Transgenerational transmission of DES effects through epigenetic modifications

The history of Distilbène® (Diethylstilbestrol) told to grandchildren – the transgenerational effect

2015 Study Abstracts

Exposure window

The foetal period is particularly conducive to the induction of abnormalities induced by exposure to DES. This may be due to the importance of sex steroids in controlling the development and differentiation of the genital tract. It is also possible that DES is minimally linked with carrier proteins (SHBG poorly secreted by the foetus or alpha-fetoprotein), and that there is an enzymatic immaturity affecting detoxification enzymes, so that defence mechanisms are still partially developed, such as the blood-testis barrier. The importance of the exposure window is also well illustrated by the phenotype difference observed in the mouse exposed during prenatal or neonatal period. Neonatal pre-exposure also leads to the development of uterine cancer in females in adulthood, while these lesions are not found in animals exposed during the prenatal period. In the same way, foetal exposure to weak doses of DES leads to an increase in prostate cancer in male adult animals with an increase in the number of androgen receptors.

Epigenetic modifications

It is likely that by reproducing in rodents the harmful effects ofin utero exposure to DES, allowed the first argumentsin favour of epigenetic modifications originating from the programming of adult diseases. Of course, we cannot exclude the mutagenic effect of high doses of DES that were prescribed to pregnant women. However, such abnormalities that could be induced by oxydated oestrogen derivatives were never really highlighted. Expression of genes involved in the development and structural differentiation of the reproductive tract such as the HOX genes has been shown to be disrupted without DNA structure modifications. In 1997, Li et al. first illustrated epigenetic modifications in an oestrogen-dependent gene, i.e., lactoferrin, determined in the uteri of mice treated with DES neonatally. This gene is overexpressed in adulthood, due to its promoter demethylation, and this overexpression is dose-dependent on neonatal exposure to DES and is associated with susceptibility to uterine cancer in adulthood. This seemingly innocuous experience is an early example of a modification that is not genetic, but epigenetic, induced by foetal or perinatal hormonal environment modulation that will be expressed afterwards in adulthood by induced malignant tumours. By adulthood, it is presumable that these epigeneticmodifications, as demonstrated in hamsters, equally affect the expression of oestrogen-regulated genesin the uterus such as c-jun, c-fos, c-myc, BALC, BCL-2 and BCLX and are involved in uterine cell proliferation and apoptosis as demonstrated in mouse for c-fos.

Transgenerational transmission mechanisms

These epigenetic modifications are also highlighted in a very interesting model developed by Anway et al. This model involved rats that were exposed in utero to the oestrogen-mimicking organochlorine pesticide methoxychlor or to the anti-androgen, antifungal agent, vinclozolin. Their male offspring developed subfertility with decreased production in sperm quality and an increase in post-meiotic germ cell apoptosis associated with epigenetic modifications (hyper- or hypomethylation of CpG islands) of the promoter region from genes expressed by male germ cells. Surprisingly, these changes are found up to the fifth generation, transmitted by the male and not by the female, and therefore transmitted by sperm, which, except for the second-generation male, was not directly exposed to the endocrine disruptor. As we have seen, this DES transgenerational transmission was also found in mice after neonatal exposure in a uterine cancer model during the third generation, or following exposure to a harmful foetal environment with respect to nutrition, stress, hormonal or metabolic disruption, chemical pollutants. Theoretically, in the early stages of gametogenesis, and during the first divisions of the fertilized egg, there is an epigenetic counter reset and the implementation of imprinting phenomena. The molecular mechanisms which may explain the maintenance of multigenerational epigenetic modifications induced by environment are still poorly understood. However, recent works suggest the involvement of small non-coding RNAs, such as the microRNAs proposed in various mouse models, where phenotypic changes could be induced by simply injecting the fertilised egg with microRNA from animal sperm, which has been exposed to the harmful environment and which is responsible for the observed epigenetic modifications.

Sources

  • The history of Distilbène® (Diethylstilbestrol) told to grandchildren – the transgenerational effect, Annales d’endocrinologie, NCBI PubMed PMID: 25934356, 2015 Jul.
  • Featured image credit Kevin Delvecchio.
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