Animal models of prenatal exposure to diethylstilboestrol

The multigeneration effect of DES provides a model to test the mechanism of transmission of cancer risk from one generation to the next

1989 Study Abstract

Animals of several species exposed perinatally to diethylstilboestrol (DES) have been evaluated for anomalies and tumours.

In male offspring, anomalies of the testis and epididymis have been reported, but evidence for tumours has been very limited.

Many anomalies and tumours have been recorded in female offspring, and some of these duplicate the anomalies and tumours reported in DES-exposed women, whereas others either have not yet been discovered or else do not occur in the human species..

Animal models of prenatal exposure to diethylstilboestrol, US National Library of Medicine National Institutes of Health, IARC scientific publications, NCBI PubMed PMID: 2680952, 1989.

A variety of abnormal physiological responses has been identified in animals exposed perinatally to DES.

There were altered levels of hormones and receptors; responses to postnatal injection of hormones were often modified; and an increased susceptibility to other carcinogens has been established.

Several mechanisms have been postulated to explain tumour production later in life after perinatal exposure to DES:

  1. Deficiencies in immune function indicate a mechanism of impaired immune surveillance.
  2. The presence of DES and its metabolites in the fetus and neonate raise the issue of somatic mutation. Evidence for sister chromatid exchange, cell transformation in tissue culture and other toxic effects on chromosomes support the somatic mutation hypothesis.
  3. A third hypothesis is involvement of abnormal differentiation of the hypothalamus. Structural, hormonal and behavioural changes support this idea.

Possible additional problems in humans after exposure to DES, on the basis of animal model studies, are increased tumour frequency with ageing and transmission of cancer risk to the third generation.

The multigeneration effect of DES provides a model to test the mechanism of transmission of cancer risk from one generation to the next.

The outcome of such experiments could have considerable impact on the understanding of the association between DES and cancer specifically and transplacental cancer generally.

More DES DiEthylStilbestrol Resources

Perinatal Exposure to DES Increases the Susceptibility to Develop Mammary Gland Lesions after Estrogen Replacement Therapy

Hormones and Cancer, April 2017, Volume 8, Issue 2, pp 78–89

2017 Study Abstract

The development of the mammary gland is a hormone-regulated event.

Several factors can dysregulate its growth and make the gland more susceptible to cellular transformation.

Among these factors, perinatal exposure to xenoestrogens and hormone replacement therapy has been associated with increased risk of developing breast cancer.

Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats, US National Library of Medicine National Institutes of Health, Hormones and Cancer, April 2017, Volume 8, Issue 2, pp 78–89, NCBI PubMed PMID: 28078498, 2017 Apr 8.

Here, we assessed the effects induced by estrogen replacement therapy (ERT) in ovariectomized (OVX) middle-aged rats and whether perinatal exposure to diethylstilbestrol (DES) or bisphenol A (BPA) modified these effects in the mammary gland.

Pregnant rats were orally exposed to vehicle, 5 μg DES/kg/day, or 0.5 or 50 μg BPA/kg/day from gestational day 9 until weaning. Then, 12-month-old offspring were OVX and treated with 17β-estradiol for 3 months.

Morphological changes and the percentage of epithelial cells that proliferated or expressed estrogen receptor alpha (ESR1) and progesterone receptor (PR) were analyzed in mammary gland samples of 15-month-old animals.

ERT induced lobuloalveolar hyperplasia and ductal cysts in the mammary gland of middle-aged rats, associated with a higher proliferation index of epithelial cells.

Perinatal exposure to DES followed by ERT increased the number of cysts and induced the formation of fibroadenoma and ductal carcinoma in situ, without modifying the expression of ESR1 or PR.

Also, after 3 months of ERT, BPA-exposed rats had a higher incidence of ductal hyperplasia and atypical lobular hyperplasia than animals under ERT alone.

In conclusion, perinatal exposure to xenoestrogens increases the susceptibility of the mammary gland to develop cysts and hyperplastic lesions when confronted with ERT later in life.

