NUTRITIONAL MODULATORS OF TRANSGENERATIONAL EPIGENETIC INHERITANCE

Since 1999 ISSN 2226-7425 The journal of scientific articles “Health & education millennium” (series Medicine), 2012, tom 14 [1]

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Singh Ram B., S. Shastun, Radzhesh Agarval, Chibisov S.M., D.W. Wilson. 1. Halberg Hospital and Research Institute, Moradabad, India 2. People,s Friendship University of Russia, Moscow, Russia 3. School of Medicine and Health, Durham University, UK.,[email protected] NUTRITIONAL MODULATORS OF TRANSGENERATIONAL EPIGENETIC INHERITANCE

Several experts have proposed that genes are the primary units of inheritance and that evolution may be a change in the genetic composition of the population, although molecular mechanisms were unknown in 1942 when Modern Synthesis was published. Nutrition appears to be important in the evolutionary biology, biochemis-try, genomics, developmental biology, systems biology. The impact of the diet and environmental factors on genes concerning mechanism of evolution have grown significantly beyond the Modern Synthesis. Epigenetic in-heritance is the passing of phenotypic change to subsequent generations in ways that are outside the genetic code of DNA. The interaction of specific nutrient, with the genetic code possessed by all nucleated cells can be recog-nised. Recently, polymorphisms of the human Delta-5 (FADS1) and Delta-6 (FADS2) desaturase genes have been described to be associated with the level of several long-chain n-3 and n-6 polyunsaturated fatty acids (PUFAs) in serum phospholipids. Increased consumption of refined starches and sugar increases generation of superoxide anion in the tissues, and free fatty acids(FFA) in the blood. There is increased amount and activity of nuclear factor-kB(NF-kB), a transcriptional factor regulating the activity of at least 125 genes, most of which are pro-inflammatory. The consumption of glucose may be associated with an increase in two other pro-inflammatory transcription factors; activating protein-1 (AP-1) and early growth response protein-1 (Egr-1). The AP-1 regulates the transcription of matrix metallo-proteinases and the second one modulates the transcription of tissue factor and plasminogen activator inhibitor-1.The dietary factors in general a could be important in the patho-biology of epigenetic inheritance. It may be the basis of evolution of diet and the Tsim Tsoum concept.

Key words: epigenetic inheritance, Tsim Tsoum concept, evolution, diet.

Introduction. There is evidence that primary risk factors; diet,

physical inactivity, tobacco, stress, pollutants, radia-tions and drugs can influence genetic structure func-tions. It has been discussed, in the last two decades, that certain environmental factors like nutrition could be important in the patho-biology of epigenetic inheritance (1-4). Julian Huxley who published his landmark Monograph; ‘Evolution: The Modern Syn-thesis in 1942 was not aware about the role of nutri-tion in evolution. This monograph brought Darwin’s ideas into the 20th century and incorporated a knowledge of genes that was emerging in this centu-ry. Gregor Mendel’s experiments on inheritance in this context were quite interesting (‘ Monograph: Ex-periments with Plant Hybrids) at Hynčice (Vražné) in the now Czech Republic. Barbara McClintock discov-ered transposable elements in the mid of the century, where parts of the genome can jump around and cause mutations or alter the gene expression, skewing Mendelian ratios and inheritance patterns. Darwin believed that organisms gradually adapt to their envi-ronments via minute physical adjustments. Biologists have since found evidence that dramatic adaptations can also occur, for instance in the form of major mor-

phological changes. These adaptations appear to be the cause of changes in structure from apes to man and various human races. Such adaptations may be responsible for the development of diseases or health or for conversion of man to humans.

Evolutionary biology, biochemistry, genomics, developmental biology, systems biology and the im-pact of the environment on genes concerning mecha-nism of evolution have grown significantly beyond the Modern Synthesis (1-6). This landmark mono-graph emphasizes that “ populations containing some level of genetic variations evolve via changes in gene frequency, induced mostly by natural selection and phenotypic changes are gradual with speciation and diversification into higher taxonomic levels come about over long periods of change. There is now sci-entific evidence to support that these ideas remained largely unchallenged for more than 50 years from now, because phenotypic changes have occurred rap-idly in the last 100 years in every race species but more slowly among hunter-gatherers (1-6). Genetic variation and evolvability.

