Can a Pregnancy Drug Trigger ADHD Generations Later ? You Bet !

Aattention-Deficit/Hyperactivity Disorder Much More Common in Grandchildren of Women Who Were Prescribed the DES Drug in Pregnancy

A cohort study – Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits – published May 21, 2018, shows that prenatal diethylstilbestrol exposure may lead to neurodevelopmental disorders across several generations : DES grandchildren are more likely to be diagnosed with ADHD (36% to 63%).

The audio summary above reviews the cohort study that uses Nurses’ Health Study data to investigate associations between diethylstilbestrol (DES) use in pregnancy and self-reported development of ADHD in grandchildren.

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Much Higher Risk of ADHD in DES GrandChildren

Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits

New research published today, May 21, 2018, shows that prenatal diethylstilbestrol exposure may lead to neurodevelopmental disorders across several generations : DES grandchildren are more likely to be diagnosed with ADHD (36% to 63%).

Key Points

Question
Is exposure to diethylstilbestrol during pregnancy associated with adverse multigenerational neurodevelopmental outcomes?

Findings
A cohort study of 47 450 women in the Nurses’ Health Study II found significantly elevated odds for attention-deficit/hyperactivity disorder in the grandchildren (third generation) of users of diethylstilbestrol, a potent endocrine disruptor.

Meaning
Exposure to endocrine disruptors during pregnancy may be associated with multigenerational neurodevelopmental deficits.

Abstract

Importance
Animal evidence suggests that endocrine disruptors affect germline cells and neurodevelopment. However, to date, the third-generation neurodevelopmental outcomes in humans have not been examined.

Objective
To explore the potential consequences of exposure to diethylstilbestrol or DES across generations—specifically, third-generation neurodevelopment.

Design, Setting, and Participants
This cohort study uses self-reported health information, such as exposure to diethylstilbestrol during pregnancy and attention-deficit/hyperactivity disorder (ADHD) diagnosis, from 47 540 participants enrolled in the ongoing Nurses’ Health Study II. The 3 generations analyzed in this study were the participants (F1 generation), their mothers (F0 generation), and their live-born children (F2 generation).

Main Outcomes and Measures
Participant- and mother-reported exposure to diethylstilbestrol during pregnancy and physician-diagnosed child ADHD.

Results
The total number of women included in this study was 47 540. Of the 47 540 F0 mothers, 861 (1.8%) used diethylstilbestrol and 46 679 (98.2%) did not while pregnant with the F1 participants. Use of diethylstylbestrol by F0 mothers was associated with an increased risk of ADHD among the F2 generation: 7.7% vs 5.2%, adjusted odds ratio (OR), 1.36 (95% CI, 1.10-1.67) and an OR of 1.63 (95% CI, 1.18-2.25) if diethylstilbestrol was taken during the first trimester of pregnancy. No effect modification was observed by the F2 children’s sex.

Conclusions and Relevance
This study provides evidence that diethylstilbestrol exposure is associated with multigenerational neurodevelopmental deficits. The doses and potency level of environmental endocrine disruptors to which humans are exposed are lower than those of diethylstilbestrol, but the prevalence of such exposure and the possibility of cumulative action are potentially high and thus warrant consideration.

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Fetal Origin of Adult Disease

Abstract from “Environmental Exposures and Adverse Pregnancy Outcomes: A Review of the Science”

During the last two decades, chronic disease has replaced infectious disease as the major focus of public health concern. The top 4 leading causes of death in the United States are chronic diseases. There remains much unknown about the etiology of many chronic conditions, which in most cases is probably multifactorial. Studies from the 1990s found that effects on the fetal environment, such as through poor or inadequate nutrition, can result in an increased risk of adult onset of chronic conditions, such as coronary heart disease. This has been called the fetal origins hypothesis (also known as the Barker theory), which proposes that external influences on the fetal environment can increase the risk of later disease in adulthood.

Diethylstilbestrol (DES)—a synthetic estrogen given to US women between 1938 and 1971 to prevent pregnancy complications illustrates the fetal origins of later in life disease. In utero DES exposure left mature female offspring at increased risk of clear cell adenocarcinoma of the vagina and cervix, breast cancer, structural reproductive tract anomalies, an increased infertility rate, and poor pregnancy outcomes, while male offspring have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. These observed human effects have been confirmed in numerous animal models, which have also predicted changes later found in DES-exposed humans, such as increased incidence of uterine fibroids, oviductal malformations, and second generational effects such as increased menstrual irregularities and possibly ovarian cancer in DES granddaughters and increased hypospadias in DES grandsons.

