Impact and mechanisms of fetal physiological programming

Abstract

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][1], [23][2]). 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. A relatively new perspective on programming is the impact and mechanisms of change to physiological regulatory systems that occur in response to the maternal environment before there is any direct impact on the fetus. In rats, Drake and colleagues ([10][3]) have shown that exposure of female fetal rats to excess glucocorticoid can cause physiological changes in their male offspring, a transgenerational effect. Specifically, the investigators found that the offspring of females exposed to dexamethasone as fetuses have diminished birth weight, and male offspring exhibited diminished glucose tolerance and increased hepatic levels of phospho enol pyruvate carboxykinase (PEPCK). These studies are consistent with a growing body of literature that demonstrates programming across generations ([6][4]) and provides evidence for the biochemical mechanisms by which altered metabolic regulation can occur. Another early time period during which it is becoming increasingly apparent that physiological regulation may be subject to programming is the periconceptional period. For example, maternal undernutrition before implantation in rats results in hypertensive offspring ([30][5]). Decreased maternal nutrition in sheep from 61 days before to 30 days after mating (term gestation is ∼150 days), a time when the nutritional burden added by the fetus is nil to negligible, is associated with precocious activation of the hypothalamo-pituitary-adrenal (HPA) axis later in gestation ([29][6]). The early activation of the HPA axis may not only lead to inappropriate elevation of prostaglandins and early birth but, as noted above, may also be associated with further programming effects due to inappropriate exposure of the fetus to glucocorticoids. Other reports have also noted that HPA activity is altered as a consequence of changes in the periconceptional environment ([11][7], [14][8], [15][9]). Another recent study in sheep emphasizes differences in early versus late undernutrition and singleton versus twin pregnancies ([13][10]). Undernutrition and maternal and fetal hypoglycemia in late gestation significantly increases perirenal fat in twins, suggesting a clear effect on metabolic regulation when the environmental conditions reach certain limits. Kind and colleagues ([28][11]) have examined the effects of moderate early nutrient restriction in pregnant guinea pigs, a species that for development arguably resembles humans more than do sheep or rats. When fetuses were examined late in gestation (0.87G), those in food-restricted dams (70% of normal from 4 wk before to 0.5G) were smaller, with disproportionately smaller liver, biceps, thymus and spleen, and relatively larger brain and lungs. Importantly, interscapular and retroperitoneal fat were also increased relative to body weight. These findings are significant because they resemble the characteristics at birth of humans born after developing in an environment of decreased nutrient availability. These individuals appear to be at risk of developing metabolic syndrome if postnatal life is spent in more affluent conditions ([51][12], [52][13]). Another study has utilized moderate early food restriction in pregnant sheep to further examine the programming of cardiovascular changes. Symonds and associates ([19][14]) fed sheep 50% recommended caloric intake until 0.65G, followed by 100%. At 3 yr of age, the offspring had higher resting blood pressure and heart rate than controls and a decreased heart rate response to elevation of blood pressure by norepinephrine. The transgenerational...