It seems that basic genetic variation may have some influence on some lineages causing greater ‘evolvability’ than others. In this connection, herita-

Since 1999 ISSN 2226-7425 Журнал научных статей «Здоровье и образование в XXI веке» (Серия медицина), 2012, том 14 [1]

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ble phenotype variations may depend on the biology and biochemistry of the genes (2-5). The populations having greater genetic variation than others, are ex-pected to generate phenotypic variation more rapidly. The Modern Synthesis addresses ‘evolvability’ in a population which may not be a distinct trait, inde-pendent of genetic variation. The Modern synthesis also does not place emphasis on the influence of pho-tosynthesis, flight, multicellularity which stands out against a backdrop of slow and steady evolution. It seems to us that Modern Synthesis should be modi-fied by the experts because Life Sciences are dynamic, and can alter with alteration in environmental fac-tors by epigenetic inheritance.

The ability to evolve at a different speed than other species needs some particular characteristics. A prion that results from the mis-folding of the Sup35 protein in the yeast; Saccharomyces cerevisiae, may serve as a conduit for evolution of novel traits and as molecular vehicle for evolvability. The functional domain of Sup35 is highly conserved in a variety of organismal groups which serves as a translation ter-mination factor. It may also help ribosomes to recog-nize stop codons on mRNA and thus mediates the normal translation of proteins. The yeast cells, which have aggregates of prions, read through about 5 to 10 % of stop codons in a given cell, so the mis-folded prions are not able to function correctly. The mRNA may stick around longer in cells enabling the expres-sion of more proteins, so the cells with prions can express normally silent sequences beyond the termini of genes or express different levels of normal pro-teins. These cells are capable of expressing a wide variety of phenotypes (6). This study (6) found that nearly half of the conditions having the prion (PSI) led to significant phenotypic effects in some of the strains, which uncovered previously-hidden pheno-typic variation in the yeast cells. This variation was advantageous in some of the conditions to which yeast cells were subjected. It is possible that prion (PSI) may act as capacitor and potentiator of ‘evolva-bility’, because switching into the PSI state sensitizes the yeast more efficiently to produce phenotypic di-versity, with change in nutrition and other environ-mental conditions (6).

The low ω-6/ω-3 fatty acid ratio and coenzyme Q10 present in the cell membrane to which humans adapted during evolution, may have beneficial effects on this phenotypic diversity. The prion (PSI) can pass from mother to daughter yeast cells when they divide either mitotically or meiotically despite lineage where they revert back to non-prion state selection, result-ing into beneficial adaptations (6). Depending on the

strain, this occurs naturally at every 100,000-1000,000 cell divisions or so depending on the strain. There are more extreme phenotypes, if the cell is stressed-out of an organism, compared to a benign environment which may possibly be independent of natural selec-tion but this is not yet established. It is also possible that “natural selection” may not actually be “natural” but it is our ignorance about the environmental fac-tors that are causing phenotypic variations, which would be clearer from the evidence on the facilitation of genetic variation. Facilitated genetic variation.

A complex set of physical and chemical factors, coming into play during development, which can in-fluence structures and functions that are beyond simple genome to phenotype translation, may be called facilitated variation. Several mechanisms have been proposed to explain facilitated variations includ-ing those related to oscillations of certain regulatory elements affecting segmentation in embryo and chemicals acting during development which can cause patterns of stripes or spots in the organism. In this connection, the role of nutrients causing birth defects and other biochemical phenotypes appear to be important. It seems that nutritional status of mothers and the psychological environment during the perinatal period could be important influencers in the facilitated variations. These variations may spark faster evolutionary alterations compared to random mutations, because developmental changes can create additional phenotypes upon which selec-tion can act. However, many of these random muta-tions may be due to less known environmental fac-tors and astrochronobiological factors like solar activ-ity, geomagnetic forces and nutrients excess or defi-ciency, developing according to time structures.

