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DNA damage from micronutrient deficiencies is likely to be a major cause of cancer

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Abstract

A deficiency of any of the micronutrients: folic acid, Vitamin B12, Vitamin B6, niacin, Vitamin C, Vitamin E, iron, or zinc, mimics radiation in damaging DNA by causing single- and double-strand breaks, oxidative lesions, or both. For example, the percentage of the US population that has a low intake (<50% of the RDA) for each of these eight micronutrients ranges from 2 to >20%. A level of folate deficiency causing chromosome breaks was present in approximately 10% of the US population, and in a much higher percentage of the poor. Folate deficiency causes extensive incorporation of uracil into human DNA (4 million/cell), leading to chromosomal breaks. This mechanism is the likely cause of the increased colon cancer risk associated with low folate intake. Some evidence, and mechanistic considerations, suggest that Vitamin B12 (14% US elderly) and B6 (10% of US) deficiencies also cause high uracil and chromosome breaks. Micronutrient deficiency may explain, in good part, why the quarter of the population that eats the fewest fruits and vegetables (five portions a day is advised) has about double the cancer rate for most types of cancer when compared to the quarter with the highest intake. For example, 80% of American children and adolescents and 68% of adults do not eat five portions a day. Common micronutrient deficiencies are likely to damage DNA by the same mechanism as radiation and many chemicals, appear to be orders of magnitude more important, and should be compared for perspective. Remedying micronutrient deficiencies should lead to a major improvement in health and an increase in longevity at low cost.

Introduction

Approximately 40 micronutrients (the vitamins, essential minerals and other compounds required in small amounts for normal metabolism) are required in the human diet [1]. For each micronutrient, metabolic harmony requires an optimal intake (i.e. to give maximal life span); deficiency distorts metabolism in numerous and complicated ways many of which may lead to DNA damage. The recommended dietary allowance (RDA) [2], [3], [4] of a micronutrient is mainly based on information on acute effects, because the optimum amount for long term health is generally not known. For many micronutrients, a sizable percentage of the population is deficient relative to the current RDA [5]. Remedying these deficiencies, which can be done at low cost, is likely to lead to a major improvement in health and an increase in longevity. The optimum intake of a micronutrient can vary with age and genetic constitution, state of well being, and be influenced by other aspects of diet. Determining these optima, and remedying deficiencies, and in some cases excesses, will be a major public health project for the coming decades. Long term health is also influenced by many other aspects of diet. Though this paper uses most examples from the US, the situation seems similar in many other countries.

Micronutrient deficiency can mimic radiation (or chemicals) in damaging DNA by causing single- and double-strand breaks, or oxidative lesions, or both. Chromosomal aberrations such as double strand breaks are a strong predictive factor for human cancer [6]. Those micronutrients whose deficiency mimics radiation are folic acid, B12, B6, niacin, C, E, iron, and zinc, with the laboratory evidence ranging from likely to compelling. The percentage of the US population, for example, that is deficient (<50% of the RDA) for each of these eight micronutrients ranges from 2 to >20%, and may comprise in toto a considerable percentage of the US population (Table 1). We have used <50% of the US RDA as a measure of low intake because these numbers are available [5]. However, the level of each micronutrient that minimizes DNA damage remains to be determined.

Micronutrient deficiency is a plausible explanation for the strong epidemiological evidence that shows an association between low consumption of fruits and vegetables and cancer at most sites.

Section snippets

Dietary fruits and vegetables and cancer prevention

Greater consumption of fruits and vegetables is associated with a lower risk of degenerative diseases including cancer, cardiovascular disease, cataracts, and brain dysfunction [7]. More than 200 studies in the epidemiological literature have been reviewed and show, with great consistency, an association between low consumption of fruits and vegetables and the incidence of cancer [8], [9], [10]. The quarter of the population with the lowest dietary intake of fruits and vegetables has roughly

Folic acid

Folate deficiency, a common vitamin deficiency in people who eat few fruits and vegetables, causes chromosome breaks in human genes [18]. Approximately, 10% of the US population [19], [20] are deficient at the level causing chromosome breaks in humans. In two small studies of low income (mainly African-American) elderly [21] and adolescents [22] done nearly 20 years ago about half had a folate deficiency at this level, though the issue should be reexamined. The mechanism of chromosome breaks