More DES DiEthylStilbestrol Resources

Time Bomb: a Journey into Old Exposures, Gametic Glitches, and the Autism Explosion

Slides from Society for Neuroscience Wonder, February 2017

This presentation to a student-run chapter of SFN explained the history and science behind the “Time Bomb” hypothesis of autism.

DES DiEthylStilbestrol Resources

RDD2017 : With Research, Possibilities are Limitless!

Rare Disease Day Official Video 2017

Feb 28 is Rare Disease Day !

The main objective of Rare Disease Day (RDD) is to raise awareness among the general public and decision-makers about rare diseases and their impact on patients’ lives.

OrphaNet, portal for rare diseases and orphan drugs, includes the Diethylstilbestrol DES syndrome as rare disease ORPHA:1916.

MORE INFORMATION

How much do you know about DES?

Environmental factors, epigenetics, and developmental origin of reproductive disorders

US National Library of Medicine National Institutes of Health, Reproductive toxicology, 2016

Highlights

  • Epidemiological and model system studies support an early origin of reproductive dysfunction.
  • Estrogenic/anti-androgenic chemicals as endocrine disrupting chemicals (EDCs) have vast developmental influences on adult reproductive outcomes.
  • Gestational, perinatal, neonatal, and pubertal periods are “windows of susceptibility” for epigenetic programming.
  • EDCs induce exposure-specific epigenetic modifications in regulatory genes in organs of the reproductive system.
  • Germline epigenetic disruption is a mechanism underlying transgenerational inheritance of reproductive disorders.

2017 Study Abstract

Environmental factors, epigenetics, and developmental origin of reproductive disorders, US National Library of Medicine National Institutes of Health, Reproductive toxicology (Elmsford, N.Y.), NCBI PubMed PMID: 27421580, 2016 Jul.

Image credit Daniel Friedman.

Sex-specific differentiation, development, and function of the reproductive system are largely dependent on steroid hormones.

For this reason, developmental exposure to estrogenic and anti-androgenic endocrine disrupting chemicals (EDCs) is associated with reproductive dysfunction in adulthood.

Human data in support of “Developmental Origins of Health and Disease” (DOHaD) comes from multigenerational studies on offspring of diethylstilbestrol-exposed mothers/grandmothers.

Animal data indicate that ovarian reserve, female cycling, adult uterine abnormalities, sperm quality, prostate disease, and mating behavior are susceptible to DOHaD effects induced by EDCs such as bisphenol A, genistein, diethylstilbestrol, p,p’-dichlorodiphenyl-dichloroethylene, phthalates, and polyaromatic hydrocarbons.

Mechanisms underlying these EDC effects include direct mimicry of sex steroids or morphogens and interference with epigenomic sculpting during cell and tissue differentiation.

Exposure to EDCs is associated with abnormal DNA methylation and other epigenetic modifications, as well as altered expression of genes important for development and function of reproductive tissues.

Here we review the literature exploring the connections between developmental exposure to EDCs and adult reproductive dysfunction, and the mechanisms underlying these effects.

DES DiEthylStilbestrol Resources

The Diethylstilbestrol Legacy

A Powerful Case Against Intervention in Uncomplicated Pregnancy

2016 Report Abstract

Although the basic tenet of medicine is “First, do no harm,” history is filled with good intentions that were at best unhelpful and at worst harmful. Because medicine seeks to cure afflictions, there is an overwhelming desire on the part of health providers and patients to administer treatment. In certain settings, treatment can be reasonable despite a risk of adverse consequences: for example, if the disease is cured or its morbidity abated and the treatment consequences are less disabling than the disease itself.

In the absence of overt disease, the question of whether to apply an intervention is far more challenging. The safety of interventions must be weighed against the population’s level of risk, the morbidity and/or mortality associated with the disease, and the intervention’s efficacy (eg, BRCA1 mutation, mastectomy, reduced breast cancer risk). Interventions must meet an especially high standard of safety and efficacy when administered in low-risk populations or in settings in which the morbidity associated with the disease is minor. In the worst-case scenario, an intervention may be both ineffective for its primary purpose and cause iatrogenic illness.

The Diethylstilbestrol Legacy: A Powerful Case Against Intervention in Uncomplicated Pregnancy,
Pediatrics, November 2016, VOLUME 138 / ISSUE Supplement 1, Supplement_1/S42.abstract, November 2016.

