Neonatal Exposure to Diethylstilbestrol Alters Expression of DNA Methyltransferases and Methylation of Genomic DNA in the Mouse Uterus

Sato, Koji; Fukata, Hideki; Kogo, Yasushi; Ohgane, Jun; Shiota, Kunio; Mori, Chisato

doi:10.1507/endocrj.k08e-239

Cited by 77 publications

(50 citation statements)

References 48 publications

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“…For example the estrogen-responsive lactoferrin gene seems to be up-regulated in the mouse uterus, after neonatal exposure to DES; this abnormal expression persists later in life (Nelson et al 1994) and may be attributed to an abnormal demethylation in the lactoferrin gene promoter, which seems to occurr specifically in response to neonatal DES exposure . Moreover, this demethylation state is continuously maintained in uterine tumours of DES-exposed mice, suggesting that neonatal DES treatment may not only induce tumour formation but also gene-specific demethylation, through a common cellular process, such as alterations of the expression of DNA methyltransferases and methylation of genomic DNA Sato et al 2009). Subsequent work demonstrated that other developmental genes, up-regulated after exposure to DES, also exhibit modified methylation patterns.…”

Section: Des and Epigeneticsmentioning

confidence: 99%

The developing female genital tract: from genetics to epigenetics

Massé¹,

Watrin²,

Laurent³

et al. 2009

Int. J. Dev. Biol.

118

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The mammalian female reproductive tract develops from the Müllerian ducts which differentiate, in a cranial to caudal direction, into oviducts, uterine horns, cervix and the anterior vagina. The developmental processes taking place during this organogenesis are notably under the control of steroid hormones, such as members of the Wnt and Hox families, which regulate key developmental genes. At later stages, steroid hormones also participate in the development of the female genital tract. Chemical compounds homologous to steroids can thus act as agonists or antagonists in fetuses exposed to them. These so-called endocrine disruptors are nowadays found in increasing amounts in the environment and may therefore have a particular impact on such developing organs. Epidemiological studies have revealed that endocrine disruptors have had drastic effects on female health and fertility during the last decades. Furthermore, these adverse effects might be transmitted to subsequent generations through epigenetic modifications. Given the potential hazard of inherited epigenetic marks altering reproduction and/or human health, such molecular mechanisms must be urgently investigated. This review aims to summarize the cellular and molecular mechanisms involved in female genital tract development, to highlight key genes involved in this process and to present epigenetic mechanisms triggered by endocrine disruptors and their consequences in regard to female reproductive tract development. KEY WORDS: genital tract, Hox, Wnt, genetics, epigenetics Development of the urogenital system Relation between urinary and genital tractsMammalian genital tract development is closely related to the urinary system embryogenesis. This relation is ancient in evolution and phylogenetically well conserved. In simple organisms like annelids, they both consist in metamerized nephritic tubules composed of a ciliated funnel oriented towards the coelomic cavity and connected to a vascularised duct that opens to the exterior. This system is involved in metabolites and mature genital cells excretion. In higher vertebrates, the urogenital apparatus comprises the kidneys, gonads, urinary and reproductive ducts. The urinary tract embryonic formation is the result of a three steps process that gives rise to three successive structures emerging rostrocaudally in the intermediate mesoderm. Nephrotomes first develop in the cervical part of the embryo; they consist in a ciliated funnel emerging in the coelomic cavity and in a nephritic tubule Int. J. Dev. Biol. 53: 411-424 (2009) doi: 10.1387/ijdb.082680jm connected to a common excretory duct (the Wolffian duct, WD). At this stage, they form a primitive kidney called pronephros which is not functional. This transitory organ can only be observed in vertebrate embryos and agnathe larvae (Saxen and Sariola 1987;Bouchard et al. 2002). Then, while the pronephros is regressing, the mesonephros develops posteriorly, allowing the WD to grow in the same direction. This intermediary kidney, comprising a Bowman ...

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Section: Des and Epigeneticsmentioning

confidence: 99%

The developing female genital tract: from genetics to epigenetics

Massé¹,

Watrin²,

Laurent³

et al. 2009

Int. J. Dev. Biol.