The Modern Synthesis emphasizes that geno-types translate directly into phenotypes and evolu-tionary changes stemmed from the slow, gradual ac-cumulation of the random genetic mutations. It seems that this simple explanation is quite complex in view of the developmental biology and biochemis-try and astrochronobiology in the light of nutritional content of the cell. The Modern Synthesis ignores the complex gene interactions and sudden morphological reorganizations that occur during development, be-cause in experiments and natural setups, there is dis-cordance between genotype and phenotype. In one study, house finches which were natives to deserts began spreading throughout the United States in the 1940s through the pet trade (7). The birds were tracked for 19 generations over a span of 15 years at a study site in Montana which showed that the popula-


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tion of birds was developing unique beak morpholo-gies as adaptations to the new environment related to availability of foods, at a surprisingly rapid rate (7).This finding is also against the view expressed in the Modern Synthesis that it may be a random muta-tion. This evidence clearly shows the capability of the flinch to adapt rapidly to survive, against the envi-ronmental factors related to housing, the new habi-tats. The interacting embryonic processes resulted in an initial level of phenotypic variation greater than that predicted from underlying genotypic variation (7). The selection was essentially blind, during devel-opment of the egg; to the creation of the initial pool of phenotypic variation, because it occurred only later when young birds began feeding on the foods availa-ble in their new habitat. The selection was able to determine which beaks were more or less suited to the environment, which was related to the availability of foods, without looking into developmental process, by which this beak was produced, due to opportunity for diversification. It is not clear as to what extent the quality of the food or method of eating or nutrient content was responsible for phenotypic variation. Multilevel epigenetic inheritance.

Passing of phenotypic change to subsequent generations in ways that are outside the genetic code of DNA are described as multilevel inheritance. It is known that chromatin structure, remodeled histone proteins or methylated DNA, often mediated by envi-ronmental factors, can pass from parent to offspring without changing the actual sequence of the inherit-ed genome. The Modern Synthesis proposed that genes were the primary units of inheritance and that evolution may be a change in the genetic composi-tion of the population, although molecular mecha-nisms were unknown in 1942. If epigenetics play any role in evolutionary change, we must demonstrate that the changes last and are stable and cause herita-ble effects through several generations (8). Two groups of genetically identical Arabodopsis plants (Brassicaceae) were exposed to either hot or cold conditions for two; P and F1 generations in an exper-iment (9). The next generation; F2 from both groups was grown at normal temperatures, but the offspring (F3) from both groups were grown in either hot or cold conditions. The F3 plants grown in hot condi-tions and descended from P and F1 plants also grown in hot conditions produced five-fold more seeds compared to F3 plants grown in hot conditions but descended from cold treated ancestors ((9). It seems that epigenetic factors affecting flower productions and early stage seed survival, due to molecular adap-

tations, in these plants may have caused these muta-tions.

An epigenetic memory of stress has been ob-served in dandelions (Taraxacum officinale) (Verhoeven et al. 2010). Dandelions are apomictic, i.e., they reproduce through unfertilized seeds, and are therefore assumed to be genetically identical, providing the opportunity of studying epigenetic var-iation in the absence of genotypic variation. In a re-cent study, isogenic dandelions were exposed to a variety of stresses (biotic and abiotic) and, together with the first generation of unstressed offspring, were analyzed for genome-wide DNA methylation changes using methylation-sensitive amplified-fragment-length polymorphism. The results showed that stress-induced DNA methylation changes occurred, and that these changes were transmitted to the next gen-eration (Verhoeven et al. 2010). The nature of the dif-ferentially methylated loci, i.e., whether they are genes or transposable elements, is not yet clear. Moreover, in the absence of a complete genome se-quence it is hard to rule out underlying genetic changes. Despite the technical challenges in studying dandelions, they provide an interesting example of a situation in which genetic variation is limited and where transgenerational epigenetic inheritance could provide a useful mechanism for adaptation to envi-ronmental changes.

Whereas inbred mouse strains and apomictic dandelions provide an opportunity to study epigenet-ic variation in a situation in which genetic variation is greatly mimimized, the situation is different in out-bred populations, such as humans. Studies in monozygotic (MZ) twin pairs, which are genetically identical, provide some evidence for epigenetic varia-tion between individuals within a twin pair (Fraga et al. 2005; Mill et al. 2006; Oates et al. 2006; Kaminsky et al. 2009). However, a more recent genome-wide study of the genetic, epigenetic, and transcriptomic differences in monozygotic twins discordant for mul-tiple sclerosis failed to find any significant genetic or epigenetic differences (Baranzini et al. 2010). Clearly, more work needs to be carried out in this area. MZ twins provide a unique opportunity to unravel the extent to which the epigenome is hard-wired in hu-mans. (10) Can nutrition influence inheritance?

