Mouse offspring conceived by in vitro fertilization exhibit accelerated reproductive aging through premature ovarian insufficiency
Eric A. Rhon-Calderon, Cassidy N. Hemphill, Alexandra J. Savage, Ana Domingo-Muelas, Zhengfeng Liu, Christopher J. Krapp, Laren Riesche, Nicolas Plachta, Richard M. Schultz, Marisa S. Bartolomei
Eric A. Rhon-Calderon, Cassidy N. Hemphill, Alexandra J. Savage, Ana Domingo-Muelas, Zhengfeng Liu, Christopher J. Krapp, Laren Riesche, Nicolas Plachta, Richard M. Schultz, Marisa S. Bartolomei
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Research Article Development Reproductive biology

Mouse offspring conceived by in vitro fertilization exhibit accelerated reproductive aging through premature ovarian insufficiency

Abstract

Reproductive aging is characterized by a progressive decline of reproductive function, with broad implications for overall health and longevity. Environmental factors, including assisted reproductive technologies (ARTs), can accelerate reproductive aging by promoting premature ovarian insufficiency in females. In vitro fertilization (IVF), though widely used and generally considered safe, has been associated with lasting effects on offspring health. Using a mouse model that closely approximates human IVF, we demonstrated that IVF accelerated reproductive aging in female offspring by inducing premature ovarian insufficiency. IVF-conceived female mice exhibited altered ovarian function, reduced follicle reserve, disrupted endocrine profiles, and transcriptomic and epigenetic changes consistent with premature reproductive decline. These findings reveal long-term consequences of IVF on female reproductive health and highlight the need to understand how early-life interventions influence reproductive longevity.

Authors

Eric A. Rhon-Calderon, Cassidy N. Hemphill, Alexandra J. Savage, Ana Domingo-Muelas, Zhengfeng Liu, Christopher J. Krapp, Laren Riesche, Nicolas Plachta, Richard M. Schultz, Marisa S. Bartolomei

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Figure 5

Transcriptome analysis of cumulus cells by RNA-seq at 2 developmental time points.

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Transcriptome analysis of cumulus cells by RNA-seq at 2 developmental ti...
(A) PCA of cumulus cell transcriptomes at 12 weeks showing separation between Natural and IVF samples. (B) Volcano plot of DEGs in cumulus cells at 12 weeks, with significantly upregulated genes shown in blue and downregulated genes shown in tan. (C) Heatmap of the top upregulated and downregulated DEGs at 12 weeks. (D) Top enriched Hallmark pathways at 12 weeks. (E) Top enriched Reactome pathways at 12 weeks. (F) PCA of cumulus cell transcriptomes at 39 weeks showing separation between Natural and IVF groups. (G) Volcano plot of DEGs in cumulus cells at 39 weeks. (H) Heatmap of the top upregulated and downregulated DEGs at 39 weeks. (I) Top enriched Hallmark pathways at 39 weeks. (J) Top enriched Reactome pathways at 39 weeks. Heatmaps depict row-scaled normalized expression values, and color bars above heatmaps indicate experimental group assignment. Differential expression analysis was performed using DESeq2, with an adjusted P value of less than 0.05. Hallmark and Reactome pathway enrichment analyses were performed using significantly dysregulated genes from each age group.