Fertility Treatment, Not Maternal Age, Causes Epigenetic Changes in Mouse Offspring
Nov 25, 2019
PITTSBURGH, Nov. 25, 2019 – Though epigenetic disorders – diseases caused by faulty gene expression – are still rare overall, babies born using fertility treatments, such as in vitro fertilization, have up to a 11-fold higher risk of inheriting them. A new mouse study from the Magee-Womens Research Institute (MWRI) suggests that the problem lies with the technology, not the mother’s age.
The study, published today in Clinical Epigenetics, found that fertility treatments, not maternal age, leads to epigenetic changes associated with Beckwith-Wiedemann, Silver-Russell and Angelman syndromes, which could explain why these disorders are more common among children born through assisted reproductive technology.
“Women of advanced maternal age might have one less thing to worry about,” said lead author Audrey Kindsfather, a medical student researcher at MWRI. “We need clinical studies to back that up, but this is a promising animal model that clinical studies could be based on.”
Women are increasingly delaying childbirth, but as a woman ages, so does her reproductive system. Older women tend to rely more on fertility treatments to conceive, and their eggs are more prone to genetic disorders, such as Down syndrome.
The researchers reasoned that maternal age might contribute to epigenetic disorders as well, but it’s impossible to answer that question using human data, so they turned to mice.
Kindsfather and colleagues grouped female mice by age, ranging from adolescence to the mouse equivalent of a 45-year-old woman. Some of the mice in each age group went through common steps involved in several fertility treatments – either hormone injections to kick ovulation into high gear, culturing embryos in a Petri dish, or both – while control mice conceived naturally.
Then, the researchers quantified epigenetic changes in the mouse mothers’ embryos by measuring the amount of DNA methylation – the molecular locks clasped around a particular gene, keeping it from being expressed. Surprisingly, maternal age had no impact.
“It wasn’t what we were expecting,” said senior author Mellissa Mann, Ph.D., associate professor of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh. “We know that as a woman ages, there are a lot of molecular changes happening to her eggs, so we thought that these changes could be leading to abnormal DNA methylation. We were quite surprised that it didn’t.”
In contrast, hormone therapy and embryo culture both disrupted DNA methylation at the genes associated with human epigenetic disorders. When used in combination, the effects were amplified.
Fertility treatments have come a long way since the first “test-tube baby” was born over 40 years ago, but this study highlights that there’s still room for improvement.
“These are wonderful technologies, but not the same as spontaneously conceiving,” Kindsfather said. “Lots more research needs to be done to improve fertility treatments.”
Additional authors on the study include Megan Czekalski, Catherine Pressimone, and Margaret Erisman, all of Pitt and MWRI.
The study was funded, in part, by a grant from the Pennsylvania Department of Health (2018 Health Research Formula Fund). The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. The Howard Hughes Medical Institute (Medical Fellows Research Program) also supported this research.
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About the University of Pittsburgh School of Medicine
As one of the nation’s leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region’s economy. For more information about the School of Medicine, see www.medschool.pitt.edu.
Magee-Womens Research Institute
Magee-Womens Research Institute (MWRI) is the largest research institute in the U.S. devoted exclusively to health conditions affecting women and infants. The Institute is leading discoveries and advancing knowledge in the field of reproductive biology and medicine, translating this knowledge into improved health, wellness and disease prevention for women, engaging our community in women’s health, and training the present and future generations of women’s health researchers.