The poster child for epigenetic changes in mammals is the yellow agouti mouse, an epigenetic biosensor for nutritional and environmental changes. These fat and yellow mice owe their appearance to epigenetic modification that removes methyl groups from the normally methylated agouti gene (11). In a


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developing mouse fetus, if the above modification occurs shortly after fertilization, the baby mouse may exhibit the yellow fur and obese phenotype with greater risk of developing cancer and diabetes (11). However, the genetic code remains unchanged from normal mice. In one study, Waterland and Jirtle (11) altered the nutrient intake to serve as methyl group donors in mouse mothers, to cause methylation or demethylation of the agouti gene. Increased supple-mentation of choline, betaine, folic acid and vitamin B12 in the diet of pregnant yellow agouti mice was able to decrease the incidence of deleterious pheno-types in offspring, by allowing for the remethylation of the agouti gene. If these mice be born with the agouti phenotype, they can pass that deleterious epi-genetic trait in their offspring, regardless of their diet during pregnancy. This landmark study indicate that nutrients can cause phenotypic changes which can pass on through cell division and mating to the off-spring due to their possible influence on (natural) selection (11). It is possible therefore to say; that we are what we eat and what our parents ate, and poten-tially what our grandparents ate which would be modification of the old Sanskrit saying ‘Aham Annam’ from the ancient Vedas (5000BCE). It may be also important to emphasize advances in Astrochronobi-ology particularly; time of eating, accordingly, there-fore we are not only ‘what we eat’ but also ‘we are when we eat’ and when our father and grandfather were eating (12).

A recent study in the mouse reported that etha-nol consumption by pregnant females can influence the adult phenotype of the developing embryos. De-velopmental abnormalities (decrease in body weight, smaller skull size, and differences in cranial shape) were observed in adolescent offspring from mothers that were exposed to ethanol during the first half of pregnancy (Kaminen-Ahola et al. 2010). Moreover, using the epigenetically sensitive agouti viable yellow (Avy) as a read-out system, it was shown that ethanol exposure led to an increase in transcriptional silenc-ing associated with hypermethylation at the Avy locus and a shift toward pseudoagouti (brown) (Kaminen-Ahola et al. 2010). It remains to be determined whether the effects observed after ethanol exposure can be transmitted to the next generations or are re-stricted to directly exposed animals. It is important to remember that when transgenerational phenomena are observed in mice that have been exposed to envi-ronmental stresses during pregnancy, not only the mother, but the F1 generation (embryo) and the de-veloping germ line of the F2 generation are also ex-

posed to these triggers (Youngson and Whitelaw 2008).(10)

There is a need to study the effects of low ω-6/ω-3 ratio, arginine, taurine, cysteine, coenzyme Q10 on the remethylation of the agouti gene and their effects on phenotypic variations. However this mode of in-heritance needs to penetrate more than a few genera-tions before it earns a place in evolutionary concept. Epigenetic inheritance appears to be widespread but it does not mean that it lasts and causes ‘evolutionari-ly’ important effects. It is not clear until now, that if epigenetic changes are not stable for 20 to 30 genera-tions, it would be relevant to evolution.

The biologists should be bold enough to revise the Modern Synthesis published in 1942, because sev-eral experiments related to epigenetics are underway to establish the role of environmental factors in in-heritance. There is need for modifications of this landmark monograph which may be written by mul-tiple authors including physicians observing inher-itance in 3 to 4 or more generations among patients of diabetes, hypertension and coronary artery disease. The evolutionary theory appears to be quite flexible to incorporate well-substantiated new concepts, which continue to arise during the last few decades. In 1975, we (RBS) treated a patient of type 2 diabetes mellitus whose father also had a history of diabetes mellitus and died a sudden death. This 48 years old patient was, while under treatment (RBS) developed tightness in the chest and his electrocardiogram showed changes indicating myocardial ischemia. He was treated and recovered but after a few months died a sudden cardiac death in 1977. His son who was about 40 years, presented with type 2 diabetes melli-tus, while under treatment, also died a sudden cardi-ac death next year. Diet and lifestyle history showed that they have /had a wholesale business of selling clarified butter (anhydrous milk fat) during the time of the 1st generation, clarified butter and hydrogenat-ed fat, during the 2nd generation which continued during the 3rd generation. Thus, albeit a single family, all the three generations were sedentary and were consuming more than 40% of calories from clarified butter which may have caused inheritance of delete-rious phenotypes in the offspring, resulting in to type 2 diabetes and sudden death.

