Nutriomes and nutrient arrays - the key to personalised nutrition for DNA damage prevention and cancer growth control
© Fenech; licensee BioMed Central Ltd. 2010
Received: 4 May 2010
Accepted: 12 August 2010
Published: 12 August 2010
DNA damage at the base-sequence, epigenome and chromosome level is a fundamental cause of developmental and degenerative diseases. Multiple micronutrients and their interactions with the inherited and/or acquired genome determine DNA damage and genomic instability rates. The challenge is to identify for each individual the combination of micronutrients and their doses (i.e. the nutriome) that optimises genome stability and DNA repair. In this paper I describe and propose the use of high-throughput nutrient array systems with high content analysis diagnostics of DNA damage, cell death and cell growth for defining, on an individual basis, the optimal nutriome for DNA damage prevention and cancer growth control.
Background and Current Status
Role in genomic stability
Consequence of deficiency
Vitamin C, Vitamin E, antioxidant polyphenols (e.g. caffeic acid)
Prevention of oxidation to DNA and lipid oxidation.
Increased base-line level of DNA strand breaks, chromosome breaks and oxidative DNA lesions and lipid peroxide adducts on DNA.
Folate and Vitamins B2, B6 and B12
Maintenance methylation of DNA; synthesis of dTMP from dUMP and efficient recycling of folate.
Uracil misincorporation in DNA, increased chromosome breaks and DNA hypomethylation.
Required as substrate for poly(ADP-ribose) polymerase (PARP) which is involved in cleavage and rejoining of DNA and telomere length maintenance.
Increased level of unrepaired nicks in DNA, increased chromosome breaks and rearrangements, and sensitivity to mutagens.
Required as a co-factor for Cu/Zn superoxide dismutase, endonuclease IV, function of p53, Fapy glycosylase and in Zn finger proteins such as PARP.
Increased DNA oxidation, DNA breaks and elevated chromosome damage rate.
Required as component of ribonucleotide reductase and mitochondrial cytochromes.
Reduced DNA repair capacity and increased propensity for oxidative damage to mitochondrial DNA.
Required as co-factor for a variety of DNA polymerases, in nucleotide excision repair, base excision repair and mismatch repair. Essential for microtubule polymerization and chromosome segregation.
Reduced fidelity of DNA replication. Reduced DNA repair capacity. Chromosome segregation errors.
Required as a component of mitochondrial Mn superoxide dismutase.
Increase susceptibility to superoxide damage to mitochondrial DNA and reduced resistance to radiation-induced damage to nuclear DNA.
Required as cofactor for regulation of the mitotic process and chromosome segregation.
Mitotic dysfunction and chromosome segregation errors.
Selenoproteins involved in methionine metabolism and antioxidant metabolism (e.g. selenomethionine, glutathione peroxidase I).
Increase in DNA strand breaks, DNA oxidation and telomere shortening.
Needs and Knowledge Gaps
Comparison of concentration of some micronutrients between a single sample of human serum and normal complete RPMI1640 culture medium (data not previously published).
RPMI 1640 culture medium
We and others have shown that DNA damage, cell death and cell growth in cultured cells are strongly affected by concentration of essential micronutrients such that both deficiency or excess within the physiological range can profoundly harm the genome and alter cell growth and survival kinetics [19, 27, 28, 33, 34]. The use of excessively high concentrations of methyl donors (e.g. folate, methionine, choline vitamin B12) in culture medium theoretically may lead to an adverse DNA methylation pattern that may inappropriately silence important house-keeping genes although strong evidence for this hypothesis is currently lacking . It is evident that, given the wide spectrum of micronutrients required for genome maintenance and repair, the development of physiological culture medium composition is an important pre-requisite to enable the determination of optimal culture conditions for growth of human cells in a genomically stable state and to explore the impact of various micronutrient combinations (i.e. nutriomes) and dosages against different genetic backgrounds. These developments are also critical if we are to use in vitro data reliably to predict in vivo nutritional effects on an individual basis. In this regard it is important to note that concentrations of micronutrients achievable in vitro might not be possible in vivo due to excretion and re-distribution within tissues. Furthermore, with respect to body fluids, we only have good knowledge on possible micronutrient concentrations in blood plasma and our knowledge about interstitial fluids surrounding organs (e.g. cerebrospinal fluid) or within tissues is at this stage rudimentary. We need to consider optima both within the physiological and supra-physiological range but only use "physiological dose ranges" achievable in vivo for in vivo predictions.
With respect to optimising in vitro and in vivo cellular health it is becoming increasingly recognised that parameters of genome and epigenome damage are exquisitely sensitive to changes in micronutrient concentration even within the "normal" physiological range [19, 27, 28, 34–36]. It is therefore practical, feasible and desirable to start re-examining dietary reference values so that recommended intakes coincide with the attainment of tissue concentrations that are consistent with minimised DNA damage. For a detailed recent review on the status of validation of DNA damage biomarkers for measuring the genomic impact of malnutrition and a proposed roadmap for determining nutrient and nutriome requirements for optimal genome maintenance refer to Fenech 2010 .
Testing Nutriomes in Nutrient Arrays
Prototypes of this approach have been designed by our group and others to investigate the following interactive effects on DNA damage, cell death and cell growth:
(i) different ratios of sulphur- and seleno-methionine at constant physiological methionine concentration .
(ii) folate concentration with alcohol .
(iv) folate concentration with riboflavin concentration with MTHFR C677T genotype .
