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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Epigenetics is a term in biology used today to refer to features such as chromatin and DNA modifications that are stable over rounds of cell division but do not involve changes in the underlying DNA sequence of the organism.[1] These epigenetic changes play a role in the process of cellular differentiation, allowing cells to stably maintain different characteristics despite containing the same genomic material. Epigenetic features are inherited when cells divide despite a lack of change in the DNA sequence itself and, although most of these features are considered dynamic over the course of development in multicellular organisms, some epigenetic features show transgenerational inheritance and are inherited from one generation to the next.[2]

Specific epigenetic processes of interest include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.

Etymology and Definitions

The word "epigenetics" has been associated with many different definitions, and much of the confusion surrounding the use of the word "epigenetics" relates to the fact that it was originally defined to explain phenomena without knowing their molecular basis and with time became narrowly linked to certain phenomena as their molecular basis was discovered.[3]

Originally, the word "epigenetics" (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteau of the words "genetics" and "epigenesis".[4] Epigenesis is an older word used to describe the differentiation of cells from a totipotent state in embryonic development (used in contrast to "preformationism"). At the time Waddington first used the term "epigenetics" the physical nature of genes and their role in heredity was not known. Epigenetics was Waddington's model of how genes within a multicellular organism interact with their surroundings to produce a phenotype. Because all cells within an organism inherit the same DNA sequences, cellular differentiation processes crucial for epigenesis rely strongly on epigenetic rather than genetic inheritance. Robin Holliday defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."[5]

Another usage of the word "epigenetics" was employed by the psychologist Erik Erikson, who developed an "epigenetic theory of human development" which focuses on psycho-social crises.

The modern usage of the word "epigenetic" is more narrow, referring to heritable traits (over rounds of cell division and sometimes transgenerationally) that do not involve changes to the underlying DNA sequence.[6] The Greek "epi-" prefix of the word "epigenetics" implies features that are "on top of" or "in addition to" genetics, and the current usage of the word reflects this—epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.

The similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "genome" and refers to the overall epigenetic state of a cell. The phrase "genetic code" has also been adapted—the "epigenetic code" has been used to describe the set of epigenetic features that create different phenotypes in different cells. Taken to its extreme, the "epigenetic code" could represent the total state of the cell, with the position of each molecule accounted for; more typically, the term is used in reference to systematic efforts to measure specific, relevant forms of epigenetic information such as the histone code or DNA methylation patterns.

Mechanisms

Several types of epigenetic inheritance systems may play a role in what has become known as cell memory:[7]

DNA methylation and chromatin remodelling

DNA associates with histone proteins to form chromatin.

Because the phenotype of a cell or individual is affected by which of its genes are transcribed, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression, one of which is remodelling of chromatin, the complex of DNA and the histone proteins with which it associates. Chromatin remodelling is initiated by one of two things:

  1. posttranslational modification of the amino acids that make up histone proteins,
  2. or the addition of methyl groups to the DNA, at CpG sites, to convert cytosine to 5-methylcytosine.

Whereas DNA is not completely stripped of nucleosomes during replication, it is possible that the remaining modified histones may act as templates, initiating identical modification of surrounding new histones after deposition. DNA methylation has a more clear method of propagation through the preferential methylation of hemimethylated symmetric sites by enzymes like Dnmt 1.

Although modifications occur throughout the histone sequence, the unstructured termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation, methylation and ubiquitylation. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysines of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally correlated with transcriptional competence.

One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because lysine normally has a positive charge on the nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone and prevent them from repelling each other. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge causing the DNA to repel itself. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA, thus opening it up and exposing it to enzymes like RNA polymerase so transcription of the gene can occur.

In addition, the positively charged tails of histone proteins from one nucleosome may interact with the histone proteins on a neighboring nucleosome, causing them to pack closely. Lysine acetylation may interfere with these interactions, causing the chromatin structure to open up.

Lysine acetylation may also act as a beacon to recruit other activating chromatin modifying enzymes (and basal transcription machinery as well). Indeed, the bromodomain—a protein segment (domain) that specifically binds acetyl-lysine—is found in many enzymes that help activate transcription including the SWI/SNF complex (on the protein polybromo). It may be that acetylation acts in this and the previous way to aid in transcriptional activation.

The idea that modifications act as docking modules for related factors is borne out by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive heterochromatin). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein HP1 recruits HP1 to K9 methylated regions. One example that seems to refute the biophysical model for acetylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation. Tri-methylation in this case would introduce a fixed positive charge on the tail.

It should be emphasized that differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently than acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code.