The adverse effects of trans fat (unsaturated fats with trans-isomer fatty acids) and oxidized cholester-ol present in the clarified butter consumed by the last three ‘degenerations’, on proinflammatory cytokines are well known and inflammation has been demon-strated to cause genetic damage. Sedentary behavior also enhances inflammation by its adverse effects on


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adiponectin, leptin and brain derived neurotrophic factor which are anti-inflammatory. Inflammation could be important in the pathobiology of epigenetic inheritance. Now RBS is tracking the son (4th genera-tion) who is about 30 years, to look for type 2 diabe-tes mellitus and coronary artery disease who may be a future candidate for sudden cardiac death in the 4th degeneration because he and his baby are consuming clarified butter and high ω-6/ω-3 ratio diet by using sun flower oil and they continue to be sedentary. We need to study genetic markers in this 4th generation to support this view. However, we need many more such observations and research because sufficient examples of transgenerational epigenetics are lacking. Most of the time, epigenetic characters are not inher-ited past one or two generations. The evolution of diet and the tsim tsoum con-cept:

A fundamental view of evolution in relation to human development from apes to man has been that the genetic makeup of contemporary humans which shows minor difference from that of the modern hu-mans who appeared in Africa between 100,000 and 50,000 years ago (13, 14). The human evolution has been comparatively rapid during the past 50,000 years, as revealed by the molecular geneticists. There have been marked changes in the food supply with the development of agriculture about 10,000 years ago from now. However, only non-significant change in our genes occurred, during the past 10 centuries, due to presence of ω-3 fatty acids, amino acids, vita-mins and minerals in the diet and non-significant changes in the environment (13-16). There have been some structural modifications in individual DNA se-quences, and altered gene regulation has been the dominant mechanism involved. Increased evolution-ary rapidity in humans compared with rates for other primates, has resulted from unprecedented demo-graphic expansion, which has provided a far larger pool of mutations, upon which natural selection can operate. The human Diaspora which has exposed humans to environmental changes appears to be quite different from those of their ancestral land in Africa and this rapid change may predispose deleteri-ous epigenetic inheritance.

The spontaneous mutation rate for nuclear DNA is estimated at 0.5% per million years. Hence, over the past 10,000 years there has been time for very lit-tle change in our genes, possibly 0.005%. Our genes appear to be similar to the genes of our ancestors during the Paleolithic period 40,000 years ago, the time when our genetic profile was established. Man appears to live in a nutritional environment which

completely differs from that for which our genetic constitution was selected. However, it was only dur-ing the last 100-160 years that dietary intakes and en-vironment have changed significantly, causing in-creased intake of saturated fatty acids (SFA) and lino-leic acid, and decrease in ω-3 fatty acids, from grain fed cattle, tamed at farmhouses, rather than meat from running animals. There is marked decrease in the intake of vitamins and antioxidants. The food and nutrient intake among hunter-gatherers and during the Paleolithic period showed no remarkable differ-ences. However, during the last 160 years, there is marked reduction in consumption of ω-3 fatty acids, vitamins and minerals and proteins and significant increase in the intakes of carbohydrates, (mainly re-fined,), fat ( saturated, trans fat, linoleic acid) and salt compared to Paleolithic period (1-4,13-16). There are also marked changes in the environmental factors which may also have deleterious effects on epigenetic inheritance.

