Ontogeny is a remarkable process. In humans, a single fertilized egg gives rise to tens of trillions of cells that function in an integrated fashion to enable activities ranging from the relatively basic – metabolism and growth – to the seemingly emergent – abstract thought and emotion. The sheer magnitude of this complexity presents a formidable challenge to those studying development. Thus, unlike modern evolutionary biologists who engage themselves with research programs aimed at exploring the diversity within nature, present-day developmental biologists take a more narrow view . The inherent complexity of the subject matter has resulted in the adoption of a methodology that treats diversity as noise and represents model organisms as idealized types. Central to such an idealized understanding of nature is a requirement for development to be the result of an orderly unfolding of highly choreographed internal forces. Such a predeterministic interpretation of the generation of biological form has its roots in 17th century biological thought. Developmental biology textbooks routinely contain tongue-in-cheek references to the 'homunculus' popularly attributed to early microscopist Nikolaas Hartsoeker . Hartsoeker's studies led him to suggest that each human sperm contained a fully formed miniature human (the homunculus) within it . Similar to Russian nesting dolls, in which one doll harbors within it many smaller ones, this model leads to the reductio ad absurdum conclusion that each organism contains within it countless numbers of fully formed yet progressively more minute subsequent generations. And while this theory is described as having fallen to the countering viewpoint of the epigeneticists, modern developmental biology substitutes the homunculus with a similarly preformationist agency – the gene [4–6].
As a response to the preformationist school of thought, the term 'epigenetics' referred initially to the origin of life from formless matter. Now, epigenetics refers to the transmission of heritable changes in gene expression independent of direct alterations at the nucleotide level of DNA [7–9]. Thus, epigenetic theories of inheritance dispute the strict genotype–phenotype correlation and postulate mechanisms in addition to DNA sequence, to determine gene function and, hence, phenotype during ontogeny. In addition to DNA methylation (which is largely outside the scope of this review and the reader is directed to some excellent reviews on the topic [8,10]), some of the most widely studied mediators of epigenetic inheritance involve reversible alterations of chromatin structure by enzymes that modify histones covalently. These modifications are usually composed of acetyl, methyl or phosphoryl (among others) groups [11–13]. The combined set of such modifications is referred to as the 'histone code'  and may rival the genetic code in determining biological form and function, as well as diversity.
In an expanded view, other factors, such as the environment, produce phenotypic variation. Given that mammalian development occurs in the relatively well-controlled environment of the uterus, it is not surprising that its impact on normal development has not been studied in-depth. However, the ability of environmental toxins, such as dioxins, or drugs, such as diethylstilbestrol (DES), to affect human development adversely has been appreciated for some time [15,16]. Daughters of women exposed to DES during their first trimester of pregnancy developed malformations of their reproductive tracts along with clear-cell adenocarcinomas, both at very high rates . Interestingly, the effects of DES are recapitulated in the grand-daughters of exposed women. Similar transgenerational effects of DES on development have been reproduced in mice [18,19] and may be mediated by epigenetic mechanisms involving heritable alterations of DNA methylation . Such effects on DNA methylation have also been described in rats exposed to glucocorticoids and may be responsible for the cellular memory to such hormonal stimuli . Also, the epigenetic memory of environmental exposure is not only transmissible to the next cellular generation but also through the germline .
Recently, subtler effects of the environment on human development are beginning to be understood through epidemiologic investigations. For example, studies of low birthweight as a consequence of maternal dietary restriction during times of famine have shown that the consequence of such alterations in the environment of developing human embryos/fetuses can lead to the programming of adult diseases, such as hypertension and Type 2 diabetes . More importantly, some of these effects can be heritable, as with gestational diabetes mellitus [24,25]. Women born of mothers with gestational diabetes mellitus are much more likely to develop the disease when they conceive. This increased risk is not due solely to genetic factors because the risk can be ameliorated – and the transmission of this trait to subsequent generations prevented – with aggressive blood glucose management during pregnancy. Thus, even relatively modest alterations in levels of the most basic physiological factors, such as glucose concentration, can affect developmental outcome in an epigenetically heritable manner.
