Epigenetic Effects May Influence PCOS Over Three Generations


March 15, 2021

4 minutes to read

Source / Disclosures

Source: Healio interviews

Disclosures: Boutillier and Giacobini state that their research has been supported by the European Research Council as part of the European Union’s Horizon 2020 research and innovation program. Dunaif does not report any relevant financial information.

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The neuroendocrine, reproductive and metabolic dysfunctions associated with polycystic ovary syndrome are transmitted in mice exposed prenatally to anti-Müllerian hormone for at least three generations, new data show.

In an analysis using genome-wide methylated DNA immunoprecipitation, researchers also found that several differentially methylated signatures found in the ovaries of PCOS-like mice are also present in blood samples from a small cohort. women with PCOS and daughters born to women with PCOS. .

Boutillier is research director at the Laboratory of Postnatal Brain Development and Plasticity, Lille Neuroscience & Cognition, and the University of Strasbourg-CNRS, France.

“We know that PCOS has a strong hereditary component; daughters of mothers with PCOS have a five times higher risk of being diagnosed with PCOS later in life compared to daughters born to healthy women ”, Paulo Giacobini, doctorate, The INSERM research director at the Postnatal Brain Development and Plasticity Laboratory, Lille Neurosciences & Cognition, France, told Healio. “Despite this evidence, we know that genetic variation does not fully explain the high incidence of the disease. This is why we and many other scientists have suspected for years that environmental factors – that is, hormonal disturbances that can occur in utero – could possibly predispose to the onset of the disease.

Paul Giacobini

Family reunification and twin studies indicate that PCOS is a pathology with a strong hereditary component; However, human PCOS loci identified by genome-wide association studies account for less than 10% of heritability, wrote Giacobini and colleagues in a study published in February in Cell metabolism. Environmental and epigenetic mechanisms may play an important role in the etiology of PCOS, the researchers wrote.

Mouse, human data

Giacobini, Anne-Laurence Boutillier, Doctorate, CNRS, research director at the Laboratory of Postnatal Brain Development and Plasticity, Lille Neuroscience & Cognition, and the University of Strasbourg-CNRS, France, and his colleagues injected pregnant mothers with anti-Müllerian hormone (AMH) or phosphate buffered saline (controls). Females injected with AMH exhibited all of the major criteria for PCOS in humans, including hyperandrogenism, oligo-anovulation, increased luteinizing hormone, and impaired fertility. In addition, the third generation female offspring of the AMH injected mice had higher body weight and fat mass and elevated blood sugar compared to control mice. The researchers then performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control mice and third-generation PCOS-like mice, revealing alterations in expression. ovarian genes in the third generation of mice exhibiting PCOS-like qualities.

The researchers then evaluated blood samples from 32 women with PCOS (five with a mother with PCOS) and 15 women without PCOS (three with a mother with PCOS) and found that DNA hypomethylation regulates key genes associated with PCOS. Several of the differentially methylated genes were also altered in blood samples from women with PCOS compared to healthy controls.

“Our first surprise came when we discovered that there was global methylation that could be transmitted,” Boutillier told Healio. “Another real surprise is that it shows up in the blood of women with PCOS. More should be done to try to understand how this can be, because it has great potential in terms of therapy and diagnosis. “

Giacobini noted that the study cohort was small.

“This should be repeated in larger cohorts, possibly separated by the PCOS phenotype, to see if the epigenetic signatures are limited to certain individuals,” Giacobini said. “The other thing that we haven’t fully captured is dissecting how AMH causes these epigenetic changes. Is it direct? Indirect? By testosterone? This opens up many investigations to carefully dissect what is behind these changes. “

Boutillier said the results demonstrate the impact of exposure to hormones during fetal life, possibly on a multigenerational timescale, in the context of PCOS.

“Because it is an epigenetic mechanism and not a genetic mutation, it is reversible,” Boutillier said. “This is important. Genetic diseases can be so difficult to tackle with therapy, but with gene therapy we can hope for better things. But here, showing that PCOS is epigenetically modified and transmitted suggests reversibility. “

Role of epigenetics

Andrea Dunaif, MD, Professor and Head of the Hilda and J. Lester Gabrilove Division of Endocrinology, Diabetes and Bone Diseases at the Mount Sinai Health System and a Endocrine today A member of the editorial board, who was not involved in the study, called the results exciting, while noting that the sample of women in the study – especially daughters of mothers with PCOS – was short and older than typical female cohorts, with an average age of 24.

Andrea Dunaif

“The take home message is, yes, these [data] are exciting, but some things are not addressed, and that could be a mechanism for a subset of women, ”Dunaif said in an interview.

Data from other studies suggest that genetics play a role in the heritability of PCOS. In a study that also looked at human and mouse data, published in December in Natural medicine, Sanjiv Risal, Doctorate, a postdoctoral fellow in the Department of Physiology and Pharmacology at the Karolinska Institutet in Stockholm, and colleagues assessed how obesity and high prenatal androgen levels in women with PCOS affect offspring, using Swedish data based on a register and data from a case-control study carried out in Chile. The researchers found that female mice exhibiting PCOS-like traits induced by late injection of dihydrotestosterone, with or without obesity, produced female offspring with PCOS-like reproductive and metabolic phenotypes.

“Girls in the case-control study showed typical PCOS reproductive phenotypes, including hyperandrogenism, irregular menstrual cycles, and polycystic ovarian morphology, as well as specific metabolic disturbances, including increased waist circumference, BMI. higher and higher diastolic blood pressure, ”wrote Risal and colleagues. . “Although physiological discrepancies exist between mice and humans, we have provided several evidence that prenatal androgen exposure alone, representing lean women with PCOS, predisposes female offspring to a PCOS-like phenotype, which is transmitted to subsequent generations. “

Dunaif said the robust and replicated genetic literature now shows that there is “certainly a genetic component” to PCOS that can span generations.

“There is no precedent for saying it lacks heritability and everything is epigenetic,” Dunaif said. “You can show epigenetic effects, but you can’t show in complex traits – like diabetes, obesity, or PCOS – that it’s all epigenetic and not genetic.”

Most likely, Dunaif said, genetic variants influence the changes that predispose women to developing PCOS, which are then amplified by epigenetic effects, such as prenatal or environmental exposures.

“[Epigenetics] is something that can play a role in PCOS, ”Dunaif said.

Giacobini, who said researchers “still don’t have the full picture,” said the new data should stimulate further research into epigenetic treatments in PCOS combined with phenotypic investigations. In the Cell metabolism study, treating third generation PCOS mice with neuroendocrine, reproductive and metabolic phenotypes normalized by the methyl donor S-adenosylmethionine.

“This could open up new perspectives in diagnostics and therapeutic pathways,” Giacobini said. “This is the main message for me.”

The references:

Mimouni NEH, et al. Cell Metab. 2021; doi: 10.1016 / j.cmet.2021.01.004.

Risal S, et al. Nat Med. 2019; doi: 10.1038 / s41591-019-0666-1.

For more information:

Anne-Laurence Boutillier, PhD, CNRS, contactable at [email protected]

Andrea Dunaif, MD, can be contacted at [email protected]

Paulo Giacobini, doctorate, contactable at [email protected]


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