The Columbus concept of diet means that hu-mans evolved on a diet that was low in saturated fat and the amount of ω-3 and ω-6 fatty acids was quite equal.(15) Nature recommends to ingest fatty acids in a balanced ratio (polyunsaturated:saturated: ω-6:ω-3=1:1) as part of dietary lipid pattern in which mono-unsaturated fatty acids is the major fat(P:M:S=1:6:1).These ratios represent the overall dis-tribution of fats in a natural untamed environment. (www.columbus-concept.com). The Columbus foods include egg, milk, meat, oil , and bread, all rich in ω-3 fatty acids, similar to wild foods, consumed about 160 years ago from now. Blood lipid composition does reflect one’s health status: (a) circulating serum lipo-proteins and their ratio provide information on their atherogenicity to blood vessels and (b) circulating plasma fatty acids, such as ω-6/ω-3 fatty acid ratio, gives an indication of proinflammatory status of blood vessels. (a) and (b) are phenotype-related and depend on genetic, environmental and developmen-tal factors. As such, they appear as universal markers for holistic health.

Blood cholesterol is central to this approach. Its 3D-representation shows how circulating lipoproteins affect blood vessel integrity arising from their circu-lating throughout the body. Also in most studies on dietary patterns, nuts which are a major part of Medi-terranean diet have been considered along with fruits, legumes and vegetables to demonstrate their influence on various risk factors of cardiovascular diseases(CVD).In contrast Western diet is character-ized with increased consumption of proinflammatory macronutrients such as w-6 fatty acids, trans fatty


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acids(TFA) and saturated fatty acids(SFA) as well as refined carbohydrates which may produce hypergly-cemia, oxidative stress, free fatty acids and proin-flammatory substance. These biochemical factors can also influence neuronal function and dysfunction that are majar aspects of Tsim Tsoum concept (17).

Of major importance appear to be the essential dietary nutrients (essential amino acids, fatty acids, antioxidant vitamins and minerals) and the function-al component of the regimen (diet, sport, spiritual-ism, etc) because these factors may be important in the epigenetic inheritance. An example is given of an essential dietary nutrient and of a functional compo-nent of man’s regimen that affect health in a predic-tive way derived from the 3D representation of blood cholesterol. Caption The Columbus Concept and its 3D representation of blood lipoprotein behaviours. "Bad" LDL-C, "good" HDLC, and "healthy" LDL-CC: HDL-CC ratios. CC= Columbus Concept. The Tsim Tsoum Concept is an extension of the Columbus con-cept. The word Tsim Tsoum is derived from Hebrew and it is similar to ‘ying yang’ in Chinese. (http://www.tsimtsoum.net/editorials/tsimtsoum_editorial_2009-Kosice-14th-WCCN-and-5th-ICCD.pdf). It includes the simultaneous approach of controlling of Mind-brain- body connection and in-teractions of leptin, cholecystokinin, polyunsaturated fatty acid CoA, brain derived neurotrophic factor and neuropeptide Y secreted in the hypothalamus (18-20).This can be understood by the example of meta-bolic syndrome. Physical inactivity and increased in-take of energy in association with gene expression are common predisposing factors for obesity and meta-bolic syndrome. The role of liver and beta cells of the pancreas and their interactions with the hypothala-mus and vagus nerve are important mechanisms to explain the behavioural factors in the pathogenesis of metabolic syndrome. In this relation, the Tsim Tsoum concept appears to be very interesting because it places emphasis on mind-body connec-tion/interactions in the pathogenesis of obesity and diabetes that are the components of metabolic syn-drome. Omega-3 fatty acids can also improve neu-ronal efficiency causing improvement in attention, cognitive performance, and mood-state and in the electroencephalographic alpha and theta oscillations, which are indicators of memory function. Treatment of type 2 diabetes mellitus and coronary atherosclero-sis with a ω-3 fatty acid rich Mediterranean diet may be protective by their direct effect as well as by their influence on the hypothalamic and vagal connec-tions. Therefore it is possible that liver and pancreas via vagus nerve and hypothalamic connections as well

as via humoral mechanisms can influence energy me-tabolism and food intake to maintain energy homeo-stasis which may have an independent effect on the development of obesity, type 2 diabetes and metabol-ic syndrome.ω-3 fatty acids may also have an inde-pendent effect on

Liver-pancreatic beta cells and brain connec-tions (21). The Tsim Tsoum Concept also

presumes that if, and only if, diet and environ-mental factors are designed holistically, for individu-als and populations or for any species, for several generations, they may be responsible for the altera-tion in biological functions causing epigenetic inher-itance, resulting in the development of man to hu-man and thence to superhuman.

