Association of chromosome damage detected as micronuclei with hematological diseases and micronutrient status

Mutagenesis, Jan 2011

Epidemiological studies reveal strong association between micronutrient deficiencies and development of cancer. Since chromosome breaks and abnormal chromosome segregation, identified as micronuclei (MN), are central to malignant transformation, the influence of micronutrient status upon MN frequency has been the subject of intense research. Motivating this effort is the idea that marginal micronutrient deficiencies lead to allocation of scarce cellular resources towards immediate survival at the expense of maintaining genomic integrity, placing the individual at greater risk for degenerative diseases and cancer in old age. The challenge in identifying an association between individual micronutrients and MN frequency stems from the complexity of human diet, simultaneous presence of multiple micronutrient deficiencies, variable genetic susceptibility and methodological difficulties. A unique model for studying MN in humans is provided by a group of haematological diseases, the chronic haemolytic anaemias associated with high reticulocyte count and absence of splenic function. These disorders may prove valuable for assessing the influence of micronutrient status once the effect of abnormal erythropoiesis on MN formation is adequately understood. Eventually, large population-based studies that can account for the baseline variability in MN frequency, lifestyle and genetic factors may be needed to uncover the DNA-damaging effect of poor diet. Understanding the link between micronutrient status and MN frequency will contribute towards determining optimal micronutrient intake to preserve long-term health.

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Association of chromosome damage detected as micronuclei with hematological diseases and micronutrient status

Ashutosh Lal 0 1 Bruce N. Ames 0 1 0 Center, Children's Hospital Oakland Research Institute , 5700 Martin Luther King Jr. Way, Oakland, CA 94609 , USA. Tel: 1 Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute , 5700 Martin Luther King Jr. Way, Oakland, CA 94609 , USA - Epidemiological studies reveal strong association between micronutrient deficiencies and development of cancer. Since chromosome breaks and abnormal chromosome segregation, identified as micronuclei (MN), are central to malignant transformation, the influence of micronutrient status upon MN frequency has been the subject of intense research. Motivating this effort is the idea that marginal micronutrient deficiencies lead to allocation of scarce cellular resources towards immediate survival at the expense of maintaining genomic integrity, placing the individual at greater risk for degenerative diseases and cancer in old age. The challenge in identifying an association between individual micronutrients and MN frequency stems from the complexity of human diet, simultaneous presence of multiple micronutrient deficiencies, variable genetic susceptibility and methodological difficulties. A unique model for studying MN in humans is provided by a group of haematological diseases, the chronic haemolytic anaemias associated with high reticulocyte count and absence of splenic function. These disorders may prove valuable for assessing the influence of micronutrient status once the effect of abnormal erythropoiesis on MN formation is adequately understood. Eventually, large population-based studies that can account for the baseline variability in MN frequency, lifestyle and genetic factors may be needed to uncover the DNAdamaging effect of poor diet. Understanding the link between micronutrient status and MN frequency will contribute towards determining optimal micronutrient intake to preserve long-term health. Introduction An increase in the frequency of micronuclei (MN), which reflects occurrence of chromosome breaks and abnormal chromosome segregation, is associated with future risk of cancer in humans (1). The measurement of MN has been utilised to explore the effect of genotoxic agents in populations and has also become a valuable tool to study the link between nutrition and DNA damage (2). Micronutrients are a set of 40 substances, the vitamins, essential minerals and other compounds required in small amounts for normal metabolism, that are essential for human health (35). The optimum micronutrient intake for preserving long-term health is difficult to ascertain and may be higher than the current dietary recommendations (3). The magnitude of the worldwide problem of micronutrient malnutrition is immense even by the current standards (6). Inadequate micronutrient intakes are widespread in poor countries, and in the affluent nations, large segments of society, especially the poor, children, adolescents, the obese and the elderly do not meet the dietary reference intakes (7,8). Over half of the US population consumes inadequate magnesium, and large segments of the population are extremely low in vitamin D, omega-3 fatty acids, potassium, calcium, vitamin C, vitamin E and vitamin K (9). Given the scope of the challenge, the demonstration of a link between micronutrient malnutrition and DNA damage through the measurement of MN frequency will aid in stepping up implementation of public health strategies to reduce diseases of ageing and cancer. These issues have been discussed at length in a recent publication (10). In this review, we will consider experimental evidence linking MN frequency in humans, as measured by the erythrocyte MN assay, to haematological diseases. The erythrocyte MN assay has been used less often in large human studies as opposed to the lymphocyte cytokinesis-block MN assay. The technical difficulty of using the erythrocyte MN assay partly derives from the active removal of the MNcontaining reticulocytes from circulating blood by the spleen (11). Therefore, a group of haematological diseases, chiefly the chronic haemolytic anaemias associated with the absence of splenic function and high reticulocyte count, forms an attractive and convenient model for the application of erythrocyte MN assay in peripheral blood samples. We will examine the usefulness and limitations of haematological diseases to evaluate genotoxicity in humans. MN and micronutrient status DNA damage develops rapidly during micronutrient deficiencies (12,13), but the consequences of this damage, cancer and degenerative diseases, are delayed in onset (3). This temporal dissociation can be explained by redistribution of limited nutritional resources through evolutionary adaptation of biochemical pathways (9,10,14). As the scarcity of a micronutrient increases, a triage mechanism for allocating scarce micronutrients is activated that favours short-term survival at the expense of long-term health, in part through an adjustment of the bi (...truncated)


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Ashutosh Lal, Bruce N. Ames. Association of chromosome damage detected as micronuclei with hematological diseases and micronutrient status, Mutagenesis, 2011, pp. 57-62, 26/1, DOI: 10.1093/mutage/geq081