Epigenetic transgenerational actions of environmental factors in disease etiology
2010; Elsevier BV; Volume: 21; Issue: 4 Linguagem: Inglês
10.1016/j.tem.2009.12.007
ISSN1879-3061
AutoresMichael K. Skinner, Mohan Manikkam, Carlos Guerrero‐Bosagna,
Tópico(s)Childhood Cancer Survivors' Quality of Life
ResumoThe ability of environmental factors to promote a phenotype or disease state not only in the individual exposed but also in subsequent progeny for successive generations is termed transgenerational inheritance. The majority of environmental factors such as nutrition or toxicants such as endocrine disruptors do not promote genetic mutations or alterations in DNA sequence. However, these factors do have the capacity to alter the epigenome. Epimutations in the germline that become permanently programmed can allow transmission of epigenetic transgenerational phenotypes. This review provides an overview of the epigenetics and biology of how environmental factors can promote transgenerational phenotypes and disease. The ability of environmental factors to promote a phenotype or disease state not only in the individual exposed but also in subsequent progeny for successive generations is termed transgenerational inheritance. The majority of environmental factors such as nutrition or toxicants such as endocrine disruptors do not promote genetic mutations or alterations in DNA sequence. However, these factors do have the capacity to alter the epigenome. Epimutations in the germline that become permanently programmed can allow transmission of epigenetic transgenerational phenotypes. This review provides an overview of the epigenetics and biology of how environmental factors can promote transgenerational phenotypes and disease. The current paradigm for disease etiology is that the presence of a genetic mutation, polymorphism or chromosomal abnormality promotes disease. Although this is a crucial component of disease, the environment is an equally important consideration in disease etiology (Figure 1). Because the genome is evolutionarily and chemically stable, the ability of the environment to influence or promote disease does not generally involve DNA mutations. Therefore, environmental factors must generally regulate genome activity independent of DNA sequence manipulation (e.g. epigenetics). An additional consideration for environmental influences on disease etiology is the developmental stage of exposure. Exposures during a crucial time of development can alter genome activity associated with the differentiation programming of cells or organ systems. This altered program and gene expression profile can then promote an abnormal physiology and disease at the later adult stage of development.A large number of epidemiology studies suggest that the environment is a major factor in disease etiology [1Jirtle R.L. Skinner M.K. Environmental epigenomics and disease susceptibility.Nat. Rev. Genet. 2007; 8: 253-262Crossref PubMed Scopus (771) Google Scholar, 2Szyf M. The dynamic epigenome and its implications in toxicology.Toxicol. Sci. 2007; 100: 7-23Crossref PubMed Scopus (104) Google Scholar]. Examples include phenomena such as the regional differences in disease frequency, the low frequency of the genetic component of disease, the increase in the majority of specific disease frequencies, the variability in disease frequency between identical twins, and the large number of environmental exposures that promote disease. This review focuses on how environmental factors promote adult-onset disease transgenerationally.Environmental factors and diseaseEpidemiology research suggests significant environmental effects on disease. Each geographic region around the world generally has a distinct disease frequency. For example, some regions have high rates of prostate disease and low rates of stomach disease (North America), whereas others have low rates of prostate disease and high rates of stomach disease (eastern Asia) [3Haas G.P. Sakr W.A. Epidemiology of prostate cancer.CA Cancer J. Clin. 1997; 47: 273-287Crossref PubMed Google Scholar, 4Brenner H. et al.Epidemiology of stomach cancer.Methods