DNA methylation frequently occurs in repeated sequences, and may help to suppress 'junk DNA':[8] Because 5-methylcytosine is chemically very similar to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islands where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A and DNMT3B, the loss of any of which is lethal in mice.[9] DNMT1 is the most abundant methyltransferase in somatic cells,[10] localizes to replication foci,[11] has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).[12] By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after DNA replication, and therefore is often referred to as the ‘maintenance' methyltransferase.[13] DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.[9][14]

Because DNA methylation and chromatin remodelling play such a central role in many types of epigenic inheritance, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading. Chromatin remodelling is not always inherited, and not all epigenetic inheritance involves chromatin remodelling.[15]

RNA transcripts and their encoded proteins

Sometimes a gene, after being turned on, transcribes a product that (either directly or indirectly) maintains the activity of that gene. For example, Hnf4 and MyoD enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. Other epigenetic changes are mediated by the production of different splice forms of RNA, or by formation of double-stranded RNA (RNAi). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are most often turned on or off by signal transduction, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygote by the mother during oogenesis or via nurse cells, resulting in maternal effect phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.[16]

Prions

For more details on this topic, see Prions.

Prions are infectious forms of proteins. Proteins generally fold into discrete units which perform distinct cellular functions, but some proteins are also capable of forming an infectious conformational state known as a prion. Although often viewed in the context of infectious disease, prions are more loosely defined by their ability to catalytically convert other native state versions of the same protein to an infectious conformational state. It is in this latter sense that they can be viewed as epigenetic agents capable of inducing a phenotypic change without a modification of the genome.[17]

Fungal prions are considered epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. PSI+ and URE3, discovered in yeast in 1965 and 1971, are the two most well studied of this type of prion.[18][19] Prions can have a phenotypic effect through the sequestration of protein in aggregates, thereby reducing that protein's activity. In PSI+ cells, the loss of the Sup35 protein (which is involved in termination of translation) causes ribosomes to have a higher rate of read-through of stop codons, an effect which results in suppression of nonsense mutations in other genes.[20] The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to switch into a PSI+ state and express dormant genetic features normally terminated by premature stop codon mutations.[21][22]

Structural inheritance systems

For more details on this topic, see Structural inheritance.

In ciliates such as Tetrahymena and Paramecium, genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.

Functions and consequences

Development

Somatic epigenetic inheritance, particularly through DNA methylation and chromatin remodelling, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate in many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, morphogens activate or silence genes in an epigenetically heritable fashion, giving cells a "memory". In mammals, most cells terminally differentiate, with only stem cells retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In mammals, some stem cells continue producing new differentiated cells throughout life, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin remodelling, it has been hypothesised that plant cells do not have "memories", resetting their gene expression patterns at each cell division using positional information from the environment and surrounding cells to determine their fate.[23]

Medicine

Epigenetics has many and varied potential medical applications. Congenital genetic disease is well understood, and it is also clear that epigenetics can play a role, for example, in the case of Angelman syndrome and Prader-Willi syndrome. These are normal genetic diseases caused by gene deletions, but are unusually common because individuals are essentially hemizygous because of genomic imprinting, and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.[24]

Evolution

Although epigenetics in multicellular organisms is generally thought to be a mechanism involved in differentiation, with epigenetic patterns "reset" when organisms reproduce, there have been some observations of transgenerational epigenetic inheritance (e.g., the phenomenon of paramutation observed in maize). Although most of these multigenerational epigenetic traits are gradually lost over several generations, the possibility remains that multigenerational epigenetics could be another aspect to evolution and adaptation. These effects may require enhancements to the standard conceptual framework of Neo-Darwinism.[25][26]

Epigenetic features may play a role in short-term adaptation of species by allowing for reversible phenotype variability. The modification of epigenetic features associated with a region of DNA allows organisms, on a multigenerational time scale, to switch between phenotypes that express and repress that particular gene.[27] Whereas the DNA sequence of the region is not mutated, this change is reversible. It has also been speculated that organisms may take advantage of differential mutation rates associated with epigenetic features to control the mutation rates of particular genes.[27]

Epigenetic changes have also been observed to occur in response to environmental exposure—for example, mice given some dietary supplements have epigenetic changes affecting expression of the agouti gene, which affects their fur color, weight, and propensity to develop cancer.[28][29] Although this change isn't adaptive since the underlying mutation is agouti gene was developed artificially, the observation of epigenetic change occurring in response to environmental factors opens up the possibility of organismal adaptive inheritance—a sort of Lamarckian inheritance. Although this remains speculative, if this does occur some instances of evolution would indeed be separate from standard genetic inheritance.[30]

Epigenetic effects in humans

Genomic imprinting and related disorders

Some human disorders are associated with genomic imprinting, a phenomenon in mammals where the father and mother contribute different epigenetic patterns for specific genomic loci in their germ cells.[31] The most well known case of imprinting in human disorders is that of Angelman syndrome and Prader-Willi syndrome—both can be produced by the same genetic mutation, chromosome 15q partial deletion, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father.[32] This is due to the presence of genomic imprinting in the region, a phenomenon in mammals where the father and mother contribute different epigenetic patterns in their germ cells.[33] Beckwith-Wiedemann syndrome is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.

