Association of chromosome damage detected as micronuclei with hematological diseases and micronutrient status
Ashutosh Lal
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1
Bruce N. Ames
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1
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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
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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)