Mol. Biol. 2009; 472: 467-477Crossref PubMed Scopus (178) Google Scholar]. If a person is moved early in life from one region to the other, they often develop the new region's disease frequencies. Interestingly, when identical twins develop in different geographic regions, they also have different disease frequencies [5Kukreja A. Maclaren N.K. NKT cells and type-1 diabetes and the “hygiene hypothesis” to explain the rising incidence rates.Diabetes Technol. Ther. 2002; 4: 323-333Crossref PubMed Scopus (24) Google Scholar]. Therefore, although the genetics is nearly identical, disease development is different, suggesting an environmental influence [6Williamson D.M. Studies of multiple sclerosis in communities concerned about environmental exposures.J. Womens Health (Larchmt.). 2006; 15: 810-814Crossref PubMed Scopus (2) Google Scholar]. Another example is the dramatic and rapid increase in nearly all disease frequencies over the past several decades that cannot be explained through genetics alone. There are also a large number of environmental compounds and toxicants that have been shown to promote disease, but most do not alter the DNA sequence [7Edwards T.M. Myers J.P. Environmental exposures and gene regulation in disease etiology.Environ. Health Perspect. 2007; 115: 1264-1270Crossref PubMed Scopus (107) Google Scholar]. Therefore, environmental factors are crucial in the etiology of disease.Although numerous environmental factors influence and promote adult-onset disease (such as nutrition and stress), this review focuses on endocrine disruptors, as this group of environmental compounds is one of the largest people are exposed to daily in society. Endocrine disruptors are environmental chemicals that affect the function of the endocrine system by mimicking or blocking the actions of hormones, altering hormone signaling or disrupting hormone production [8Crisp T.M. et al.Environmental endocrine disruption, an effects assessment and analysis.Environ. Health Perspect. 1998; 106: 11-56Crossref PubMed Google Scholar]. Endocrine disruption can have profound consequences because of the crucial role hormones have in development.Several disease states are promoted by endocrine disruptors (Table 1). Many endocrine disruptors with reproductive hormone actions (e.g. estrogen or androgen) influence reproduction and fertility including bisphenol-A (BPA), dichlorodiphenyltrichloroethane (the insecticide DDT) and vinclozolin. Activation of the male and female reproductive systems at an inappropriate time during development by endocrine disruptor chemicals can alter normal physiology [9Danzo B.J. The effects of environmental hormones on reproduction.Cell Mol. Life Sci. 1998; 54: 1249-1264Crossref PubMed Scopus (88) Google Scholar]. For example, prenatal exposure to diethylstilbestrol (DES) produces several developmental abnormalities in the male mouse reproductive tract and increases tumor incidence [10Bullock B.C. et al.Lesions of testis and epididymis associated with prenatal diethylstilbestrol exposure.Environ. Health Perspect. 1988; 77: 29-31Crossref PubMed Google Scholar]. Embryonic exposure to the pesticide methoxychlor during the period of sex determination affects the cellular composition of the embryonic testis, and germ cell number and survival [11Cupp A.S. et al.Effect of transient embryonic in vivo exposure to the endocrine disruptor methoxychlor on embryonic and postnatal testis development.J. Androl. 2003; 24: 736-745PubMed Google Scholar]. Embryonic testicular cord formation is also affected when embryos are exposed in vitro to vinclozolin. Transient in utero exposure to vinclozolin increases apoptotic germ cell numbers in the testis of pubertal and adult animals, which correlates with reduced sperm motility and number in the adult [12Uzumcu M. et al.Effect of the anti-androgenic endocrine disruptor vinclozolin on embryonic testis cord formation and postnatal testis development and function.Reprod. Toxicol. 2004; 18: 765-774Crossref PubMed Scopus (61) Google Scholar]. In utero exposure to the plastic-derived compounds phthalates also disrupts differentiation of androgen-dependent tissues in male rat offspring [13Gray Jr., L.E. et al.Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p’-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat.Toxicol. Ind. Health. 1999; 15: 94-118Crossref PubMed Google Scholar]. A more recent example of an endocrine disruptor is the plastic component BPA, which acts as an estrogenic compound causing numerous pathologies including prostate cancer in low doses [14Ho S.M. et al.Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4.Cancer Res. 2006; 66: 5624-5632Crossref PubMed Scopus (309) Google Scholar]. Other examples include the plant-derived estrogenic compounds (phytoestrogens) such as genistein, which influence several reproductive organs [15Moutsatsou P. The spectrum of phytoestrogens in nature, our knowledge is expanding.Hormones (Athens). 2007; 6: 173-193PubMed Google Scholar, 16Tomar R.S. Shiao R. Early life and adult exposure to isoflavones and breast cancer risk.J. Environ. Sci. Health C. Environ. Carcinog. Ecotoxicol. Rev. 2008; 26: 113-173Crossref PubMed Scopus (17) Google Scholar]; aflatoxin-contaminated food, which has been correlated with the incidence of liver cancer in Asia and Africa [17International Agency for Research on Cancer. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man, pp. V10 60, 1976:1972–Present,IARCGoogle Scholar]; tobacco, which contains cadmium, an estrogenic endocrine disruptor (18), and whose use can cause reproductive problems in addition to carcinogen-induced lung cancer. Heterocyclic amines in well-cooked meat products can result in cancer of the colon, breast and stomach in consumers [19Wogan G.N. et al.Environmental and chemical carcinogenesis.Semin. Cancer Biol. 2004; 14: 473-486Crossref PubMed Scopus (252) Google Scholar]. Abnormalities in mouse testicular Leydig cells are induced by chronic low dose exposure to arsenic [20Singh K.P. DuMond Jr., J.W. Genetic and epigenetic changes induced by chronic low dose exposure to arsenic of mouse testicular Leydig cells.Int. J. Oncol. 2007; 30: 253-260PubMed Google Scholar]. Estrogen receptor-α promoter hypomethylation might play a role in induction of hepatocellular carcinoma by arsenic exposure in utero [21Waalkes M.P. et al.Estrogen signaling in livers of male mice with hepatocellular carcinoma induced by exposure to arsenic in utero.J. Natl. Cancer Inst. 2004; 96: 466-474Crossref PubMed Google Scholar]. Therefore, it is apparent that a large number of environmental compounds have endocrine disruptor activity. How an early life exposure to an endocrine disruption can promote an adult-onset disease, long after the compound is removed, is presumed to at least partly involve the epigenetic mechanisms reviewed below.Table 1Common endocrine disruptors and their actionsEndocrine disruptorEffectReferenceDDTReproductive failure110Fry D.M. Reproductive effects in birds exposed to pesticides and industrial chemicals.Environ. Health Perspect. 1995; 103: 165-171Crossref PubMed Google ScholarPhytoestrogens (e.g. genistein)Impaired fertility, reproductive effects, breast cancer protection15Moutsatsou P. The spectrum of phytoestrogens in nature, our knowledge is expanding.Hormones (Athens). 2007; 6: 173-193PubMed Google Scholar, 16Tomar R.S. Shiao R. Early life and adult exposure to isoflavones and breast cancer risk.J. Environ. Sci. Health C. Environ. Carcinog. Ecotoxicol. Rev. 2008; 26: 113-173Crossref PubMed Scopus (17) Google ScholarDESVaginal cancer in humans111Greenwald P. et al.Vaginal cancer after maternal treatment with synthetic estrogens.N. Engl. J. Med. 1971; 285: 390-392Crossref PubMed Google Scholar, 112Herbst A.L. et al.Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women.N. Engl. J. Med. 1971; 284: 878-881Crossref PubMed Google Scholar, 113Hendry 3rd., W.J. et al.Developing a laboratory animal model for perinatal endocrine disruption: the hamster chronicles.Exp. Biol. Med. (Maywood). 2002; 227: 709-723PubMed Google ScholarDevelopmental toxicity in hamstersDicofolAbnormal ovarian follicles, high plasma estrogen levels114Guillette Jr., L.J. et al.Developmental abnormalities of the gonad and abnormal sex hormone concentrations in juvenile alligators from contaminated and control lakes in Florida.Environ. Health Perspect. 