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Developmental Biology - Epigenetic Changes
Does Mom's Age Cause Epigenetic Change in Her Eggs?
Babies born through fertility treatments have a higher risk of inheriting epigenetic disorders...
According to a new mouse study from the Magee-Womens Research Institute (MWRI), the problem likely lies with the technology, not mother's age.
The study, published in Clinical Epigenetics, found that fertility treatments caused epigenetic changes associated with Beckwith-Wiedemann, Silver-Russell and Angelman syndromes in mouse embryos. Surprisingly, maternal age itself had no effect.
"Women of advanced maternal age have one less thing to worry about. We need clinical studies to back that up, but this is a promising animal model that clinical studies could be based on."
Audrey Kindsfather, medical student researcher at Magee-Womens Research Institute (MWRI) and lead author.
Women are increasingly delaying childbirth, and as a woman ages, so does her reproductive system. The odds of conception go down, while the odds of genetic disorders, such as Down syndrome, go up.
Maternal age might increase the odds of epigenetic disorders too, the researchers reasoned. This could explain the higher incidence of these rare diseases among children born through fertility treatments, as women using these technologies tend to be older. To dissociate these factors, the scientists 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 had hormone injections to kick ovulation into high gear or their embryos cultured in a Petri dish - procedures commonly involved in fertility treatments - while control mice conceived naturally.
Researchers then quantified epigenetic changes in the mouse mothers' embryos by measuring the amount of DNA methylation - the molecular locks that are clasped around genes and associated with epigenetic disorders, preventing them from being expressed/functioningHormone therapy and embryo culture both disrupted DNA methylation in these critical spots. When these two procedures were used in combination, the effects were even stronger.
Maternal age, on the other hand, had no impact on DNA methylation patterns around these genes.
"It wasn't what we were expecting. We know that as a woman ages, there are a lot of molecular changes happening to her eggs, so we thought these changes could lead to abnormal DNA methylation. We were quite surprised that it didn't."
Mellissa Mann PhD, Principal Investigator with MWRI, and Associate Professor of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pennsylvania, USA and senior author.
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," says Kindsfather. "Lots more research needs to be done to improve fertility treatments."
Highlights
Background
Over the last several decades, the average age of first-time mothers has risen steadily. With increasing maternal age comes a decrease in fertility, which in turn has led to an increase in the use of assisted reproductive technologies by these women. Assisted reproductive technologies (ARTs), including superovulation and embryo culture, have been shown separately to alter imprinted DNA methylation maintenance in blastocysts. However, there has been little investigation on the effects of advanced maternal age, with or without ARTs, on genomic imprinting. We hypothesized that ARTs and advanced maternal age, separately and together, alter imprinted methylation in mouse preimplantation embryos. For this study, we examined imprinted methylation at three genes, Snrpn, Kcnq1ot1, and H19, which in humans are linked to ART-associated methylation errors that lead to imprinting disorders.
Results
Our data showed that imprinted methylation acquisition in oocytes was unaffected by increasing maternal age. Furthermore, imprinted methylation was normally acquired when advanced maternal age was combined with superovulation. Analysis of blastocyst-stage embryos revealed that imprinted methylation maintenance was also not affected by increasing maternal age. In a comparison of ARTs, we observed that the frequency of blastocysts with imprinted methylation loss was similar between the superovulation only and the embryo culture only groups, while the combination of superovulation and embryo culture resulted in a higher frequency of mouse blastocysts with maternal imprinted methylation perturbations than superovulation alone. Finally, the combination of increasing maternal age with ARTs had no additional effect on the frequency of imprinted methylation errors.
Conclusion
Collectively, increasing maternal age with or without superovulation had no effect of imprinted methylation acquisition at Snrpn, Kcnq1ot1, and H19 in oocytes. Furthermore, during preimplantation development, while ARTs generated perturbations in imprinted methylation maintenance in blastocysts, advanced maternal age did not increase the burden of imprinted methylation errors at Snrpn, Kcnq1ot1, and H19 when combined with ARTs. These results provide cautious optimism that advanced maternal age is not a contributing factor to imprinted methylation errors in embryos produced in the clinic. Furthermore, our data on the effects of ARTs strengthen the need to advance clinical methods to reduce imprinted methylation errors in in vitro-produced embryos.
Authors
Audrey J. Kindsfather, Megan A. Czekalski, Catherine A. Pressimone, Margaret P. Erisman and Mellissa R. W. Mann.
Funding
This work was supported by PA DOH 2018 Health Research Formula Fund, Magee-Womens Research Institute and the University of Pittsburgh to MRWM, and the Howard Hughes Medical Institute Medical Fellows Research Program to AJK.
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Dec 3 2019 Fetal Timeline Maternal Timeline News
 After fertilization, cells within a newly-formed mouse embryo divide and multiply. The cells all have the same DNA, but gene expression patterns diverge as they start to take on different roles. Once there are a few dozen cells, a fluid-filled cavity appears in the center of the embryo. Cells on the surface will become the placenta and the clump of cells nestled to one side will become the fetus. With epigenetic disorders, the gene expression instructions aren't passed down or maintained properly. In Beckwith-Wiedemann syndrome, for example, the loss of epigenetic marks causes an overgrowth of the placenta and certain parts of the fetus. CREDIT Audrey Kindsfather.
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