Diethylstilbestrol shows the adverse effects of fetal exposures to synthetic chemicals may not be apparent at birth or even for many years afterward, and that continued monitoring of this cohort of exposed children and grandchildren is necessary to inform potential effects of prenatal exposures to other contaminants.

Reference. Image credit Hush Naidoo.

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Autism outcomes in DES grandchildren : support the first study !

Help Fund Research into Neurodevelopment and Behavioral Impacts of DES

” My name is Jill Escher. I’m a science philanthropist who kickstarts pioneering research projects investigating the generational toxicity of certain potent exposures, including DES, tobacco and other drugs. While I’m not a DES daughter, I was exposed to a multitude of other synthetic steroid hormones in utero as part of a then-popular, if ineffective, “anti-miscarriage” practice. You can read my story here. You can see my science website at GermlineExposures.org.

Based on human, animal, and in vitro studies, as well as family interviews, I hypothesize that diethylstilbestrol DES, along with several other toxic substances, can damage the genomic information in early fetal-stage gametes. For a variety of reasons, the early gamete is probably the single most vulnerable stage of the human lifecycle. Damage during that phase, which could be genetic or epigenetic in nature, can manifest as abnormal development in the subsequent offspring.

For example, I hypothesize that the intensive synthetic steroid hormone drug regimen to which I was subjected as a fetus subtly deranged the molecular programming of my early eggs. This derangement I believe resulted in the starkly abnormal neurodevelopment — autism — of my children. I have met many other families with the same story.

Support Research into the Far-Reaching Generational Toxicity of DES, germline exposures, 10/10/2016.

Autism by pycik.

I am pleased to announce that I am funding the world’s first research study into the grandchild effects of DES (3d gen), looking specifically at neurodevelopment and behavioral impacts. This work will be done in collaboration with Harvard University, based on the Nurses’ Health Study II.

Thank you for your support! If you have any questions, please do not hesitate to email me. “

Jill Escher, President of Autism Society San Francisco Bay Area, 10/10/2016.

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Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters

The increased risk of developing breast cancer – for women exposed to DES – may extend to their daughters and granddaughters as well

Abstract:

image of PubMed NCBI The Endocrine Society logo
The increased risk of developing breast cancer – for women exposed to DES – may extend to their daughters and granddaughters as well.

The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression.Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.

Sources:
  • Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters,NCBI, PMID: 25032259 PMCID: PMC4053091, 2014/10/30. Full study PMC4053091.
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Findings in Female Offspring of Women exposed in Utero to DiEthylStilbestrol

None of the third-generation daughters were found to have changes usually associated with DES exposure

Abstract

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None of the third-generation daughters were found to have changes usually associated with DES exposure.

OBJECTIVE:
To examine a group of women (third-generation daughters) whose mothers were exposed in utero to diethylstilboestrol (DES) and compare their findings on pelvic examination with those noted in their mothers.

METHODS:
Letters were mailed to women documented to have been exposed in utero to DES who had given birth to a female offspring, inviting them to have their daughters come in for a detailed history and pelvic examination. Records of the mothers whose daughters appeared for examination were reviewed, and findings noted at the time of their initial examination were recorded. Detailed pelvic examination of the third-generation daughters included colposcopic examination and iodine staining of the vagina and cervix and Papanicolaou smear. The findings observed in these women were compared with those noted in their mothers at the time of their mothers’ first examination.

RESULTS:
Twenty-eight third-generation daughters were examined. Three of the daughters were delivered from one mother. Review of the mothers’ records indicated that 16 (61.5%) of the mothers exposed to DES during their pregnancy demonstrated structural changes of the cervix, upper vagina, or vaginal epithelial changes consisting of adenosis, nonstaining vaginal epithelium after application of iodine solution, or white epithelium within the vagina. None of the daughters were found to have changes usually associated with DES exposure.

CONCLUSION:
The absence of abnormalities in the lower genital tract in third-generation women compared with the high frequency of these abnormalities in their mothers suggests that third-generation carryover effects of in utero DES exposure are unlikely.