Transgenerational epigenetic observations

Pembrey and colleagues also observed that the paternal (but not maternal) grandsons of Swedish boys who were exposed to famine in the 19th Century were more likely to get diabetes, suggesting that this was a transgenerational epigenetic inheritance[34]

Cancer and developmental abnormalities

A variety of compounds are considered as epigenetic carcinogens—they result in an increased incidence of tumors, but they do not show mutagen activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include diethylstilbestrol, arsenite, hexachlorobenzene, and nickel compounds.

Many teratogens exert specific effects on the fetus by epigenetic mechanisms.[35][36] While epigenetic effects may preserve the effect of a teratogen such as diethylstilbestrol throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence.[37] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.[38] FDA label information for Vidaza(tm), a formulation of 5-azacitidine (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss, and abnormal embryo development. In rats, endocrine differences were observed in offspring of males exposed to morphine.[39] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.[40]

See also

Further reading

  • Oskar Hertwig, 1849-1922. Biological problem of today: preformation or epigenesis? The basis of a theory of organic development. W. Heinemann: London, 1896.
  • R. Jaenisch and A. Bird (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33 (Suppl) 245-254.
  • Joshua Lederberg, "The Meaning of Epigenetics", The Scientist 15(18):6, Sep. 17, 2001.
  • R. J. Sims III, K. Nishioka and D. Reinberg (2003) Histone lysine methylation: a signature for chromatin function. Trends Genet. 19, 629-637.
  • B. D. Strahl and C. D. Allis (2000) The language of covalent histone modifications. Nature 403, 41-45.
  • C.H. Waddington (1942), "The epigenotype". Endeavour 1, 18–20.
  • B. McClintock (1978) Mechanisms that Rapidly Reorganize the Genome. Stadler Symposium vol 10:25-48
  • G.W. Grimes; K.J. Aufderheide; Cellular Aspects of Pattern Formation: the Problem of Assembly. Monographs in Developmental Biology, Vol. 22. Karger, Basel (1991)
  • Eva Jablonka and Marion J. Lamb Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life The MIT Press (2005) ISBN 978-0262101073
  • Article on The Philosophy of Molecular and Developmental Biology to appear in Blackwell’s Guide to Philosophy of Science,. P.K. Machamer and M. Silberstein (Eds).