Interventions in pregnancy are especially problematic because of the complex physiology of the condition and the possibility of causing short- and long-term adverse consequences in both the mother and her offspring. The continuing story of diethylstilbestrol (DES), a synthetic estrogen, shows the importance of caution when evaluating the merits of interventions involving pregnant women. With regard to DES, investigators believed that pregnancy loss was caused in part by a decrease in estrogen and that administering DES to pregnant women would help maintain a healthy pregnancy. Moreover, because endogenous estrogen concentrations increase dramatically during a healthy pregnancy, supplementation with DES was deemed harmless. During its early years of use, DES was administered to women with threatened pregnancy loss or a history of pregnancy loss. Eventually, DES was advertised to the medical community for “routine prophylaxis in ALL pregnancies” and administered to women with otherwise healthy pregnancies.

By the time DES was formally evaluated, it was standard of care in high-risk obstetrics practices. The first clinical trial to determine the efficacy of DES, reported in 1953, showed that DES did not improve pregnancy outcome. (Indeed, a subsequent reanalysis of the data revealed that DES increased the risk of spontaneous abortion, preterm birth, and neonatal death) Despite lack of evidence supporting a benefit, DES continued to be prescribed during pregnancy until 1971, when a small study showed a stunning 40-fold increase in the risk of clear cell adenocarcinoma (CCA) of the vagina and cervix in girls and young women who were prenatally exposed to DES. Several months later, the Food and Drug Administration issued a bulletin indicating that the use of DES was contraindicated in pregnancy. By then, however, millions of women, along with their sons and daughters, had been needlessly exposed.

In addition to the increased risk of CCA of the vagina and cervix, daughters exposed in utero to DES also suffered from an increased occurrence of reproductive tract abnormalities, infertility, and pregnancy complications; earlier menopause; twice the incidence of cervical dysplasia; and a possible elevated risk of breast cancer and continued increased risk of CCA in middle age. Recent preliminary data indicate the possibility of an increased risk of cardiovascular disease and diabetes in the prenatally exposed women. Mothers administered DES during pregnancy have an increased risk of breast cancer incidence and mortality. Sons who were exposed in utero have an increased risk of genitourinary defects and a possible increase in testicular cancer. The possibility of epigenetic transmission with consequent adverse outcomes in the offspring of prenatally exposed women is under investigation. Preliminary findings showed increased menstrual irregularity and a possible excess of ovarian cancer in very young women.

The link between prenatal DES exposure and subsequent adverse health outcomes, most of which are fairly common, may easily have escaped detection. The investigation of DES outcomes was initiated solely because a rare tumor occurred in a cluster of cases at an unusually young age, decades before the usual age of presentation. This historical example underscores the necessity of carefully weighing the risks and benefits of interventions in pregnancy and long-term monitoring of the health outcomes in mothers and offspring.

Whether and/or when to use pharmaceutical intervention in pregnancy continues to pose special challenges. At the present time, progesterone used to prevent pregnancy loss appears to be effective, although more data are needed. Thus far, there is little evidence of short-term adverse consequences for the offspring, but continued monitoring of mothers and offspring is warranted to identify any short- or long-term adverse effects. The use of progestins for luteal phase and early pregnancy support after in vitro fertilization is routine, and there are even fewer data on potential short- and long-term risks of this therapy. The tragic legacy of DES supports a cautious approach to the use of pregnancy interventions and assiduous appraisal of their effects.

Rebecca Troisi, Elizabeth E. Hatch, Linda Titus,
Reviewed by Dr Robert Hoover,

Click to download the full paper.

More DES DiEthylStilbestrol Resources

Cancer Risk in Women Exposed to Diethylstilbestrol in Utero

Significant increase of breast cancer in DES Daughters

2015 Study Abstract

OBJECTIVE
To evaluate the overall cancer risk, primarily breast cancer, for women exposed to diethylstilbestrol (DES) in utero in France.

