potentiates oxidative stress (Rao and Georgieff, 2001) or can cause iron overload disease. Low maternal or fetal levels of vitamin A are associated with developmental disease, as are high levels.

The impact of some body burdens vary across time and, to be understood, must be assessed at different times. For example, a maternal body burden of PCBs causes exposure to both the fetus and to the newborn via breast milk. Body burdens at one time may also impact measures of health in later time frames. A child who has received treatment for Hodgkin’s lymphoma, increasing the genotoxic body burden, is at risk for secondary cancers (Hack et al., 2002).

Early Programming

While not without controversy (Huxley et al., 2002), there is a growing literature on the potential role of “perinatal programming,” referring to the processes in which specific influences during critical or sensitive periods of development can have lifetime consequences by altering metabolic pathways and other physiological systems. This appears to be a special case of the more general phenomenon of how environmental influences can be embedded in biology during critical and sensitive periods of development.

In humans, the relationship between fetal growth, postnatal growth, and the risk of such diseases as hypertension, coronary heart disease, and non-insulin-dependent diabetes have been frequently studied (Bertram and Hanson, 2002; Barker, 1998). Both human epidemiological and animal experimental studies support the hypothesis that relative undernutrition in the fetus results in significant and relatively permanent changes in important physiological systems (Nathanielsz, 1999). Perinatal programming indicates that sensitive or critical periods of development may have lifelong effects and influence the development of chronic diseases later in life (Ingelfinger, 2003). However, it does not discount the potential effect of the external environment (Seckl, 1998; Ingelfinger and Woods, 2002; Falkner, 2002; Roseboom et al., 2001) in modifying the effects.

Fetal undernutrition is believed to induce persistent changes in several metabolic pathways, but the exact mechanisms are only now being pieced together through a range of animal experiments and human measurement studies (Seckl, 1998; Barker, 1998). Because it is likely that events occurring at other times modify prior influences, there is a growing interest in understanding the predisease pathways and biological changes that occur prior to the recognition of a vast array of clinical outcomes. Currently many of these predisease markers are either below current limits of detection or produce changes that are not currently measured on a routine basis (Lucas et al., 1999; Keller et al., 2003; Ingelfinger, 2003).

Examples of such programming during particular sensitive or critical periods of development are coming to light. For example, low numbers of nephrons are associated with hypertension, and it has been shown that individuals whose mothers experienced severe protein-calorie malnutrition during the third trimester,



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