Sources:
  • Findings in female offspring of women exposed in utero to diethylstilbestrolNCBI, PMID: 11814496,
    Obstet Gynecol. 2002 Feb;99(2):197-200.
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Consequences of DiEthylStilbestrol during Pregnancy ; 50 Years later still a Significant Problem

From animal experiments it becomes clear that DES administration to pregnant mice results in an increased incidence of genital tumours not only in the second generation but also in the third

Abstract

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It becomes clear that DES administration during pregnancy resulted in an increased incidence of genital tumours not only in the second generation but also in the third…

Since the 1940s, diethylstilboestrol (DES) has been administered to about three million pregnant women in the United States and in the Netherlands, between 1947 and 1975, to about 220,000.
The most important consequences described are: for DES mothers an increased risk of mammary carcinomas and for DES daughters a 1 in 1000 chance of clear cell adenocarcinoma (CCAC) as well as an increased risk of (pre)malignant abnormalities of the stratified epithelium in the vagina and cervix.
In addition to this, DES daughters frequently have developmental disorders of the cervix and corpus uteri. In connection with this fertilisation disorders have been described as well as unfavourable outcomes of pregnancy: more ectopic pregnancies, abortion and premature birth. DES sons exhibit an increased frequency of several benign abnormalities of the genitalia. The DES problem continues to be an important issue. The entire cohort of DES mothers is in the age group with a high risk of mammary carcinoma. The youngest DES daughters will be of childbearing age for at least another 15 years; the risk of ectopic pregnancies and pre-term labour is increased. The oldest DES daughters are now reaching postmenopausal age. The incidence of CCAC of the vagina and cervix in the population is bimodal, with a second peak at older age. It is still unknown if at this age DES daughters will have an increased incidence of these malignancies.

From animal experiments it becomes clear that DES administration to pregnant mice results in an increased incidence of genital tumours not only in the second generation but also in the third. This has yet to be investigated in humans and deserves special attention.

The legally imposed destruction of patient files after a period of ten years is a serious threat to patient care and scientific investigation, notably in obstetrics and child medicine.

Sources:
  • Consequences of diethylstilbestrol during pregnancy; 50 years later still a significant problemNCBI, PMID: 11530703, Ned Tijdschr Geneeskd. 2001 Apr 7;145(14):675-80.
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Increased Tumors in the Female Descendants of Mice exposed developmentally to DiEthylStilbestrol

An increased incidence of malignant reproductive tract tumors, including uterine adenocarcinoma, was seen in DES lineage mice, apparently transmitted to subsequent generations

Abstract

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Increased susceptibility to tumor formation is apparently transmitted to subsequent generation.

Prenatal exposure to Diethylstilbestrol (DES) has been associated with the subsequent development of reproductive tract abnormalities, including poor reproductive outcome and neoplasia, in experimental animals and humans. Experimental animal studies with chemical carcinogens have raised the possibility that adverse effects of DES may be transmitted to succeeding generations. To evaluate this possibility and to determine if there is a sensitive window of developmental exposure, outbred CD-1 mice were treated with DES during three stages of development: group 1 was treated on days 9-16 of gestation (2.5, 5 or 10 microg/kg maternal body wt), the time of major organogenesis; group II was treated once on day 18 of gestation (1000 microg/kg maternal body wt) just prior to birth; group III was treated on days 1-5 of neonatal life (0.002 microg/pup/day). Female mice (F1) in each group were raised to sexual maturity and bred to control males. As previously reported, fertility of the F1 DES-exposed females was decreased in all groups. Female offspring (DES lineage or F2) from these matings were raised to maturity and housed with control males for 20 weeks. The fertility of these DES lineage female mice was not affected by DES exposure of their ‘grandmothers’. DES lineage mice were killed at 17-19 and 22-24 months of age. An increased incidence of malignant reproductive tract tumors, including uterine adenocarcinoma, was seen in DES lineage mice but not in corresponding controls; the range and prevalence of tumors increased with age. Because uterine adenocarcinomas were seen in all three DES groups, all developmental exposure periods were considered susceptible to the adverse effects of DES. These data suggest that the reduced fertility observed in the DES F1 female mice was not transmitted to their descendants; however, increased susceptibility to tumor formation is apparently transmitted to subsequent generations.

Sources:
  • Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol, NCBI, PMID: 9771938, 1998 Sep;19(9):1655-63.
  • Full text – Carcinogenesis vol.19 no.9 pp.1655–1663, OxfordJournals, 19/9/1655.long 1998.
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