Impact and mechanisms of fetal physiological programming.

THE PHYSIOLOGY OF FETAL PROGRAMMING is a quickly maturing science. Whereas initial studies established and expanded our perception of the phenomenon, more recent studies have begun to focus on the molecular and cellular mechanisms underlying the physiological changes considered to be programming. The reader who is unfamiliar with fetal programming is directed to an ever-expanding body of excellent works that review the history and survey a broad spectrum of scientific findings in the area. Aside from the recent references most familiar to the authors (1–3, 9, 12, 16–18, 20, 21, 24, 31, 32, 37, 39, 44–46) are many others, including special issues of Trends in Endocrinology and Metabolism (vol. 13, 2002) and British Medical Bulletin (vol. 60, 2001). While the concept of physiological programming is now widely accepted, it is fair to say that a precise definition remains a subject of discussion, or at least a definition that is still evolving. Initially, programming was perhaps too simply associated with deprivation during fetal gestation and small weight at birth. This provided us with a working definition of programming that related adjustments made during fetal life in response to adverse changes in the biological environment with permanent consequences that may have been advantageous in fetal life but confer disease after birth. One key example of this is the “thrifty phenotype” hypothesis (22, 23). That is, in order to maintain viable growth and development through episodes of maternal food restriction, genetic changes favoring the storage of metabolic energy become predominant in the fetus. After birth, the pattern of expression of these genes can alter insulin sensitivity and otherwise impair metabolic regulation. More recent studies of programming include models with abundance, as well as deprivation, and changes to the biological environment that may occur long before or after fetal life. In any event, the end point of the adjustments remains one or more altered physiological regulatory systems. The aim of this essay is to survey some of the most recent literature on the early programming of physiological regulatory systems, focusing on mechanisms and relating the latest findings to those reported in previous studies. The subjects of this essay encompass a wide variety of model systems and broad spectrum of programming effects.