AsianScientist (Mar. 29, 2016) – The very first baby to be born by in vitro fertilization (IVF) may have been a girl, but subsequent research has shown that the procedure results in the birth of more boys on average. This skewed sex ratio—observed not only in humans but also in mice and cows—has been known since the early 1990’s but is poorly understood.
Now, a team of researchers from China Agricultural University has identified both a possible mechanism and a potential means of reversing the skewed sex ratio caused by IVF. Publishing their results in the Proceedings of the National Academy of Science, the team led by Professor Tian Jianhui showed that impaired X chromosome inactivation in female embryos caused developmental defects, and that the sex ratio could be restored by adding the epigenetic modulator, retinoic acid.
IVF has enabled the birth of over five million people since it was first used in humans in 1978 and is now a routine treatment for infertility. Although it is generally safe and the large majority of IVF babies are born healthy, IVF is associated with a skewed sex ratio, resulting in three to six percent more males.
“Before our study, the mechanisms underlying the IVF-associated health complications, such as miscarriage, preterm birth, lower birth weight, skewed sex ratio, as well as higher disease risks in later life, have been never determined,” Tian told Asian Scientist Magazine.
“Our study provides a guideline for exploring the mechanism of IVF-associated health complications, and also provides a potential approach for preventing these complications.”
Working with mice, Tian and his team found that female IVF embryos had a lower survival rate and higher rate of growth defects as compared to in vivo fertilized embryos. Because these defects resembled symptoms of impaired X chromosome inactivation, the researchers then went on to study the X chromosome status of the IVF embryos.
In mammals, males of the species have an X and a Y chromosome, while females have two copies of the X chromosome. The ‘extra’ copy of the X chromosome in females is switched off during early embryo development by X chromosome inactivation, an epigenetic process that gives rise to the tortiseshell color in cats.
Using markers of X chromosome inactivation such as H3K27me3 and Xist mRNA expression, the researchers found that X chromosome inactivation was indeed impaired in female IVF embryos. Furthermore, they also showed that overexpression of Xist improved X chromosome inactivation and correct the skewed sex ratio.
Although similar experiments were not performed in human embryos for ethical reasons, the researchers found that IVF-induced X chromosome impairment also led to a skewed sex ratio in rabbit and cow embryos, supporting the notion that it is a common mechanism across different species.
Interestingly, supplementing the IVF growth culture with the epigenetic modifier retinoic acid also restored X chromosome inactivation and corrected the sex ratio, all without harming the embryos. These results suggest that retinoic acid could similarly be used to correct the sex ratio in human IVF, although the authors stress important caveats.
“To the best of our knowledge, retinoic acid is not used in IVF procedures for humans,” Tian said. “It should be noted that there are some differences in the mechanisms of X chromosome inactivation between mouse and humans, so whether the X chromosome inactivation status is impaired in human IVF embryos needs to be further determined. In addition, risk evaluation is required before the clinical application of retinoic acid in IVF.”
Noting the growing popularity of IVF and the concomitant need to minimize IVF-associated health complications, Tian said that his study highlights the need for more research into the basic scientific issues behind the technology.
“We are calling for more attention to this problem from the government and society. The exact effects of IVF-induced impairment of X chromosome inactivation in different species needs to be further explored. We also need to determine whether the it causes other X-linked disorders in IVF offspring,” Tian said.
The researchers next plan to explore the mechanisms underlying other IVF-associated health complications, such as miscarriage, preterm birth, lower birth weight, birth defects, as well as higher disease risks in later life, and provide potential strategies for preventing these complications.
The article can be found at: Tan et al. (2016) Impaired Imprinted X Chromosome Inactivation is Responsible for the Skewed Sex Ratio Following In Vitro Fertilization.
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