Diethylstilboestrol: II, pharmacology, toxicology and carcinogenicity in experimental animals

Marselos, Marios; Tomatis, Lorenzo

doi:10.1016/0959-8049(93)90597-9

Cited by 92 publications

(49 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DES had been largely used from 1948 to 1971 in the management of conditions as threatened abortions, pre-eclampsia, prior premature labor, prostatic and breast cancer, pregnancy complications in diabetic women [9][10][11]. It is estimated that 2 to 4.8 million human offspring were exposed to DES [12].…”

Section: Environmental Estrogensmentioning

confidence: 99%

The role of environmental estrogens and autoimmunity

Chighizola

Meroni

2012

Autoimmunity Reviews

View full text Add to dashboard Cite

Section: Environmental Estrogensmentioning

confidence: 99%

The role of environmental estrogens and autoimmunity

Chighizola

Meroni

2012

Autoimmunity Reviews

View full text Add to dashboard Cite

“…The exposure to synthetic and environmental estrogens is believed to have increased over the years. Diethylstilbestrol (DES), a potent synthetic estrogen, has been used as a therapeutic agent in a variety of clinical situations including threatened abortions, preeclampsia, prior premature labor, prostatic and breast cancer, pregnancy complications in diabetic women, and whenever estrogen-replacement therapy was indicated (9)(10)(11). Although DES is no longer used during pregnancy, it is estimated that 2-4.8 million human offspring were exposed to DES from the 1940s through 1971 (12).…”

Section: Gender Differences In Immune Responsesmentioning

confidence: 99%

Gender and risk of autoimmune diseases: possible role of estrogenic compounds.

Ahmed

Hissong

Verthelyi

et al. 1999

Environ Health Perspect

142

View full text Add to dashboard Cite

A striking common feature of many autoimmune diseases in humans and experimental animals, despite differences in pathology, is that females are highly susceptible to autoimmune conditions compared to males. In several animal models, estrogens promote, whereas androgens abrogate, B-cell-mediated autoimmune diseases. To understand mechanisms by which estrogens regulate autoimmunity, it is first necessary to decipher estrogen effects on the normal immune system. Estrogen treatment of nonautoimmune mice diminished lymphocyte numbers in both developmental and mature lymphoid organs. Estrogen dysregulated T-and B-cell balance by inducing selective T-cell hypoactivity and B-cell hyperactivity. Even though estrogen did not alter the relative percentages of splenic T-cell subsets, splenic lymphocytes had a reduced proliferative response to T-cell stimulants and were refractory to rescue from activation-induced apoptosis compared to cells from placebo-treated mice. In contrast, estrogen induced B-cell hyperactivity (promoted autoantibodies to double-stranded DNA and phospholipids, increased numbers of plasma cells, and increased autoantibody yield per B cell). Note that treatment of normal mice with estrogen can alter T-and B-cell regulation and overcome B-cell tolerance to result in autoimmunity in normal individuals. Could environmental estrogens promote some human autoimmune disorders? Is there a link between environmental estrogens and autoimmune disorders, especially since these disorders are reported possibly more frequently? These provocative questions warrant investigation. Our findings on immunomodulatory effects may serve as a benchmark to examine whether endocrine-disrupting chemicals will have similar immunologic effects.

show abstract

“…Animal studies that simulate the human DES experience have since shown that exposure of the developing reproductive tracts of CD-1 mice to DES imparts a permanent estrogen imprint that alters reproductive-tract morphology, induces persistent expression of the lactoferrin and c-fos genes, and induces a high incidence of uterine adenocarcinoma (13-15). Because DES is readily metabolized and cleared within days after exposure, the persistent alterations resulting from developmental DES exposure cannot be explained simply by residual body burden of the compound (16,17). DESinduced developmental programming has been demonstrated to require estrogen receptor (ER) ␣ (18), suggesting that signaling through this receptor is crucial for establishing the imprint.…”

mentioning

confidence: 99%

Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

Cook

Davis

Cai

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

102

101

View full text Add to dashboard Cite

Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumorsuppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an earlylife exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to >90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals.developmental programming ͉ gene-environment interaction ͉ Eker rat ͉ uterine leiomyoma ͉ Tsc-2 I nheritance of a defect in a tumor-suppressor gene confers a high risk for developing cancer. However, defects in these genes are rarely 100% penetrant, and, even in families harboring the same genetic mutation, the penetrance of the tumor-suppressor-gene defect can vary significantly (1-4). The importance of geneenvironment interactions in contributing to individual differences in tumor-suppressor-gene penetrance was recently highlighted in the New York Breast Cancer Study, which evaluated the breast and ovarian cancer risk in female relatives harboring mutations in the BRCA1 and BRCA2 tumor-suppressor genes. The magnitude of increase in breast cancer risk in the birth cohort born after 1940 was substantially greater than in those born before 1940 (5). These data suggest that additional factors, such as diet, exercise, hormonal milieu, and environmental exposures, can significantly modify cancer risk in the presence of an inherited cancer-susceptibility gene.Traditionally, gene-environment interactions that influence cancer risk are thought to occur over an individual's lifetime by facilitating or inhibiting acquisition of the multiple somatic mutations required for tumorigenesis (6). However, for some diseases, such as cardiovascular disease and adult-onset diabetes, a developmental programming hypothesis is proposed as an alternative mechanism for modulating adult disease. This hypo...

show abstract

Diethylstilboestrol: II, pharmacology, toxicology and carcinogenicity in experimental animals

Cited by 92 publications

References 66 publications

The role of environmental estrogens and autoimmunity

The role of environmental estrogens and autoimmunity

Gender and risk of autoimmune diseases: possible role of estrogenic compounds.

Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

Contact Info

Product

Resources

About