Each of these perturbations affects placental, maternal, fetal, neonatal, and postnatal epigenetics, which in turn affect all of the human organ systems as well as vasculogenesis and angiogenesis. These perturbations may well contribute to an array of pathologies, including cardiovascular disease, diabetes, dyslipidemia, and obesity.
The intersection of food science, nutrition, and medicine is increasingly being recognized as a model of critical components and challenges related to over- and undernutrition during prenatal life and manifestations during the adult years. Management of epigenetic information and identification of epigenetic markers are crucial for the most meaningful identification and assessment of gene expression and variation. These data will lead to a much greater understanding of the complexity of diseases, especially as people age, and will drive development of food products that reduce the risk of chronic disease for future generations.
by Roger Clemens, Dr.P.H.,
Director, Analytical Research, Professor, Molecular Pharmacology & Toxicology, USC School of Pharmacy, Los Angeles, Calif.
by Peter Pressman, M.D.,
Attending Staff, Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, Calif.
Barker, D.J., Osmond, C., Golding. J, Kuh, D., and Wadsworth, M.E. 1989. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. Brit. Med. J. 298: 564-567.
Doll, R. and Peto, R. 1981. The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today. J. Natl. Cancer Inst. 66: 1191-1308.
Waddington, C.H. 1942. The epigenotype. Endeavour 1: 18-20.