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Am J Obstet Gynecol. 2019 Feb 28. pii: S0002-9378(19)30426-0. doi: 10.1016/j.ajog.2019.02.047. [Epub ahead of print]

MicroRNA-30d deficiency during preconception affects endometrial receptivity by decreasing implantation rates and impairing fetal growth.

Author information

1
Department of Pediatrics, Obstetrics, and Gynecology, Universidad de Valencia, Valencia, Spain.
2
R&D Department, Igenomix Foundation, Valencia, Spain.
3
R&D Department, Igenomix Foundation, Valencia, Spain; Instituto de Investigación Sanitaria Hospital Clínico (INCLIVA), Valencia, Spain. Electronic address: felipe.vilella@igenomix.com.
4
Igenomix S.L., Valencia, Spain; Department of Pediatrics, Obstetrics and Gynecology, Universidad de Valencia, INCLIVA, Valencia, Spain; Department of Obstetrics and Gynecology, School of Medicine, Stanford University, Stanford, CA.

Abstract

BACKGROUND:

Maternal-embryonic crosstalk between the endometrium and the preimplantation embryo is required for normal pregnancy. Our previous results demonstrated that maternal microRNAs secreted into the endometrial fluid, specifically miR-30d, act as a transcriptomic regulator of the preimplantation embryo by the maternal intrauterine environment.

OBJECTIVE:

To investigate the reproductive and fetal effects of murine miR-30d deficiency at the maternal-embryonic interface according to the origin of its maternal or embryonic default.

STUDY DESIGN:

A miR-30d knockout murine model was used as the animal model to investigate the impact of maternal and/or embryonic origin of miR-30d deficiency on embryonic implantation and fetal development. Wild-type and miR-30d knockout pseudopregnant mice were used to study the effect of miR-30d deficiency on the receptivity markers by means of real-time quantitative polymerase chain reaction, immunofluorescence, and western blotting. We assessed receptivity markers and implantation rates in 6 different transfer conditions in which embryos obtained from wild-type, knockout, and knockout embryos pretreated with a miR-30d analog were transferred into either wild-type or knockout pseudopregnant females. The impact of miR-30d deficiency on fetal development was evaluated by analyzing the implantation sites and resorbing sites under physiological conditions at days 5, 6, 8, and 12 of pregnancy. Fetal growth was evaluated by analyzing fetuses and placentas at days 12 and 16 of pregnancy.

RESULTS:

Maternal miR-30d deficiency induced a significant downregulation of endometrial receptivity markers. In wild-type recipients, miR-30d knockout embryos had poorer implantation rates than wild-type embryos (48.86 ± 14.33% vs 75.00 ± 10.47%, respectively, P = .0061). In miR-30d knockout recipients, the lowest implantation rate was observed when knockout embryos were transferred compared to wild-type embryos (26.04 ± 7.15% and 49.71 ± 8.59%, respectively, P = .0059). A positive correlation (r = 0.9978) was observed for maternal leukemia inhibitor factor expression with implantation rates. Further, the course of gestation was compromised in miR-30d knockout mothers, which had smaller implantation sites, greater rates of resorption, and fetuses with smaller crown-rump length and fetal/placental weight ratio.

CONCLUSION:

Our results demonstrate that maternal and/or embryonic miR-30d deficiency impairs embryonic implantation and fetal development in the animal model. This finding adds a novel miRNA dimension to the understanding of pregnancy and fetal growth restriction in humans.

KEYWORDS:

epigenetic; fetal growth restriction; implantation; maternal–embryonic crosstalk; miR-30d; microRNA; pregnancy; small for gestational age

PMID:
30826341
DOI:
10.1016/j.ajog.2019.02.047

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