1994; 102: 680-688Crossref PubMed Google ScholarBPAProstate cancer14Ho S.M. et al.Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4.Cancer Res. 2006; 66: 5624-5632Crossref PubMed Scopus (309) Google Scholar, 115Prins G.S. et al.Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis.Basic Clin. Pharmacol. Toxicol. 2008; 102: 134-138Crossref PubMed Scopus (64) Google ScholarAflatoxinLiver cancer17International Agency for Research on Cancer. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man, pp. V10 60, 1976:1972–Present,IARCGoogle ScholarCadmiumLung cancer, reproductive problems18Henson M.C. Chedrese P.J. Endocrine disruption by cadmium, a common environmental toxicant with paradoxical effects on reproduction.Exp. Biol. Med. (Maywood). 2004; 229: 383-392Crossref PubMed Google ScholarHeterocyclic aminesCancer of colon, stomach and breast19Wogan G.N. et al.Environmental and chemical carcinogenesis.Semin. Cancer Biol. 2004; 14: 473-486Crossref PubMed Scopus (252) Google ScholarArsenicLiver cancer21Waalkes M.P. et al.Estrogen signaling in livers of male mice with hepatocellular carcinoma induced by exposure to arsenic in utero.J. Natl. Cancer Inst. 2004; 96: 466-474Crossref PubMed Google ScholarDioxins (TCDD)Mammary tumor116Birnbaum L.S. Fenton S.E. Cancer and developmental exposure to endocrine disruptors.Environ. Health Perspect. 2003; 111: 389-394Crossref PubMed Google ScholarVinclozolinImpaired male fertility33Anway M.D. et al.Epigenetic transgenerational actions of endocrine disruptors and male fertility.Science. 2005; 308: 1466-1469Crossref PubMed Scopus (884) Google ScholarMethoxychlorImpaired male fertility117Skinner M.K. Anway MD Seminiferous cord formation and germ-cell programming, epigenetic transgenerational actions of endocrine disruptors.Ann N. Y Acad. Sci. 2005; 1061: 18-32Crossref PubMed Scopus (26) Google ScholarPhthalatesImpairs male reproductive tract and testis13Gray Jr., L.E. et al.Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p’-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat.Toxicol. Ind. Health. 1999; 15: 94-118Crossref PubMed Google ScholarTCDD, 2,3,7,8-Tetrachlorodibenzo-p-dioxin . Open table in a new tab EpigeneticsAlthough the history and definition of epigenetics has evolved (Box 1), the majority of the molecular elements of epigenetic regulatory processes have only been recently elucidated [1Jirtle R.L. Skinner M.K. Environmental epigenomics and disease susceptibility.Nat. Rev. Genet. 2007; 8: 253-262Crossref PubMed Scopus (771) Google Scholar]. The first epigenetic molecular factor identified was DNA methylation in the 1970s [22Holliday R. Pugh J.E. DNA modification mechanisms and gene activity during development.Science. 1975; 187: 226-232Crossref PubMed Scopus (20) Google Scholar] (Table 2). Significant focus was put on DNA methylation with the analysis of X chromosome inactivation and imprinted genes in the late 1980s and early 1990s [23Chen Z.X. Riggs A.D. Maintenance and regulation of DNA methylation patterns in mammals.Biochem. Cell Biol. 2005; 83: 438-448Crossref PubMed Scopus (48) Google Scholar]. The next epigenetic element identified was histone modifications in the mid 1990s and the appreciation of chromatin structure in the regulation of the genome [24Turner B.M. Histone acetylation as an epigenetic determinant of long-term transcriptional competence.Cell Mol. Life Sci. 1998; 54: 21-31Crossref PubMed Scopus (123) Google Scholar]. This was followed by the identification of non-coding RNA around 2000 and the first whole epigenome analysis in 2005 [25Pokholok D.K. et al.Genome-wide map of nucleosome acetylation and methylation in yeast.Cell. 2005; 122: 517-527Abstract Full Text Full Text PDF PubMed Scopus (698) Google Scholar] (Table 2). Epigenetic processes are likely to be expanded in the future. For example, the recent identification of hydroxymethylcytosine residues in the brain is a new epigenetic mark whose function remains to be elucidated [26Kriaucionis S. Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain.Science. 