Genetic defects in the embryo could lead to early pregnancy loss

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Early pregnancy loss (EPL), or miscarriage, occurs in around one in four pregnancies. The most common causes of EPL are genetic, including embryonic chromosome abnormalities and DNA mutations in the sperm or egg. Other causes include maternal hormonal disorders such as polycystic ovary syndrome, infections and anatomical abnormalities affecting the mother’s reproductive system. EPL that occurs in the first trimester of pregnancy is usually due to embryonic problems, whereas EPL in the second trimester is more commonly caused by health conditions in the mother. It is estimated that embryonic chromosome abnormalities are responsible for approximately two thirds of first trimester miscarriages.


Despite its high prevalence, the molecular mechanisms underlying EPL have not been fully characterized. DNA methylation, a process that alters gene expression in cells, is known to be important for embryonic development; aberrant DNA methylation caused by inactivation of enzymes responsible for the process, called DNA methyltransferases (DNMTs), has been associated with birth malformations.


In a new study published in BMC Medicine, He-Feng Huang and colleagues showed that levels of DNA methylation in the chorionic villi between mother and embryo were significantly lower in women with EPL, compared with unaffected pregnancies. However, there was no change in the level of DNA methylation in the lining of the uterus. These findings suggest that aberrant DNA methylation in the embryo, but not in the mother, could be responsible for EPL.


The authors explored these findings further in a mouse model, and showed that disrupting DNA methylation using a DNMT inhibitor leads to abnormal embryonic development. Importantly, DNMT inhibition also reduced embryonic attachment to cells of the uterus. Together, the data demonstrate that defects in DNA methylation in the embryo are associated with abnormal development and could give rise to EPL.


The study shows for the first time that aberrant DNA methylation in the embryo rather than the mother could be involved in EPL, uncovering a potential new target for monitoring women at risk of EPL. Following this important finding, further investigations to fully characterize the mechanisms responsible in the embryo could validate DNA methylation as a target to monitor the risk of EPL, and could improve our understanding of the genes involved.