118

View full text Add to dashboard Cite

show abstract

“…after subcutaneous injection of DES in mice and at least five investigated genomic loci showed decreased DNA methylation in the uterus of the investigated mice (Sato et al, 2009 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 12 used similar methods and experimental setup to study the changes in DNA methyltransferase (DNMT) expression and DNA methylation in epididymis of mice and found altered but increased expression of DNMT-s. (Sato et al, 2006) In some instances the transgenerational change is simply a sensitization of the organism towards a second signal. As an example, neonatal exposure of rats to BPA resulted in an increased incidence of prostate intraepithelial neoplasia (Ho et al, 2006).…”

Section: Endocrine Disruptors and Nrsmentioning

confidence: 92%

Nuclear receptors in transgenerational epigenetic inheritance

Ozgyin

Erdős

Bojcsuk

et al. 2015

Progress in Biophysics and Molecular Biology

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Nuclear Receptors are ligand-activated transcription factors that translate information about the lipid environment into specific genetic programs, a property that renders them good candidates to be mediators of rapid adaptation changes of a species. Lipid-based morphogens, endocrine hormones, fatty acids and xenobiotics might act through this class of transcription factors making them regulators able to fine-tune physiological processes. Here we review the basic concepts and current knowledge on the process whereby small molecules act through nuclear receptors and contribute to transgenerational changes. Several molecules shown to cause transgenerational changes like phthalates, BPA, nicotine, tributylin bind and activate nuclear receptors like ERs, androgen receptors, glucocorticoid receptors or PPARγ. A specific subset of observations involving nuclear receptors has focused on the effects of environmental stress or maternal behaviour on the development of transgenerational traits. While these effects do not involve environmental ligands, they change the expression levels of Estrogen and glucocorticoid receptors of the second generation and consequently initiate an altered genetic program in the second generation. In this review we summarize the available literature about the role of nuclear receptors in transgenerational inheritance.

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“…Subsequently, it was also found that exon 4 of the c-fos gene was extensively hypomethylated while the promoter region and intron 1 was unaffected, thereby potentially allowing for the upregulation of c-fos expression [138]. QPCR studies performed by Sato and colleagues examining the expression of Dnmts in neonatally DES exposed C57BL/6 mice, revealed that expression of Dnmt1 and Dnmt3b was decreased at PND5 in DES-treated mice, and the pattern continued until PND14 [139]. Interestingly, it was found that human leiomyoma samples had alterations in the levels of Dnmts as well, with concomitant global hypomethylation [140].…”

Section: Des In Vivo Studiesmentioning

confidence: 99%

Effects of Endocrine-disrupting Chemicals on Female Reproductive Health

Zama¹,

Bhurke²,

Uzumcu³

2016

TOBIOTJ

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Endocrine-disrupting chemicals (EDCs) are increasingly prevalent in the environment and the evidence demonstrates that they affect reproductive health, has been accumulating for the last few decades. In this review of recent literature, we present evidence of the effects of estrogen-mimicking EDCs on female reproductive health especially the ovaries and uteri. As representative EDCs, data from studies with a pharmaceutical estrogen, diethylstilbestrol (DES), an organochlorine pesticide methoxychlor (MXC), a phytoestrogen (genistein), and a chemical used in plastics, bisphenol a (BPA) have been presented. We also discuss the effects of a commonly found plasticizer in the environment, a phthalate (DEHP), even though it is not a typical estrogenic EDC. Collectively, these studies show that exposures during fetal and neonatal periods cause developmental reprogramming leading to adult reproductive disease. Puberty, estrous cyclicity, ovarian follicular development, and uterine functions are all affected by exposure to these EDCs. Evidence that epigenetic modifications are involved in the progression to adult disease is also presented.

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Neonatal Exposure to Diethylstilbestrol Alters Expression of DNA Methyltransferases and Methylation of Genomic DNA in the Mouse Uterus

Cited by 77 publications

References 48 publications

The developing female genital tract: from genetics to epigenetics

The developing female genital tract: from genetics to epigenetics

Nuclear receptors in transgenerational epigenetic inheritance

Effects of Endocrine-disrupting Chemicals on Female Reproductive Health

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