Vitamin B12

The main dietary source of B12 is meat. About 4% of the US population consumes below half of the RDA of Vitamin B12 [5]. About 14% of elderly Americans and about 24% of elderly Dutch have mild B12 deficiency, in part accountable by the Americans taking more vitamin supplements [44]. Vitamin B12 would be expected to cause chromosome breaks by the same mechanism as folate deficiency. Both B12 and methyl-THF are required for the methylation of homocysteine to methionine. If either folate or B12 is

Vitamin B6

About 10% of the US population consumes less than half of the RDA (1.6 mg/day) of Vitamin B6 [5]. Vitamin B6 deficiency causes a decrease in the enzyme activity of serine hydroxymethyl transferase, the only source of the methylene group for methylene-THF [48]. If the methylene-THF pool is decreased in B6-deficiency, then uracil incorporation, with associated chromosome breaks, would be expected, and evidence for this has been found in women at a level of 32 nmol/l of Vitamin B6 in blood (0.5 

Vitamin C

About 15% of the population consumes less than half the RDA (60 mg/day) of ascorbate [5] which comes from dietary fruits and vegetables. The new RDAs for Vitamin C (90 mg/day for men, 75 mg/day for women and >35 mg for smokers) will make this percentage even higher.

There is a large literature on supplementation studies with Vitamin C in humans using biomarkers of oxidative damage to DNA, lipids (lipid oxidation releases mutagenic aldehydes), and protein. Though there are positive and negative

Vitamin E

Vitamin E, the major fat-soluble antioxidant, is consumed primarily from dietary vegetable oils and nuts. The RDA is 10 mg/day for men and 8 mg/day for women. About 20% of the population consumes less than half of the RDA [5]. Evidence is accumulating that the optimum intake may be higher, as discussed below. Studies on Vitamin E supplementation have all been done with α-tocopherol, but γ-tocopherol, the main form in the US diet, has a different function than α-tocopherol, and the two complement

Selenium

Selenium is important in enzymatic defenses against oxidants, and deficiency would be expected to lead to oxidative DNA damage [114]. An RDA of 70 μg/day of selenium and an upper limit of 350 μg/day has been proposed [115]. The average intake in the US is about 100 μg/day, though different areas of the country have different selenium levels in the soil, and the bioavailability depends on the selenium form in foods [114].

A growing body of evidence suggests that selenium plays an important role in

Niacin

The main dietary sources of niacin include meat and beans. About 2.3% of the US population consumes less than half the RDA of niacin [5]. Tryptophan from protein can also provide niacin equivalents [135]. About 15% of some populations have been reported to be severely deficient [136]. Niacin contributes to the repair of DNA-breaks by maintaining nicotinamide adenine dinucleotide levels for the poly-ADP ribose protective response to DNA damage [137], [138], [139]; deficiency compromises repair

Iron

A major dietary source of iron is meat. The United Nations Food and Agriculture Organization has estimated that the world has about two billion people at risk for iron deficiency, mainly women and children. In the US, about 19% of women, aged 12–50, and about 7% of the population, ingest below 50% of the RDA [5]; about nine million people have been estimated to be clinically deficient [141]. Iron deficiency, or iron excess, leads to oxidative DNA damage [142], [143]. Iron deficiency in children

Zinc

Major sources of zinc are meat, eggs, nuts, and whole grains. Zinc deficiency causes a variety of health effects which have been reviewed in depth [151]. About 18% of the US population consumes less than half the RDA for zinc (12 mg women, 15 mg men) [5]. Mean daily intakes reported for poor children (5 mg), middle income children (6.3 mg) and vegetarians (6.4 mg) in the US appear insufficient [151]. Zinc is a component of over 300 proteins, over 100 DNA-binding proteins with zinc fingers, Cu/Zn

Conclusion

Optimizing micronutrient intake (through better diets, fortification of foods, or multivitamin-mineral pills [167]) can have a major impact on public health at low cost. Other micronutrients are likely to be added to the list of those whose deficiency causes DNA damage in the coming years. Tuning-up human metabolism, which varies with genetic constitution and changes with age, is likely to be a major way to minimize DNA damage, improve health and prolong healthy lifespan.

Acknowledgements

This work was supported by National Foundation for Cancer Research Grant M2661, National Institutes of Health Grant AG17140, US. Department of Energy Grant DE-FG03-00ER62943, Tobacco-Related Disease Research Program Grant 7RT-0178, Wheeler Fund for the Biological Sciences at the University of California Berkeley, the Ellison Medical Foundation Grant SS-042-99 and National Institute of Environmental Health Sciences Center Grant ESO1896.

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    This paper was adapted, in part, from the work by B.N. Ames [168] and [169].

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