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Weekly UpdatesABSTRACT
The term nutrigenomics refers to the effect of diet on gene expression. The term nutrigenetics refers to the impact of inherited traits on the response to a specific dietary pattern, functional food or supplement on a specific health outcome. The specific fields of genome health nutrigenomics and genome health nutrigenetics are emerging as important new research areas because it is becoming increasingly evident that: (a) damage to genome is the most fundamental disease; (b) risk for developmental and degenerative disease increases with DNA damage which in turn is dependent on nutritional status; and (c) optimal dietary intake and tissue concentration of micronutrients for prevention of genome damage is dependent on genetic polymorphisms that alter the function of genes involved directly or indirectly in uptake and metabolism of micronutrients and those genes required for DNA repair and DNA replication.
Development of dietary patterns, functional foods and supplements--that are designed to improve genome health maintenance in humans with specific genetic backgrounds--may provide an important contribution to a new optimum health strategy, based on the diagnosis and individualised nutritional prevention of genome instability--ie Genome Health Clinics. Although it is not yet possible to make distinct dietary recommendations for prevention of DNA damage based solely on an individual's genetic background, it is feasible to use current diagnostics to determine whether dietary pattern or supplement recommendations actually cause benefit or harm to the genome of an individual.
Keywords: nutrigenomics; nutrigenetics; genome health; DNA damage; micronutrients; vitamins; minerals; nutrition; genetics.
INTRODUCTION
The central role of the genetic code in determining genome stability and related health outcomes such as developmental defects and degenerative diseases such as cancer is well established (Ames 2003, 2006; Ames and Wakimoto 2002; Fenech 2002, 2005; Fenech & Ferguson 2001; Egger et al 2004; Rajagopolan & Lengauer 2004; Nathanson et al 2001; Thompson and Schild 2002). In addition, it is evident that DNA metabolism and repair is dependent on a wide variety of dietary factors that act as co-factors or substrates in these fundamental metabolic pathways (Ames 2003, 2006; Ames and Wakimoto 2002; Fenech 2002, 2005; Fenech & Ferguson 2001). DNA is continuously under threat of major mutations from conception onwards by a variety of mechanisms which include point mutation, base modification due to reactive molecules such as the hydroxyl radical, chromosome breakage and rearrangement, chromosome loss or gain, gene silencing due to inappropriate methylation of CpG at promoter sequences, activation of parasitic DNA expression due to reduced methylation of CpG as well as accelerated telomere shortening (Fenech 2002, 2005; Fenech & Ferguson 2001; Egger et al 2004; Rajagopolan & Lengauer 2004). The main challenge to a healthy and long life is the ability to continue to replace senescent cells in the body with fresh new cells with normal genotypes and gene expression patterns that are tissue-appropriate. Understanding the nutritional requirements for genome health maintenance of stem cells is essential in this regard but has so far not been adequately explored.
While much has been learnt of the genes involved in DNA metabolism and repair and their role in a variety of pathologies, such as defects in BRCA1 and BRCA2 genes that cause increased risk for breast cancer (Nathanson et al 2001; Thompson and Schild 2002), much less is known of the impact of cofactor and/or micronutrient deficiency on DNA repair. Put simply, a deficiency in a micronutrient required as a co-factor or as an integral part of the structure of a DNA repair gene (eg Zn as a component of the DNA repair glycosylase OGG1 involved in removal of oxidised guanine or Mg as a co-factor for several DNA polymerases) could mimic the effect of a genetic polymorphism that reduces the activity of that enzyme (Ames 2003, 2006; Ames and Wakimoto 2002). Table 1 provides examples of nutrients for which the mechanism of their role in prevention of DNA damage has been determined. It is evident that nutrition has a critical role in DNA metabolism and repair and this awareness is leading to the development of the new fields of genome health nutrigenomics and genome health nutrigenetics (Fenech 2005). The critical aim of these fields is to define optimal dietary intakes for prevention of DNA damage and aberrant gene expression for genetic subgroups and ultimately for each individual.
Evidence linking genomic damage with adverse health outcomes
Genome damage impacts on all stages of life. There is good evidence to show that infertile couples exhibit a higher rate of genome damage than fertile couples (Trkova et al 2000) when their chromosomal stability is measured in lymphocytes using the cytokinesis-block micronucleus (CBMN) assay (Fenech 2000, 2007) (Figure 1). Infertility may be due to a reduced production of germ cells because genome damage effectively causes programmed cell death or apoptosis which is one of the mechanisms by which grossly mutated cells are normally eliminated (Narula et al 2002; Ng et al 2002; Hsia et al 2003).