Notes and references

  1. Adrian Bird (2007). "Perceptions of epigenetics". Nature. 447: 396–398.  PMID 17522671
  2. V.L. Chandler (2007). "Paramutation: From Maize to Mice". Cell. 128: 641–645. 
  3. Roloff, T.C., Nuber, U.A., 2005 Chromatin , epigenetics and stem cells. Eur J Cell Biol. 84, 123-135
  4. C.H. Waddington (1942). "The epigenotype". Endeavour. 1: 18–20. 
  5. Holliday, R., 1990. Mechanisms for the control of gene activity during development. Biol. Rev. Cambr. Philos. Soc. 65, 431-471
  6. Russo, V.E.A., Martienssen, R.A., Riggs, A.D., 1996 Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press, Plainview, NY.
  7. Jablonka, E; Lamb MJ and Lachmann M (1992). "Evidence, mechanisms and models for the inheritance of acquired characteristics". J. Theoret. Biol. 158 (2): 245–268.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)
  8. Chédin, F (1992). "The Chedin Laboratory". Retrieved 2006-12-28. 
  9. 9.0 9.1 Li, E; Bestor TH and Jaenisch R (1992). "Targeted mutation of the DNA methyltransferase gene results in embryonic lethality". Cell. 69 (6): 915–926.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)
  10. Robertson, KD; Uzyolgi E, Lian G et al (1999). "The human DNA methyltransferases (DNMTs) 1, 3a, 3b: Coordinate mRNA expression in normal tissues and overexpression in tumors". Nucleic Acids Res. 27 (11): 2291–2298.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)
  11. Leonhardt, H; Page AW, Weier HU, Bestor TH (1992). "A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei". Cell. 71 (5): 865–873.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)
  12. Chuang, LS; Ian HI, Koh TW et al (1997). "Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1". Science. 277 (5334): 1996–2000.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)
  13. Robertson, KD; Wolffe AP (2000). "DNA methylation in health and disease". Nat Rev Genet. 1 (1): 11–19.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)
  14. Li, E; Beard C and Jaenisch R (1993). "Role for DNA methylation in genomic imprinting". Nature. 366 (6453): 362–365.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)
  15. Mark Ptashne, 2007. On the use of the word ‘epigenetic’. Current Biology, 17(7):R233-R236. doi:10.1016/j.cub.2007.02.030
  16. Choi CQ (2006-05-25). "The Scientist: RNA can be hereditary molecule". The Scientist. Retrieved 2006.  Check date values in: |access-date= (help)
  17. A. Yool and W.J. Edmunds (1998). "Epigenetic inheritance and prions". Journal of Evolutionary Biology. 11: 241–242. 
  18. B.S. Cox (1965). "[PSI], a cytoplasmic suppressor of super-suppression in yeast". Heredity. 20: 505–521. 
  19. F. Lacroute (1971). "Non-Mendelian mutation allowing ureidosuccinic acid uptake in yeast". Journal of Bacteriology. 106: 519–522. 
  20. S.W. Liebman and F. Sherman (1979). "Extrachromosomal psi+ determinant suppresses nonsense mutations in yeast". Journal of Bacteriology. 139 (3): 1068–1071.  Free full text available
  21. H.L. True and S.L. Lindquist (2000). "A yeast prion provides a mechanism for genetic variation and phenotypic diversity". Nature. 407: 477–483. 
  22. J. Shorter and S. Lindquist (2005). "Prions as adaptive conduits of memory and inheritance". Nature Reviews Genetics. 6 (6): 435–450. 
  23. Silvia Costa and Peter Shaw. 2006. 'Open Minded' cells: how cells can change fate. Trends in Cell Biology 17(3):101-106. doi:10.1016/j.tcb.2006.12.005
  24. Online 'Mendelian Inheritance in Man' (OMIM) 105830
  25. Jablonka, Eva; Marion J. Lamb (2005). Evolution in Four Dimensions. MIT Press. ISBN 0-262-10107-6.  Cite uses deprecated parameter |coauthors= (help)
  26. See also Denis Noble The Music of Life see esp pp93-8 and p48 where he cites Jablonka & Lamb and Massimo Pigliucci's review of Jablonka and Lamb in Nature 435, 565-566 (2 June 2005)
  27. 27.0 27.1 O.J. Rando and K.J. Verstrepen (2007). "Timescales of Genetic and Epigenetic Inheritance". Cell. 128: 655–668. 
  28. Cooney, CA, Dave, AA, and Wolff, GL (2002). "Maternal Methyl Supplements in Mice Affect Epigenetic Variation and DNA Methylation of Offspring". Journal of Nutrition. 132: 2393S–2400S. available online
  29. Waterland RA and Jirtle RL (2003). "Transposable elements: Targets for early nutritional effects on epigenetic gene regulation". Molecular and Cellular Biology. 23 (15): 5293–5300.  Unknown parameter |month= ignored (help)
  30. Shorter J, Lindquist S (2005). "Prions as adaptive conduits of memory and inheritance". Nat. Rev. Genet. 6 (6): 435–50. PMID 15931169. 
  31. A.J. Wood and A.J. Oakey (2006). "Genomic imprinting in mammals: Emerging themes and established theories". PLOS Genetics. 2 (11): 1677–1685.  available online
  32. J.H.M. Knoll, R.D. Nicholls, R.E. Magenis, J.M. Graham Jr, M. Lalande, S.A. Latt (1989). "Angelman and Prader-Willi syndromes share a common chromosome deletion but differ in parental origin of the deletion". American Journal of Medical Genetics. 32: 285–290. 
  33. K.D. Robertson (2005). "DNA methylation and human disease". Nature Reviews Genetics. 6 (8): 597–610. 
  34. Pembrey ME, Bygren LO, Kaati G, et al. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006; 14: 159-66. PMID 16391557. Robert Winston refers to this study in a lecture; see also discussion at Leeds University, here
  35. Bishop, JB; Witt KL and Sloane RA (1997). "Genetic toxiticities of human teratogens". Mutat Res. 396 (1-2): 9–43.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)
  36. Gurvich, N; Berman MG, Wittner BS et al (2004). "Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo". FASEB J. 19 (9): 1166–1168.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)
  37. Smithells, D (1998). "Does thalidomide cause second generation birth defects?". Drug Saf. 19 (5): 339–341.  Unknown parameter |month= ignored (help)
  38. Friedler, G (1996). "Paternal exposures: impact on reproductive and developmental outcome. An overview.". Pharmacol Biochem Behav. 55 (4): 691–700.  Unknown parameter |month= ignored (help)
  39. Cicero, TJ; Adams NL, Giodarno A et al (1991). "Influence of morphine exposure during adolescence on the sexual maturation of male rats and the development of their offspring". J Pharmacol Exp Ther. 256 (3): 1086–1093.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)
  40. Newbold, RR; Padilla-Banks E and Jefferson WN (2006). "Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations". Endocrinology. 147 (6 Suppl): S11–S17.  Unknown parameter |month= ignored (help); Cite uses deprecated parameter |coauthors= (help)

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