Diet, nutrition and cancer

(Conclusion) Individual life cycle: linkage of cellular to population life cycle

Growth and development is a structured process in time and space that is absolutely dependent on an ongoing adequate supply of energy and nutrients that matches the variable needed as growth progresses. Any limitation in this supply is likely to constrain the pace and pattern of development. In functional terms, growth represents a progressive increase in metabolic capacity, and maturity marks the acquisition of the full adult capacity. The ability of individuals to adapt and cope with a wide range of environments and environmental stresses reflects a reserve capacity, the magnitude of which might be exposed with a suitable stress test. From maturity there is a gradual loss of capacity, and aging represents the more extreme manifestation of the process. As capacity is lost progressively and the reserve falls, the ability to cope with any form of stress or environmental challenge decreases and eventually becomes manifest as chronic disease. A constraint on growth and development imposed by nutritional limitation at a critical stage of development can have a substantial effect on the acquisition of capacity, particularly if the limitation is of sufficient severity and imposed for sufficient duration during critical stages of organ or tissue development.

The nutrient demands vary with the stage of pregnancy and have to be satisfied, regardless of the current dietary intake of the mother. Thus, for a successful pregnancy, the mother draws on nutrient reserves as and when necessary to best satisfy this changing pattern of demands. A woman in a poor nutritional state with limited reserves increasingly depends on her current dietary intake to meet the variable needs of the pregnancy, and this may be considered to be a high-risk strategy. Thus, the mother’s nutritional status at the start of pregnancy best predicts her ability to support the needs of the fetus, as required, the greater choice for the fetus to meet its needs.

Thus, for a well-nourished population of women, the current pattern of food intake does not relate strongly to birth outcomes compared with the nutritional status of the mother at the start of a pregnancy and the capacity to engage in extensive metabolic interchange. The imposition of any stress is likely to alter nutritional state, either by changing appetite, changing the partitioning of nutrients between tissues, increasing nutrient losses, or altering the pattern of demand for nutrients. Thus, the stress imposed by infection, the stress imposed by behaviors such as alcohol consumption or cigarette smoking, the stress of metabolic ill health such as diabetes or hypertension, or stresses imposed by deprived social circumstance can all operate to alter the potential availability of nutrients to the fetus and its ability to meet its needs.

Animal studies

The epidemiological evidence on its own is not sufficient to be persuasive of causality. However, evidence obtained from animal studies demonstrates that modest manipulation of the maternal diet before and during pregnancy leads to reproducible change in a wide range of functions and illustrates possible mechanisms through which these intergenerational changes might be achieved. These changes are specific but may be widespread across a number of systems of the body, reflecting changed cellular and metabolic function that is reflected in altered glucose tolerance, abnormal appetite control, obesity, immune dysfunction, altered inflammatory responsiveness, and changed behavior.

It has been possible to explore possible mechanisms that underlie these phenomena in different animal species. If, before and during pregnancy, rats are given diets in which the protein content is varied across the normal range of intakes, the pregnancies are carried successfully, and to superficial observation the offspring are well. However, more detailed investigation shows that the animals have wide-ranging but subtle changes to the structure and function of many organ systems that are life long and eventually lead to metabolic changes representative of disease states.

The mechanisms that underlie these profound changes are likely multiple, but profound differences in structure and function can be elicited from a period of altered nutritional exposure as short as the first 4 d of a rat pregnancy. One important way in which the mother’s nutrient and environmental exposure might alter the delivery of nutrients to the fetus might be through altered structure or function of the placenta. The fetus is normally protected from the effects of glucocorticoids in the maternal circulation through the placental activity of 11B-hydroxyseroid dehydrogenase.

When pregnant dams are offered a diet lower in protein (9 percent), downregulation of placental 11B-hydroxyseroid dehydrogenase occurs. As a consequence, the fetus is overexposed to maternally derived glucocorticoids, leading to altered development of glucocorticoid-sensitive systems. This is reflected in the resetting of hormonal axes, which include the hypothalmus-pituitary-adrenal stress axis, the growth hormone-insulin-like growth factor-insulin axis; the thyroid axis, and the sex steroid axis. This resetting leads to altered metabolic responsiveness at later ages, including altered responses to diet and a wide range of stressors. The effect of environmental changes being communicated through successive generations of cells implies epigenetic modification. When rats are fed a low-protein diet throughout pregnancy, there was modified expression of the glucocorticoid receptor, peroxisome proliferators-activated receptor-, and histone acetylase in the liver of the off-spring. The altered expression was associated with differential methylation of the promoter region of the gene from the glucocorticoid receptor and peroxisome proliferators-activated receptor-.

The effect of the low-protein diet was reverse when it was supplemented with folic acid during pregnancy. The persistence of the effect of the reduced-protein diet and folic acid supplementation after the end of the dietary intervention show that maternal diet can program epigenetic mechanisms and hence alter gene expression in the offspring. Epigenetic effects and their modification are recognized as important changes associated with altered risk of neoplastic change. The fact that programming effect is mediated by similar processes raises the possibility that programmed effect might be directly related to susceptibility to cancer. Programmed differences in metabolic competence carry a range of possible implications in terms of differential risk of cancer because of altered responsiveness to potential toxins or stressors in the environment or changes in immune and inflammatory responses.