2009; 324: 929-930Crossref PubMed Scopus (643) Google Scholar]. These epigenetic processes are equally important in regulating genome activity (i.e. gene expression) and DNA sequence (i.e. genetics).Box 1EpigeneticsThe term ‘epigenetics’ was coined by Conrad Waddington in the 1940s. Waddington integrated the new knowledge about genes and genetics to embryology. The study of embryological growth and differentiation was commonly known as ‘epigenesis’, a concept that had been around since Aristotelian times. The integration of the concepts of epigenesis and genetics gave origin to the term ‘epigenetics’ [101Van Speybroeck L. From epigenesis to epigenetics, the case of C. H. Waddington.Ann. N. Y. Acad. Sci. 2002; 981: 61-81Crossref PubMed Google Scholar, 102Waddington C.H. Organisers and Genes. Cambridge University Press, 1940Google Scholar]. Waddington's goal with epigenetics was to provide insight into gene–environment interactions that influence development and embryology [101Van Speybroeck L. From epigenesis to epigenetics, the case of C. H. Waddington.Ann. N. Y. Acad. Sci. 2002; 981: 61-81Crossref PubMed Google Scholar, 102Waddington C.H. Organisers and Genes. Cambridge University Press, 1940Google Scholar, 103Waddington C.H. Principles of Embryology. George Allen & Unwin Ltd, 1956Google Scholar]. Pioneering epigenetic experiments from Waddington on Drosophila demonstrated that a temperature shock 17–23 hours after puparium formation produced cross veinless wings in flies. Flies with this phenotype were culled from the population and only those showing normal wings were used to carry on the line. After an expected initial reduction of the cross wingless phenotype in the population, it surprisingly recurred after generation 16 [104Waddington C.H. Gene assimilation of an acquired character.Evolution. 1953; 7: 118-126Crossref Google Scholar]. This phenotype was considered a ‘genetic assimilation’ and dealt with environmental exposures early in development with subsequent consequences on phenotypic inheritance.The definition of epigenetics has evolved with greater clarity of the molecular mechanisms involved and a better understanding of genetic phenomena. The initial definition of Waddington focused on gene–environment interactions but had no molecular insights to consider [102Waddington C.H. Organisers and Genes. Cambridge University Press, 1940Google Scholar]. In 1990, Holliday defined epigenetics as ‘the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms’. His definition rescues Waddington's original meaning of developmental biology, although it does not differentiate between the action of what we currently know as epigenetic mechanisms and the action of genetic regulators of gene expression such as transcription factors [105Holliday R. Mechanisms for the control of gene activity during development.Biol. Rev. Camb. Philos. Soc. 1990; 65: 431-471Crossref PubMed Google Scholar]. Another early definition by Riggs and colleagues states that epigenetics is ‘the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence’ [106Russo V.E.A. et al.Epigenetic Mechanisms of Gene Regulation. Cold Spring Harbor Laboratory Press, Woodbury1996Google Scholar]. However, the term heritable is generally used in reference to generational inheritance and is not associated with growth of cells or tissues. Perhaps a more direct term would be ‘mitotically stable’. A more recent definition focuses on molecular elements that influence chromatin, independent of DNA sequence. Bird defines epigenetics as the ‘structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states’ [107Bird A. Perceptions of epigenetics.Nature. 