In these studies the CBMNcyt assay was used to obtain multiple measures of chromosomal instability, cell death and cell division [48, 49]. The results of this approach are very promising because not only can they readily define the % variation in genotoxicity, cytotoxicity, metabolite and cell growth biomarkers that is attributable to a specific micronutrient, genotype and interactions between these parameters but also define the shape of the nutrient/DNA damage dose-response curve for genetically defined cell types. The use of the CBMNcyt assay is particularly relevant for this purpose because the relative incidence of DNA damage, cell death events and cytostasis varies as micronutrients and their concentrations within a nutriome are increased or decreased in multiple combinations. The relevant nutriomes within a single metabolic pathway may involve more than just two micronutrients; for example the folate-methionine cycle requires folate in various forms as a substrate and betaine, vitamin B12, vitamin B6 and vitamin B2 as co-factors. Therefore, the nutrient array should also be designed to interrogate combinations of multiple micronutrients simultaneously in a dose-related manner and at different or contrasting dosage levels for each micronutrient relative to the others.
The in vitro nutrient array system would also be an ideal mechanism to test whether the predictions of emerging nutrigenomic mathematical models in specific key metabolic pathways [50, 51] actually hold true because this system is less likely than in vivo human models to be affected by problems relating to compliance to dietary intervention and unexpected life-style and exposure variables such as stress and recreational drug consumption as well as environmental genotoxicants which can impact on the genome damage indices measured. Furthermore it is financially prohibitive to test multiple micronutrient combinations in vivo.
Realisation of the promise of nutrient array systems is dependent on the following technological developments:
1. Physiological culture systems based on appropriate composition of the culture medium to reflect exactly the actual extracellular fluid composition in diverse tissue environments (e.g. plasma, cerebrospinal fluid) as well as the correct oxygen tension which can modify susceptibility and rate of nuclear and cell division.
2. The issue of nutrient requirements based on cell division kinetics could be significant but remains unexplored. Nutrient array systems will need to be developed for both dividing and non-dividing (confluent) cell cultures including 3 D cultures with mixed populations of dividing and non-dividing cells to test whether nutritional requirements for genome maintenance might vary depending on cell division status.
4. Ideally such systems will be able to interrogate not only the optimal nutritional requirements for growth and genome maintenance of normal cells from an individual but also to verify that such a nutriome does not stimulate growth of cancer cells that the individual might have. Cancer cells are likely to have a markedly different genotype to that of the host's normal cells and could respond differently to the same nutriome environment. For example some cancer cells amplify the high affinity folic acid receptor  giving them a distinct advantage over normal cells, when folate is limiting, in accessing folate from the surrounding fluid. The ideal nutriome for an ageing or cancer-prone individual would be the combination that not only sustains the replenishment of normal cells in a genetically integral manner but also inhibits the growth of cancer cells. It is conceivable that both normal cells and cancer cells from an individual could be simultaneously tested within a single nutrient array system.
5. Ultimately, although such systems can be readily implemented for optimising in vitro culture conditions of cells, their practical use will be greatly enhanced once they have been validated for predicting the in vivo nutritional requirements of an individual. The data from the optimal in vitro nutriome, after comparison to plasma concentration, can then be used to estimate deficiencies or excesses of micronutrients in body fluids and appropriate dietary intervention can then be designed to make the necessary adjustments to optimise genome stability. This approach could be used in the emerging integrative and preventive medicine modality based on Genome Health Clinics in which developmental and degenerative diseases are prevented via diagnosis and nutritional prevention of DNA damage [11, 53]. Whether such attempts to optimise micronutrient status should be limited to those with above average DNA damage levels will remain an open question until we can find out what is the lowest DNA damage level achievable in vitro or in vivo.
6. Whether the nutrient array system can be adapted for use directly with an individual's sample of their own body fluids is an important question as this may be a better basis for in vitro testing of the efficacy of multiple nutritional adjustments under conditions that reflect exactly the individual's current physiological status. Although this approach seems attractive its feasibility has yet to be explored and could be limited by the difficulty of culturing cells in human serum.
7. There will always be a need to review and revise the DNA damage biomarkers that are most suitable for use in the nutrient array system based on their status of validation. At this point in time the cytokinesis-block micronucleus assay is the best validated with respect to its sensitivity to nutritional status and prospective association with cancer and cardiovascular disease mortality [1, 54–57]. Ultimately an automated high content analysis approach that integrates multiple complementary biomarkers of genome damage and instability (e.g. mitochondrial DNA mutations, telomere length, DNA methylation, micronuclei, nucleoplasmic bridges) would be required to achieve a deeper understanding of optimal nutritional requirements for genome maintenance on an individual basis.
8. Peripheral blood lymphocytes are ideal for use in the nutrient array system because they are easy to obtain and culture and have been used extensively to measure DNA damage in vitro and in vivo. Furthermore, because they travel throughout the body they experience fluctuations in micronutrient concentrations and nutriome profiles that may occur in different tissues and therefore can integrate the genomic impacts of sub-optimal nutrition throughout the body. Whether, the effects in lymphocytes might reflect what would happen in other tissues, such as epithelial tissues, is an important question because it is difficult to culture easily accessible epithelial tissues such as buccal mucosa. Two recent studies suggest that the level of micronuclei in lymphocytes correlates well with micronuclei in buccal cells and with DNA damage in sperm [58, 59]. However, despite these promising results more evidence is needed to justify the sole use of lymphocytes in the nutrient array system and ideally a practical epithelial cell culture alternative is also developed in the future.
In conclusion the use of nutrient array systems to interrogate genomic responses to multiple nutrient doses and combinations is in principle feasible and holds great promise to define the nutriome requirements of any cell type to either sustain its growth and reproduction in a genetically stable manner in the case of normal cells and stem cells or to suppress its growth and cause its death in the case of cancer cells.
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