METHODS
A cohort of 3 436 prenatally DES exposed women and a comparable cohort of 3256 unexposed women were recruited retrospectively from voluntary responses to questionnaires, and cases were ascertained by medical history at the time of recruitment.

Cancer Risk in Women Exposed to Diethylstilbestrol in Utero, US National Library of Medicine National Institutes of Health, Therapie, NCBI PubMed PMID: 26071143, 2015 Sep-Oct.

Image credit Amy the Nurse.

RESULTS
One hundred ninety-five cancers were observed in exposed women (136 breast cancers, and 59 in other sites) and 141 cancers in unexposed women (90 breast cancers, and 51 others). A significant increase of breast cancers was found in exposed women, with a multivariate incidence rate ratio of 2.10 (95% CI 1.60-2.76) when compared with unexposed women. When exposed women were compared with the general population in France, the standardized incidence ratio was 2.33 (95% CI 1.93-2.72).

CONCLUSION
Our results suggest a significant increase of breast cancer in prenatally DES exposed women when compared with unexposed women and with the general population. For other cancers, except clear cell carcinoma of the cervix or vagina, there was a global non-significant increase.

More DES DiEthylStilbestrol Resources

Impact of prenatal exposure to diethylstilbestrol (DES) on psychological outcome

A national survey of DES daughters and unexposed controls

2017 Study Abstract

To explore whether prenatal exposure to diethylstilbestrol (DES) is associated with increased risk of poor psychological outcome independently of the occurrence of major somatic complications related to DES exposure.

Data on health outcome were collected in women prenatally exposed to DES (n = 2566) and unexposed women (n = 2967) recruited in a French national survey.

Women prenatally exposed to DES were 1.7 times more likely to have consulted a mental health specialist compared to unexposed women (adjusted odds ratio = 1.69, 95% confidence interval 1.47-1.96), independently of demographic characteristics, poor gynecological or obstetrical outcome, or history of cancer.

Impact of prenatal exposure to diethylstilbestrol (DES) on psychological outcome: a national survey of DES daughters and unexposed controls, US National Library of Medicine National Institutes of Health, Archives of women’s mental health, NCBI PubMed PMID: 28064340, 2017 Jan 7.

Image credit Alessandra.

Frequency of consultation with a mental health specialist in persons with a history of gynecological complications or cancer was comparable in women prenatally exposed to DES and unexposed women.

Findings regarding psychological outcome obtained in the high-risk group of women prenatally exposed to DES may contribute to improving identification of psychological needs of all women presenting with gynecological abnormalities.

More DES DiEthylStilbestrol Resources

14 Filles Distilbène, telles qu’elles sont…

3’35 pour “parler” autrement du DES…

Vidéo publiée le 13 janvier 2017 par la chaine Association Réseau DES FRANCE DISTILBENE.

Une série de portraits de femmes touchées, traversées, abîmées par le Distilbène DES.

“Je veux que chaque femme touchée par le DES dans le monde puisse s’y retrouver : française, américaine, australienne, hollandaise, africaine, allemande… Je veux que ce témoignage muet soit entendu dans toutes les langues par toutes les cultures. Je souhaite qu’il permette aux femmes qui y participeront de déposer quelque chose derrière la caméra et de repartir plus légères et fières du courage qu’elles ont eu à le faire. Je veux que la gravité et la beauté de ces visages sans mots résonnent puissamment aux oreilles des lobby, dans les couloirs de la commission européenne, dans l’antichambre des tribunaux où se rejoue David contre Goliath à chaque procès de ‘fille DES’ “

Laetitia Dormoy, créatrice du projet.
Sources : la chronique de Marie Darrieussecq.

Le Distilbène DES, en savoir plus

Normal vs. T-shaped Uterus

Utero-salpingography showing Diethylstilboestrol exposure in-utero uterus

Diethylstilboestrol (DES) exposure in-utero has been shown to have a potentially negative impact on pregnancy. Negative effects include an increased risk of early pregnancy loss, ectopic gestation and infertility.

These women may also present reproductive tract abnormalities leading to pregnancy complications. The most common anomalies include uterine defects such as T-shaped uterus or hypoplastic uterine cavity.

Image Sources

More DES DiEthylStilbestrol Resources