Polymorphisms of the human Delta-5 (FADS1) and Delta-6 (FADS2) desaturase genes have been re-cently described to be associated with the level of several long-chain n-3 and n-6 polyunsaturated fatty acids (PUFAs) in serum phospholipids. We have gen-otyped 13 single nucleotide polymorphisms (SNPs) located on the FADS1-FADS2-FADS3 gene cluster (chromosome 11q12-13.1) in 658 Italian adults (78% males; mean age 59.7 +/- 11.1 years) participating in the Verona Heart Project. Polymorphisms and statis-tically inferred haplotypes showed a strong associa-tion with arachidonic acid (C20:4n-6) levels in serum phospholipids and in erythrocyte cell membranes (rs174545 adjusted P value for multiple tests, P < 0.0001 and P < 0.0001, respectively). Other significant associations were observed for linoleic (C18:2n-6), alpha-linolenic (C18:3n-3) and eicosadienoic (C20:2n-6) acids. Minor allele homozygotes and heterozygotes were associated to higher levels of linoleic, alpha-linolenic, eicosadienoic and lower levels of arachi-donic acid. No significant association was observed for stearidonic (C18:4n-3), eicosapentaenoic (C20:5n-3) and docosahexaenoic (C22:6n-3) acids levels. The observed strong association of FADS gene polymor-phisms with the levels of arachidonic acid, which is a precursor of molecules involved in inflammation and immunity processes, suggests that SNPs of the FADS1 and FADS2 gene region are worth studying in diseas-es related to inflammatory conditions or alterations in the concentration of PUFAs.

In brief, it is possible that diet and other envi-ronmental changes can modulate biological functions including genetic variations. If these environmental changes are subjected to species for several genera-tions, they might predispose epigenetic inheritance.

However, more evidence is necessary to demon-strate the role of environment in the epigenetic in-


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heritance. The Modern Synthesis needs modification in the light of above advances.

Acknowledgements are due to Tsim Tsoum In-stitute, Krakow, Poland and International College of Nutrition for the support to produce this work.

REFERENCES:

1. Singh RB, Mori H. Risk factors for coronary heart disease: syn-thesis of a new hypothesis through adaptation. Med Hypoth 1992; 39:334-341. (http://www.sciencedirect.com/science/article/pii/030698779290058K) 2. Mishra S, Singh RB, Dwivedi SP, et al. Effects of nutraceuticals on gene expression. The Open Nutra J 2009; 2:70-80. (http://www.benthamscience.com/open/tonutraj/articles/V002/70TONUTRAJ.pdf) 3. Singh RB. Darwin, evolution and origin of species. The Open Nutr J 2009; 2: 86-87. 4. Singh RB, Moshiri M, De Meester F, Juneja L, Muthusamy V, Manoharan S. The evolution of low ω -6/ ω-3 ratio dietary pattern and risk of cardiovascular diseases and diabetes. JAMR 2011; 3: (In Press). 5. Verhoeven KJF, Jansen JJ, van Dijk PJ, Biere A. Stress induced DNA methylation, changes and their heritability in asexual dendil-ions. New Phyto 2010: 1108-1118. (http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8137.2009.03121.x/full) 6. True HL, Lindquist SL. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 2000; 407: 477-483. (http://isites.harvard.edu/fs/docs/icb.topic459133.files/Papers/True-Lindquist-2000.pdf) 7. Badyaey A. The beak of the other finch: Coevolution of genetic covariance structure and developmental modularity during adap-tive evolution. Phil Trans Royal Soc 2010; 365: (in press) (http://rstb.royalsocietypublishing.org/content/365/1543/1111.short) 8. Jablonka F, Raz G. Transgenerational epigenetic inheritance: prevalence, mechanisms and implications for the study of heredity and evolution. Q Rev Biol 2009; 84:131-176. (http://www.jstor.org/pss/10.1086/598822) 9. Whittle CA, Otto SP, Johnston MO, Krochko JE. Adaptive epi-genetic memory of ancestral temperature regime in Arabidopsis thaliana. Botany 2009; 87: 650-657. (http://www.nrcresearchpress.com/doi/abs/10.1139/B09-030) 10. Lucia Daxinger, Emma Whitelaw. Transgenerational epigenetic inheritance: More questions than answers. Genome Res.2010;20: 1623-1628 (http://genome.cshlp.org/content/20/12/1623.full) 11. Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 2003; 23: 5293-300. (http://mcb.highwire.org/content/23/15/5293.abstract) 12. Halberg F , Cornélissen G, Otsuka K, et al and the BIOCOS project. Extended consensus on need and means to detect vascular variability disorders (vvds) and vascular variability syndromes (vvss). Intl. J. Of Geronto-Geriatics, 2008; 11: 119-146. (http://www.muni.cz/research/publications/857835/)

