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Mouse placentae generated by in vitro fertilization exhibit altered gene expression, activated hypoxia responses and reduced fitness.

ABSTRACT: In this study, we utilized single-nucleus RNA sequencing to quantify alterations in the gene expression programs of mouse placentas conceived through in vitro fertilization (IVF). We identified genetic programs exhibiting both global and cell type specific differences between IVF and natural in vivo fertilization groups. Gene set enrichment analysis revealed pathways associated with parietal trophoblast giant cell differentiation and implicated in the regulation of lactation (placental lactogens), along with Hypoxia-inducible factor dependent gene expression. Importantly, IVF-derived conceptuses showed increased abortion rates when their surrogate mothers were exposed to hypoxia (10.5% O2) during pregnancy (from E7.5 to 12.5). Collectively, our findings shed light on the cellular and molecular underpinnings driving differences in pregnancy outcomes associated with these conception methods and indicate that IVF can sensitize embryos to additional stressful events, as proposed by the developmental origin of health and disease hypothesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE303258 | GEO | 2025/08/08

REPOSITORIES: GEO

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Project description:OBJECTIVE: To determine whether deoxyribonucleic acid (DNA) methylation alterations exist in the first trimester human placenta between conceptions using fertility treatments and those that do not and, if so, whether differences are the result of underlying infertility or fertility treatments. We also assessed whether significant alterations led to changes in gene expression using bulk total RNA-seq from the same cohort (see Lee et al 2019, PMID: 30611556, NCBI GEO GSE215421). DESIGN: We compared DNA methylation of the first trimester placenta from singleton pregnancies that resulted in live births from unassisted, in vitro fertilization (IVF), and non-IVF fertility treatment (NIFT) conceptions using the Infinium MethylationEPIC BeadChip array. Differentially methylated probes (DMPs) were identified using a generalized linear model adjusted for fetal sex. Associated genes for significant CpG sites were cross-references in RNA-seq results to determine whether methylation alterations lead to differences in gene expression. SETTING: Academic medical center. PATIENTS: A total of 138 singleton pregnancies undergoing chorionic villus sampling resulting in a live birth were recruited for methylation analysis (56 unassisted, 38 NIFT, and 44 IVF conceptions). INTERVENTIONS AND TREATMENTS: In vitro fertilization-conceived pregnancy or pregnancy conceived via NIFT, such as ovulation induction and intrauterine insemination. RESULTS: Of the 741,145 CpG probes analyzed in the placenta, few were significant at Bonferroni <0.05: 185 CpG sites (0.025%) significant in pregnancies conceived with the fertility treatments (NIFT + IVF) versus unassisted conceptions; 28 in NIFT versus unassisted; 195 in IVF versus unassisted; and only 13 (0.0018%) in IVF versus NIFT conceptions. CONCLUSION: Underlying infertility is the most significant contributor to the minimal differences in first trimester placental methylation, and not the specific fertility treatment used, such as IVF.

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Mouse placentae generated by in vitro fertilization exhibit altered gene expression, activated hypoxia responses and reduced fitness.

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