When the latter mechanism fails reproductive cells with genomic abnormalities may survive leading to serious developmental defects (Liu et al 2002; Vinson and Hales 2002). That an elevated rate of chromosomal damage is a cause of cancer has been demonstrated by ongoing prospective cohort studies in Italy and the Scandinavian countries which showed a two- to three-fold increased risk of cancer in those whose chromosomal damage rate in lymphocytes was in the highest tertile when measured 10-20 years before cancer incidence was measured (Bonassi et al 2000). It has also been shown that an elevated micronucleus frequency in lymphocytes predicts cancer risk in humans (Bonassi et al 2007). Chromosomal damage is also associated with accelerated ageing and neurodegenerative diseases (Thompson and Schild 2002; Fenech 1998; Bonassi et al 2001; Joenje and Patel 2001; Shen and Loeb 2001; Lansdorp 2000; Migliore et al 1999, 2001). Those individuals with accelerated ageing syndromes (eg Down syndrome) and sub-optimal DNA repair (eg carriers of deleterious mutations in the ATM or BRCA1 genes) may be particularly susceptible to the genome damaging effects of sub-optimal micronutrient intake.
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The concept of genome damage as a marker of nutritional deficiency
There is overwhelming evidence that several micronutrients (vitamins and minerals) are required as cofactors for enzymes or as part of the structure of proteins (metalloenzymes) involved in DNA synthesis and repair, prevention of oxidative damage to DNA as well as maintenance methylation of DNA. The role of micronutrients in maintenance of genome stability has recently been extensively reviewed (Ames 2006; Ames and Wakimoto 2002; Fenech and Ferguson 2001; Fenech 2003). The main point is that genome damage caused by moderate micronutrient deficiency is of the same order of magnitude as the genome damage levels caused by exposure to significant doses of environmental genotoxins such as chemical carcinogens, ultraviolet radiation and ionising radiation. An example from our laboratory is the observation that chromosomal damage in cultured human lymphocytes caused by reducing folate concentration (within the normal physiological range) from 120 nmol/L to 12 nmol/L is equivalent to that induced by an acute exposure to 0.2 Gy of low linear energy transfer (LET) ionising radiation (eg X-rays), a dose of radiation which is approximately ten times greater than the annual allowed safety limit of exposure for radiation workers (IAEA 1986) (Fenech 2005). If moderate deficiency in just one micronutrient can cause significant DNA damage it is reasonable to be concerned about the possibility of additive or synergistic effects of multiple moderate deficiencies on genome stability. Clearly there is a need to start exploring the genotoxic effects of multiple micronutrient deficiencies, as well as excesses, which are prevalent in human populations. This aspect is analogous to genetic studies that explore, for example, the combined effects of polymorphisms in DNA repair genes on DNA damage.
Results from a recent epidemiology study suggest that at least nine micronutrients affect genome stability in humans in vivo
We recently reported the results of an epidemiological study on 190 healthy individuals (mean age 47.8 years, 46% males) designed to determine the association between dietary intake, measured using a food frequency questionnaire, and genome damage in lymphocytes (Fenech et al 2005) measured using the CBMN assay (Figure 1). Multivariate analysis of baseline data showed that (a) highest tertile of intake of vitamin E, retinol, folic acid, nicotinic acid (preformed) and calcium is associated with significant reductions in MN frequency, ie, -28%, -31%, -33%, -46%, and -49% respectively (all P < 0.005) relative to lowest tertile of intake and (b) highest tertile of intake of riboflavin, pantothenic acid and biotin was associated with significant increases in MN frequency, ie, +36% (P = 0.054), +51% (P = 0.021), and +65% (P = 0.001), respectively, relative to lowest tertile of intake (Figure 2). Mid-tertile [beta]-carotene intake was associated with an 18% reduction in MN frequency (P = 0.038), however, the highest tertile of intake (>6400 [micro]g/d) resulted in an 18% increment in MN frequency. We were interested in investigating the combined effects of calcium or riboflavin with folate consumption because epidemiological evidence suggests that these dietary factors tend to interact in modifying the risk of cancer (Lamprecht and Lipkin 2003; Willett 2001; Xu et al 2003) and they are also associated with reduced risk of osteoporosis and hip fracture (Cagnacci et al 2003; Sato et al 2005; MacDonald et al 2004). Interactive additive effects were observed such as the protective effect of increased calcium intake (-46%) and the exacerbating effect of riboflavin (+42%) on increased genome damage caused by low folate intake. The results from this study illustrate the strong impact of a wide variety of micronutrients and their interactions on genome health depending on level of intake.
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