13. Eaton B. Evolution and cholesterol. World Rev Nutr Diet 2009; 100: 46-54. (http://books.google.co.in/books?hl=en&lr=&id=GoGURxGzedkC&oi=fnd&pg=PA46&dq=Evolution+and+cholesterol&ots=iJ_87Uz9w7&sig=h6ikRbG_WRoBm7ldePB837x-hEU#v=onepage&q=Evolution%20and%20cholesterol&f=false) 14. De Meester F. Progress in lipid nutrition: the Columbus con-cept addressing chronic diseases. World Rev Nutr Diet 2009; 100: 110-21. (http://books.google.co.in/books?hl=en&lr=&id=GoGURxGzedkC&oi=fnd&pg=PA46&dq=Evolution+and+cholesterol&ots=iJ_87Uz9w7&sig=h6ikRbG_WRoBm7ldePB837x-hEU#v=onepage&q=Evolution%20and%20cholesterol&f=false) 15. Simopolous AP, Genetic variation and dietary response: nutri-genetics/ nutrigenomics. Asia Pac J Clin Nutr 2002, 11:S117-S128. (http://onlinelibrary.wiley.com/doi/10.1046/j.1440-6047.11.s6.3.x/full) 16. Eaton SB, Eaton SB III, Sinclair AJ, Cordain I, Mann NJ. Dietary intake of long chain polyunsaturated fatty acids during the Paleo-lithic period. In Simopoulos AP edition. The return of ω -3 fatty acids in the food supply. Land based Animal Food Products and their Health Effects. World Rev Nutr Dietetics 1998; 83: 12-23. (http://www.direct-ms.org/pdf/EvolutionPaleolithic/Long%20chain%20fatty%20acids.pdf) 17. Viola Vargova, Viola Mechirova, Jan Fedacko, Rafai Ryber, Daniel Pella, Agnieska Wilczynska, FabienDe Meeste and Ram B. Singh. Can Nuts Consumption Modulate Cardiovascular Diseases? Report of a Case and Review of Literature. The Open Nutraceuticals Journal, 2011, 4: 88-96. (http://www.benthamscience.com/open/tonutraj/articles/V004/SI0025TONUTRAJ/88TONUTRAJ.pdf) 18. Kwiatek AW, Singh RB, De Meester F. Nutrition and behav-iour: the role of ω-3 fatty acids. The Open Nutra J 2010; 3:119-128. (http://tsimtsoum.net/yyijjournal/tsimtsoumjournal_nutrandbehav.pdf) 19. Thaler JP, Cummings DF. Metabolism: food alert. Nature 2008; 452: 941-942. (http://www.nature.com/nature/journal/v452/n7190/full/452941a.html) 20. Wang PY, Caspi L, Lam CK, et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 2008; 452:1012-16. (http://www.nature.com/nature/journal/v452/n7190/full/nature06852.html) 21. Singh, R.B., De Meester, F., Wilczynska, A., Wilson, D.W., Hungin, A.P.S. The liver-pancreas and the brain connection in the pathogenesis of obesity and metabolic syndrome. World Heart J 2011:3: (in press) 22. Malerba G, Schaeffer L, Xumerle L, Klopp N, Trabetti E, Bis-cuola M, Cavallari U, Galavotti R, Martinelli N, Guarini P, Girelli D, Olivieri O, Corrocher R, Heinrich J, Pignatti PF, Illig T.SNPs of the FADS gene cluster are associated with polyunsaturated fatty acids in a cohort of patients with cardiovascular disease. Lipids. 2008 Apr; 43(4):289-99. Epub 2008 Mar 5.

Correspondence.

Dr Ram B Singh, Halberg Hospital and Research Institute,

Civil Lines, Moradabad (UP)244001, India

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NUTRITIONAL MODULATORS OF TRANSGENERATIONAL EPIGENETIC INHERITANCE