Epigenetic effects may influence PCOS across three generations
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 of women with PCOS and from daughters born to women with PCOS.
“We know PCOS has a strong, heritable component; daughters of mothers with PCOS have a fivefold increased risk for being diagnosed with PCOS later in life compared with daughters born to healthy women,” Paolo Giacobini, PhD, INSERM research director at the Laboratory of Development and Plasticity of the Postnatal Brain, Lille Neuroscience & Cognition, France, told Healio. “Despite this evidence, we know that genetic variation does not fully explain the high incidence of disease. This is why we and many other scientists have suspected for years that environmental factors — meaning hormonal disturbances that might occur in utero — might eventually predispose for the onset of disease.”
Familial clustering and twin studies point to PCOS as a pathology with a strong heritable component; however, the human PCOS loci identified by genome-wide association studies account for less than 10% of heritability, Giacobini and colleagues wrote 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, PhD, CNRS, director of research at the Laboratory of Development and Plasticity of the Postnatal Brain, Lille Neuroscience & Cognition, and the University of Strasbourg-CNRS, France, and colleagues injected pregnant dams with anti-Müllerian hormone (AMH) or phosphate buffered saline (controls). The AMH-injected females manifested all the major criteria of PCOS in humans, including hyperandrogenism, oligo-anovulation, increased luteinizing hormone and impaired fertility. Additionally, the third-generation female offspring of the AMH-injected mice had a higher body weight and fat mass and elevated glucose compared with control mice. The researchers then performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice, revealing alterations in ovarian gene expression in the third generation of mice with PCOS-like qualities.
Researchers then assessed 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 with healthy controls.
“Our first surprise came when we found out there was a global methylation that could be transmitted,” Boutillier told Healio. “Another real surprise is that this shows up in the blood of women with PCOS. More should be done to try to understand how this can be, because it has strong potential in terms of therapeutics and diagnostics.”
Giacobini noted that the study cohort was small.
“This should be repeated in larger cohorts, eventually segregated by PCOS phenotype, to see if epigenetic signatures are limited to certain individuals,” Giacobini said. “The other thing we did not fully capture is to dissect how AMH causes these epigenetic changes. Is it direct? Indirect? Through testosterone? This opens many investigations to carefully dissect what is behind these changes.”
Boutillier said the findings demonstrate the impact of hormone exposure during fetal life, eventually on a multigenerational timescale, in the context of PCOS.
“Because it is an epigenetic mechanism and not a genetic mutation, it is reversable,” Boutillier said. “That is important. Genetic diseases can be so difficult to approach with a therapeutic, though with gene therapy, we can hope for better things. But here, showing PCOS is epigenetically modified and transmitted, it suggests reversibility.”
Role of epigenetics
Andrea Dunaif, MD, professor and chief of the Hilda and J. Lester Gabrilove division of endocrinology, diabetes and bone disease at the Mount Sinai Health System and an Endocrine Today Editorial Board Member, who was not involved in the study, called the findings exciting, while noting the sample of women in the study — particularly daughters of PCOS mothers — was small and older than typical daughter cohorts, with a mean age of 24 years.
“The take-home message is, yes, these [data] are exciting, but some things are not addressed, and this could be a mechanism for a subset of women,” Dunaif said in an interview.
Data from other studies suggest genetics does play a role in PCOS heritability. In a study that also looked at human and mouse data, published in December in Nature Medicine, Sanjiv Risal, PhD, a postdoctoral fellow in the department of physiology and pharmacology at the Karolinska Institutet in Stockholm, and colleagues assessed how obesity and elevated prenatal androgen levels in women with PCOS affect offspring, using Swedish registry-based data and data from a case-control study conducted in Chile. The researchers found that female mice with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female offspring with PCOS-like reproductive and metabolic phenotypes.
“The daughters in the case-control study showed typical PCOS reproductive phenotypes, including hyperandrogenism, irregular menstrual cycles and polycystic ovarian morphology, along with specific metabolic perturbations, including increased waist circumference, higher BMI and higher diastolic blood pressure,” Risal and colleagues wrote. “Although physiological discrepancies exist between mice and humans, we provided several lines of evidence that prenatal androgen exposure alone, representing lean women with PCOS, predisposes female offspring to a PCOS-like phenotype, which passes on to subsequent generations.”
Dunaif said replicated, robust genetic literature now shows there is “definitely a genetic component” to PCOS that can span generations.
“There is no precedent to say there is missing heritability and it is all epigenetics,” Dunaif said. “You can show epigenetic effects, but you cannot show in complex traits — like diabetes, or obesity or PCOS — that it is all epigenetics and not genetic.”
Most likely, Dunaif said, genetic variants influence changes that predispose women to developing PCOS, which are then amplified by epigenetic effects, such as prenatal or environmental exposures.
“[Epigenetics] is something that may play a role in PCOS,” Dunaif said.
Giacobini, who said researchers still “do not have the full picture,” said the new data should spur further research on epigenetic treatments in PCOS combined with phenotypic investigations. In the Cell Metabolism study, treating third-generation PCOS mice with methyl donor S-adenosylmethionine normalized neuroendocrine, reproductive and metabolic phenotypes.
“This could open new prospects into diagnostics and therapeutic avenues,” Giacobini said. “That for me is the main message.”
For more information:
Anne-Laurence Boutillier, PhD, CNRS, can be reached at firstname.lastname@example.org.
Andrea Dunaif, MD, can be reached at email@example.com.
Paolo Giacobini, PhD, can be reached at firstname.lastname@example.org.