Current perspective of diethylstilbestrol (DES) exposure in mothers and offspring

DES is one of the major disasters in medicine and it is mandatory to tackle and promote programs of DES-related cancer prevention

2017 Study Highlights

  • Diethylstilbestrol (DES) is a synthetic, non-steroidal estrogen of the stilbestrol group acting as an endocrine disruptor.
  • Adverse pregnancy outcomes, infertility, cancer, and early menopause have been identified in women exposed to DES, their offspring, and subsequent generations.

Abstract

Diethylstilbestrol (DES) was an orally active estrogen prescribed to the pregnant women to prevent miscarriages.

DES is known as a ‘biological time bomb’ and long-term effects of DES have been recorded in the mothers exposed to DES and their offspring (DES-daughters and DES-sons). Adverse pregnancy outcomes, infertility, cancer, and early menopause have been discovered in women exposed to DES, and some events occur in their offspring and subsequent generations. An increased risk of breast cancer is not limited to the DES-exposed daughters.

There is an urgent need to find ways to stop the inheritance cycle of DES and prevent adverse effects of DES in the future generations. The present article reviews the health implications of DES exposure and screening exams currently recommended to DES daughters and their offspring.

  • Reproductive toxicology (Elmsford, N.Y.)., Volume 71, August 2017, Pages 71–77, 2017 Apr 28. Image credit jason wilson.
DES DiEthylStilbestrol Resources

Methylomic changes in individuals with psychosis, prenatally exposed to endocrine disrupting compounds

Lessons from diethylstilbestrol : psychosis associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity in the DES-exposed.

2017 Study Abstract

BACKGROUND
In the Western world, between 1940 and 1970, more than 2 million people were exposed in utero to diethylstilbestrol (DES). In exposed individuals, and in their descendants, adverse outcomes have been linked to such exposure, including cancers, genital malformations, and less consistently, psychiatric disorders. We aimed to explore whether prenatal DES exposure would be associated with DNA methylation changes, and whether these epigenetic modifications would be associated with increased risk of psychosis.

METHODS
From 247 individuals born from mothers exposed to DES, we selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to DES. We performed a methylome-wide association study using HumanMethylation450 DNA Analysis BeadChip® in peripheral blood. We analyzed methylation changes at individual CpGs or regions in exposed (n = 37) versus unexposed individuals (n = 32). We also compared exposed individuals with (n = 7) and without psychosis (n = 30).

RESULTS
There were more individuals with schizophrenia in the DES-exposed group. We found no significant differences between exposed and unexposed individuals with respect to differentially methylated CpGs or regions. The largest difference was in a region near the promoter of an ADAMTS proteoglycanase gene (ADAMTS9). Compared to exposed individuals without psychosis, exposed individuals with psychosis had differential methylation in the region encompassing the gene encoding the zinc finger protein 57 (ZFP57).

CONCLUSIONS
In utero exposure to DES was not associated with methylation changes at specific CpG or regions. In exposed individuals, however, psychosis was associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity.

  • Image credit Morgaine. Read and download the full study (free access) on the NCBI, PubMed, PMC5390994, 2017 Apr 13.
DES DiEthylStilbestrol Resources

Diethylstilbestrol induces oxidative DNA damage

DES exposure results in apoptosis of spermatogonial stem cells in vitro

2017 Study Highlights

  • Exposure of the spermatogonial stem cells to DES produced significant increases in superoxide anion, DNA damage and apoptosis.
  • The male reproductive system can be disrupted by foetal exposure to DES.
  • The flavonoid quercetin reduced intracellular superoxide anions induced by DES.

Abstract

The spermatogonial stem cells (SSCs) are the only germline stem cells in adults that are responsible for the transmission of genetic information from mammals to the next generation. SSCs play a very important role in the maintenance of progression of spermatogenesis and help provide an understanding of the reproductive biology of future gametes and a strategy for diagnosis and treatment of infertility and male reproductive toxicity.

Androgens/oestrogens are very important for the suitable maintenance of male germ cells. There is also evidence confirming the damaging effects of oestrogen-like compounds on male reproductive health.

Diethylstilbestrol induces oxidative DNA damage, resulting in apoptosis of spermatogonial stem cells in vitro, US National Library of Medicine National Institutes of Health, Toxicology, NCBI PubMed PMID: 28315349, 2017 Mar.

Image credit Alessandro.

We investigated the effects in vitro, of diethylstilbestrol (DES) on mouse spermatogonial stem cells separated using Staput unit-gravity velocity sedimentation, evaluating any DNA damage using the Comet assay and apoptotic cells in the TUNEL assay.

Immunocytochemistry assays showed that the purity of isolated mouse spermatogonial cells was 90%, and the viability of these isolated cells was over 96%. Intracellular superoxide anion production (O2) in SSCs was detected using p-Nitro Blue Tetrazolium (NBT) assay. The viability of cells after DES treatment was examined in the CCK8 (cell counting kit-8) cytotoxicity assay.

The study results showed that DES-induced DNA damage causes an increase in intracellular superoxide anions which are reduced by the flavonoid, quercetin. Investigating the molecular mechanisms and biology of SSCs provides a better understanding of spermatogonial stem cell regulation in the testis.

DES DiEthylStilbestrol Resources

Autism pathway from gene to brain found by UNC scientists

Researchers discover a potential cause of autism

Key enzymes are found to have a ‘profound effect’ across dozens of genes linked to autism. The insight could help illuminate environmental factors behind autism spectrum disorder and contribute to a unified theory of how the disorder develops.

… “Mark Zylka, a professor at the UNC School of Medicine, and his team believe they have figured out the rough outlines of one such pathway, from the tiny genetic glitch on the gene to the physical changes that the glitch causes in the brain. Like many discoveries, it piggybacked on the work of others, involved a little luck and has raised more questions for researchers. ” …

… “Both Zylka and Birnbaum of the National Institute of Environmental Health Sciences believe that in many cases, genetic mutations and outside factors probably work together to trigger autism. As Birnbaum puts it, people whose DNA puts them at risk may be “kind of pushed over the edge” when exposed to one or more of these triggers. With more and more people living with autism, it is becoming increasingly urgent to solve this question.” …

Sources and more information

  • UNC scientists pinpoint how a single genetic mutation increases autism risk,
    newsobserver, AUGUST 6, 2015.
  • UNC scientists trace autism ‘pathway’ from gene to brain,
    newsobserver, AUGUST 19, 2015.
  • Researchers discover a potential cause of autism,
    news.unchealthcare, August 28, 2013.