1 .Raff RA: The Shape of Life. Genes, Development, and the Evolution of Animal Form. The University of Chicago Press, Chicago, IL, USA (1996). 2 .Pinto-Correia C: The Ovary of Eve: egg and sperm and prefoormation. The University of Chicago Press, Chicago, IL, USA (1997). [CrossRef] 3 .Hartsoeker N: Essai de dioptique. Paris, France (1694). 4 .Lewontin RC: The Triple Helix: gene, organism, and environment. Harvard University Press, Cambridge, MA, USA (2000). 5 .Moss L: What Genes Can't Do.The MIT Press, Cambridge, MA, USA (2003). 6 .Oyama S: The Ontogeny of Information. Developmental Systems and Evolution. 2nd Ed. Duke University Press, Raleigh, NC, USA (2000). 7 .Kurdistani SK, Grunstein M: Histone acetylation and deacetylation in yeast. Nat. Rev. Mol. Cell Biol.4(4), 276–284 (2003). [CrossRef] [Medline] [CAS] 8 .Costello JF, Plass C: Methylation matters. J. Med. Genet.38(5), 285–303 (2001). [CrossRef] [Medline] [CAS] 9 .Roloff TC, Nuber UA: Chromatin, epigenetics and stem cells. Eur. J. Cell Biol.84(2–3), 123–135 (2005). [CrossRef] [Medline] [CAS] 10 .Jaenisch R, Bird A: Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet.33(Suppl.) 245–254 (2003). [CrossRef] [Medline] [CAS] 11 .Berger SL: Histone modifications in transcriptional regulation. Curr. Opin. Genet. Dev. 12(2), 142–148 (2002). [CrossRef] [Medline] [CAS] 12 .Lund AH, van Lohuizen M: Epigenetics and cancer. Genes Dev. 18(19), 2315–2335 (2004). [CrossRef] [Medline] [CAS] 13 .Iizuka M, Smith MM: Functional consequences of histone modifications. Curr. Opin. Genet. Dev. 13(2), 154–160 (2003). [CrossRef] [Medline] [CAS] 14 .Strahl BD, Allis CD: The language of covalent histone modifications. Nature403(6765), 41–45 (2000). [CrossRef] [Medline] [CAS] 15 .SchmidtJV, Bradfield CA: Ah receptor signalling pathways. Annu. Rev. Cell Dev. Biol. 12,55–89 (1996). [CrossRef] [Medline] [CAS] 16 .Ruden DM, Xiao L, Garfinkel MD, Lu X: Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer. Hum. Mol. Genet. 14(Spec No 1), R149–155 (2005). [CrossRef] [CAS] 17 .Li S, Hursting SD, Davis BJ, McLachlan JA, Barrett JC: Environmental exposure, DNA methylation, and gene regulation: lessons from diethylstilbesterol-induced cancers. Ann. NY Acad. Sci. 983, 161–169 (2003). [CrossRef] [Medline] [CAS] 18 .Newbold RR, Hanson RB, Jefferson WN, Bullock BC, Haseman J, McLachlan JA: Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis19(9), 1655–1663 (1998). 19 .Walker BE, Haven MI: Intensity of multigenerational carcinogenesis from diethylstilbestrol in mice. Carcinogenesis 18(4), 791–793 (1997). [CrossRef] [Medline] [CAS] 20 .Li S, Hansman R, Newbold R, Davis B, McLachlan JA, Barrett JC: Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus. Mol. Carcinog. 38(2), 78–84 (2003). [CrossRef] [Medline] [CAS] 21 .Thomassin H, Flavin M, Espinas ML, Grange T: Glucocorticoid-induced DNA demethylation and gene memory during development. EMBO J. 20(8), 1974–1983 (2001). [CrossRef] [Medline] [CAS] 22 .Roemer I, Reik W, Dean W, Klose J: Epigenetic inheritance in the mouse. Curr. Biol. 7(4), 277–280 (1997). [CrossRef] [Medline] [CAS] 23 .Barker DJ: The developmental origins of adult disease. J. Am. Coll. Nutr. 23(6 Suppl.), 588S–595S (2004). [Medline] [CAS] 24 .Aerts L, Van Assche FA: Intra-uterine transmission of disease. Placenta 24(10), 905–911 (2003). [CrossRef] [Medline] [CAS] 25 .Aerts L, Van Assche FA: Animal evidence for the transgenerational development of diabetes mellitus. Int. J. Biochem. Cell Biol. (In Press) (2005
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