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Developmental biology - Cell Metabolism

Taking hormones affects your DNA

Low doses of endocrines leads to epigenetic changes in DNA of pregnant pigs...


Chemicals such as bisphenol A or phthalates (used to soften plastics) may be connected to rising infertility rates among men and women. They are "Endocrine Disrupting Chemicals" or commonly referred to as EDCs.

In an experiment with pigs, researchers from ETH Zurich and the Technical University of Munich for the first time demonstrate that even extremely low doses of an endocrine disruptor - in this case, an endogenous oestrogen - lead to epigenetic changes in a pregnant sow's DNA. The same changes were seen in all the sows' embryos, and similar changes occurred in these same offspring as adults.

The study is published in the journal Scientific Reports.

A time window of increased sensitivity

"EDCs, especially oestrogens, are highly effective even at very low doses," says Susanne Ulbrich, Professor of Animal Physiology at ETH Zurich. Whether endo or exogenous, chemicals have an effect and how strong that effect is depends on the point in time the exposure occurs. Ulbrich explains: "For example, the body is particularly susceptible to external disruptive hormonal influence during the embryonic phase (the First Trimester) of early pregnancy."

Ulbrich and her colleagues examined exactly such a time window in their study with pigs. Simulating the intake of EDCs via drinking water or food, they exposed pregnant sows to varying doses of oestradiol-17, a natural oestrogen. Exposure was via daily feeding over the course of the entire gestation or just during the first ten days following fertilisation.

The lowest dose administered corresponded to what is considered an acceptable daily intake for humans (0.05 micrograms per kilogram body weight). In the same experiment, scientists administered two other dosages: one close to the "no observed effect" level (10 micrograms per kilogram body weight daily) as well as a higher dosage (1,000 micrograms per kilogram daily) - to simulate an 'accidental taking of the contraceptive pill' in early pregnancy. The experiment included a control group of pigs that did not receive any oestradiol.

The scientists then tested for gene expression (function) and epigenetic changes in various tissues of the pregnant sows and their offspring for both (1) the ten-day-old embryos (blastocysts) and (2) one-year-old mature females.

Changes in gene expression
Of the 57 oestrogen-related genes, oestradiol affected tissue-specific expression in about two dozen. Most of these genes regulate cell cycle or suppress the growth of tumours. The changes were the most pronounced in pregnant sows' corpora lutea, endometria, hearts and skeletal muscle.

In addition, they observed epigenetic changes in select genes in their livers. Similar changes to those same genes also appeared in both embryos and adults grown from those embryos. The researchers were able to determine epigenetic patterns of these genes and how they were altered by looking for the addition or removal of small chemical groups - known as methyl groups - at strategic points on the DNA molecules. These methylation points can alter the expression (function) of a selected gene, and in turn change the cell's function.

Lasting changes

"We didn't find any serious impact on the health of the adult offspring. And, we saw only slight changes, in bone density and the ratio of fat to muscle mass," Ulbrich explains. However, it remains unclear what long-term cumulative affects such epigenetic changes might have, and whether the interaction of the many EDCs humans are exposed to on a daily basis render the situation more acute.

"There is an urgent need to observe this phenomenon over several generations in a long-term study," adds Professor Ulbrich. "Epigenetic changes can emerge within just one generation, but in certain circumstances they will continue to be transmitted to succeeding generations. We can already clearly demonstrate that hormones, even after a brief exposure period and in very small amounts, can have a measurable effect."

Based on these results, Ulbrich, an expert in reproductive physiology, is calling for a re-assessment of the acceptable daily intake value and the ambiguity of the dosage terminology:"no observed effect level." She notes that pigs' hormonal changes during pregnancy closely resemble those in humans, so results of the study are highly applicable to humans and may be more appropriate than findings from studies in mice.

Ulbrich says no matter how tiny the oestrogen dosage, epigenetic changes she and her team observed gave clear evidence that test subjects were exposed to an EDC. Ulbrich: "How exactly that resulted in changes and what impact these changes will have in the long run, requires closer study. The sensitivity of embryos in the early days of pregnancy should under no circumstances be underestimated."

Abstract
Endocrine disrupting chemicals (EDC) interfere with the natural hormone balance and may induce epigenetic changes through exposure during sensitive periods of development. In this study, the effects of short-term estradiol-17 (E2) exposure on various tissues of pregnant sows (F0) and on day 10 blastocysts (F1) were assessed. Intergenerational effects were investigated in the liver of 1-year old female offspring (F1). During gestation, sows were orally exposed to two low doses and a high dose of E2 (0.05, 10, and 1000 g/kg body weight/day). In F0, perturbed tissue specific mRNA expression of cell cycle regulation and tumour suppressor genes was found at low and high dose exposure, being most pronounced in the endometrium and corpus luteum. The liver showed the most significant DNA hypomethylation in three target genes; CDKN2D, PSAT1, and RASSF1. For CDKN2D and PSAT1, differential methylation in blastocysts was similar as observed in the F0 liver. Whereas blastocysts showed hypomethylation, the liver of 1-year old offspring showed subtle, but significant hypermethylation. We show that the level of effect of estrogenic EDC, with the periconceptual period as a sensitive time window, is at much lower concentration than currently presumed and propose epigenetics as a sensitive novel risk assessment parameter.

Authors: Vera A. van der Weijden, Veronika L. Flter and Susanne E. Ulbrich.


Acknowledgements
V.v.d.W. performed the analytical experiments, analysed the data and wrote the manuscript. V.L.F. conceived of the study, performed the animal experiments, wrote the manuscript. S.E.U. conceived of the study, supervised data analysis, and critically reviewed the manuscript. All authors reviewed the final version of the manuscript.

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Jul 9, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




The experimental plan reflects how taking twice daily oral estradiol-17 (E2) (RED BARS) affected pregnant pigs (F0). Slaughtered one hour after their last treatment, embryos (F1) were flushed from each pig uterus. Female offspring (F1) were then tested at one year of age during the short period of sexual quiet between two estrus periods, when the uterus is preparing for a fertilized egg.


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