2007; 447: 396-398Crossref PubMed Scopus (676) Google Scholar]. Because there are several epigenetic elements that do not fit into this definition such as non-coding RNA and minor modifications of histones and DNA methylation of promoters, this definition appears insufficiently global to encompass all of epigenetics. Therefore, we propose a definition that is more global and encompasses all molecular elements and includes the use of the term ‘epi’ for ‘around DNA’. Thus, we define epigenetics as ‘molecular factors and processes around DNA that are mitotically stable and regulate genome activity independent of DNA sequence’.Table 2History of epigeneticsYear(s)Event1940sConrad Waddington defined epigenetics as environment–gene interactions that induce developmental phenotypes1975Holliday and Pugh identify DNA methylation1988X-chromosome inactivation and DNA methylation1990sImprinted genes, allelic expression and DNA methylation1995Histone modifications and chromatin structure2000sSmall non-coding RNAs2005Epigenome mapping Open table in a new tab A special category of genes called imprinted genes are subject to epigenetic programming and can be influenced by environmental exposures. For example, in vitro treatment of preimplantation embryos with the contaminant 2,3,7,8-tetra-chlorodibenzo-p-dioxin alters DNA methylation in the H19 and IGF-2 imprinted genes [27Wu Q. et al.Exposure of mouse preimplantation embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the methylation status of imprinted genes H19 and Igf2.Biol. Reprod. 2004; 70: 1790-1797Crossref PubMed Scopus (55) Google Scholar]. From an epigenetic perspective, imprinted genes are a special class of genes because they have relatively unchanged DNA methylation patterns over generations and are not affected by the overall reset in methylation patterns that occur early in development [28Constancia M. et al.Imprinting mechanisms.Genome Res. 1998; 8: 881-900Crossref PubMed Scopus (239) Google Scholar]. Imprinted genes carry a molecular memory of their parent of origin allele acquired early in the germline [29Surani M.A. Reprogramming of genome function through epigenetic inheritance.Nature. 2001; 414: 122-128Crossref PubMed Scopus (280) Google Scholar]. This molecular memory is associated with differential methylation patterns between the two alleles, which affect monoallelic gene expression [30Costello J.F. Plass C. Methylation matters.J. Med. Genet. 2001; 38: 285-303Crossref PubMed Google Scholar]. These allelic differences in methylation are defined in the developing embryo during the establishment of germline development [28Constancia M. et al.Imprinting mechanisms.Genome Res. 1998; 8: 881-900Crossref PubMed Scopus (239) Google Scholar]. Methylation of imprinted genes initiated during germline development can be completed after fertilization [28Constancia M. et al.Imprinting mechanisms.Genome Res. 1998; 8: 881-900Crossref PubMed Scopus (239) Google Scholar, 31Park C.H. Methylation status of differentially methylated regions at Igf2/H19 locus in porcine gametes and preimplantation embryos.Genomics. 2009; 93: 179-186Crossref PubMed Scopus (18) Google Scholar]. Some imprinted genes remain imprinted throughout the organism's life; however, a group of them are imprinted in specific tissues in a temporally specific manner [32Ideraabdullah F.Y. Genomic imprinting mechanisms in mammals.Mutat. Res. 2008; 647: 77-85Crossref PubMed Scopus (96) Google Scholar]. Interestingly, if external agents alter DNA methylation in these imprinted genes or induce new methylation sites during crucial periods of their establishment, such changes can persist transgenerationally [33Anway M.D. et al.Epigenetic transgenerational actions of endocrine disruptors and male fertility.Science. 2005; 308: 1466-1469Crossref PubMed Scopus (884) Google Scholar, 34Guerrero-Bosagna C. et al.Environmental signaling and evolutionary change, can exposure of pregnant mammals to environmental estrogens lead to epigenetically induced evolutionary changes in embryos?.Evol. Dev. 2005; 7: 341-350Crossref PubMed Scopus (36) Google Scholar] (Figure 2). This heritable transmission of environmentally induced phenotypes is referred to as transgenerational inheritance [1Jirtle R.L. Skinner M.K. Environmental epigenomics and disease susceptibility.Nat. Rev. Genet. 