Placental Abnormalities are Associated With Specific Windows of Embryo Culture in a Mouse Model

Assisted Reproductive Technologies (ART) employ gamete/embryo handling and culture in vitro to produce offspring. ART pregnancies have an increased risk of low birth weight, abnormal placentation, pregnancy complications, and imprinting disorders. Embryo culture induces low birth weight, abnormal placental morphology, and lower levels of DNA methylation in placentas in a mouse model of ART. Whether preimplantation embryos at specific stages of development are more susceptible to these perturbations remains unresolved. Accordingly, we performed embryo culture for several discrete periods of preimplantation development and following embryo transfer, assessed fetal and placental outcomes at term. We observed a reduction in fetal:placental ratio associated with two distinct windows of preimplantation embryo development, one prior to the morula stage and the other from the morula to blastocyst stage, whereas placental morphological abnormalities and reduced imprinting control region methylation were only associated with culture prior to the morula stage. Extended culture to the blastocyst stage also induces additional placental DNA methylation changes compared to embryos transferred at the morula stage, and female concepti exhibited a higher loss of DNA methylation than males. By identifying specific developmental windows of susceptibility, this study provides a framework to optimize further culture conditions to minimize risks associated with ART pregnancies.

Automated summary

Assisted Reproductive Technologies (ART) involve manipulating gametes and embryos in vitro to produce offspring. ART pregnancies have increased risks of low birth weight, abnormal placenta formation, pregnancy complications, and imprinting disorders. This study found that embryo culture during specific stages of preimplantation development can lead to reduced fetal:placental ratio, abnormal placental morphology, and reduced DNA methylation in placentas. The findings also suggest that extended culture to the blastocyst stage induces additional placental DNA methylation changes compared to embryos transferred at the morula stage, and there are sex differences in DNA methylation loss. By identifying the vulnerable developmental windows, this study provides a basis for optimizing culture conditions to reduce risks associated with ART pregnancies.