2007; 8: 253-262Crossref PubMed Scopus (771) Google Scholar, 35Whitelaw N.C. Whitelaw E. Transgenerational epigenetic inheritance in health and disease.Curr. Opin. Genet. Dev. 2008; 18: 273-279Crossref PubMed Scopus (74) Google Scholar].Figure 2Role of the germline in epigenetic transgenerational inheritance. (i) An environmental factor acts on the F0 generation gestating female to influence (ii) the developing F1 generation fetus and alter gonadal development to reprogram the primordial germ cell DNA methylation. (iii) This altered DNA methylation in the germline becomes permanently programmed, similar to an imprinted-like gene, and is transferred through the germline to subsequent generations. The embryo generated from this germline starts with an altered epigenome that (iv) affects developing somatic cells and tissues to have an altered transcriptome. This altered somatic cell transcriptome can then promote adult-onset disease associated with the transgenerational phenotype.View Large Image Figure ViewerDownload (PPT)From a human health perspective, a number of disease states exist that have an epigenetic origin. Several diseases and syndromes have abnormal DNA methylation or imprinted gene sites leading to various pathologies [32Ideraabdullah F.Y. Genomic imprinting mechanisms in mammals.Mutat. Res. 2008; 647: 77-85Crossref PubMed Scopus (96) Google Scholar]. These include Silver–Russell syndrome [36Yamazawa K. et al.Molecular and clinical findings and their correlations in Silver-Russell syndrome, implications for a positive role of IGF2 in growth determination and differential imprinting regulation of the IGF2-H19 domain in bodies and placentas.J. Mol. Med. 2008; 86: 1171-1181Crossref PubMed Scopus (21) Google Scholar], Beckwith–Weidemann syndrome [37Temple I.K. Imprinting in human disease with special reference to transient neonatal diabetes and Beckwith-Wiedemann syndrome.Endocr. Dev. 2007; 12: 113-123Crossref PubMed Scopus (22) Google Scholar], and Angelman and Prader–Willi syndromes [38Mann M.R. Bartolomei M.S. Towards a molecular understanding of Prader-Willi and Angelman syndromes.Hum. Mol. Genet. 1999; 8: 1867-1873Crossref PubMed Scopus (80) Google Scholar]. Another epigenetic disease caused by abnormal DNA methylation of the X-chromosome is fragile X syndrome [39Walter E. et al.Insights into brain development from neurogenetic syndromes, evidence from fragile X syndrome, Williams syndrome, Turner syndrome and velocardiofacial syndrome.Neuroscience. 2009; 164: 257-271Crossref PubMed Scopus (28) Google Scholar]. Several brain disorders such as autism, schizophrenia and Rett's syndrome also appear to have major epigenetic components [39Walter E. et al.Insights into brain development from neurogenetic syndromes, evidence from fragile X syndrome, Williams syndrome, Turner syndrome and velocardiofacial syndrome.Neuroscience. 2009; 164: 257-271Crossref PubMed Scopus (28) Google Scholar, 40Schanen N.C. Epigenetics of autism spectrum disorders.Hum. Mol. Genet. 2006; 15: R138-150Crossref PubMed Scopus (132) Google Scholar, 41Graff J. Mansuy I.M. Epigenetic dysregulation in cognitive disorders.Eur. J. Neurosci. 2009; 30: 1-8Crossref PubMed Scopus (60) Google Scholar]. Cancer also has an epigenetic component to regulate genome stability, and is associated with transformation and disease phenotype [42Ellis L. et al.Epigenetics in cancer, targeting chromatin modifications.Mol. Cancer Ther. 2009; 8: 1409-1420Crossref PubMed Scopus (169) Google Scholar, 43Sadikovic B. et al.Cause and consequences of genetic and epigenetic alterations in human cancer.Curr. Genomics. 2008; 9: 394-408Crossref PubMed Scopus (36) Google Scholar]. A growing list of diseases with an epigenetic component suggests that epigenetics will have a crucial role in disease etiology for many disease states (Figure 1).Epigenetics and environmental factorsInitial observations of how the environment can influence epigenetics and phenotype were shown in plants [44Cuzin F. et al.Inherited variation at the epigenetic level, paramutation from the plant to the mouse.Curr. Opin. Genet. Dev. 2008; 18: 193-196Crossref PubMed Scopus (40) Google Scholar]. In animals, many examples associate environmental influences to epigenetic changes. Epigenetic influences have been observed with environmental compounds, nutritional factors [45Bertram C. et al.Transgeneration
Referência(s)