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 2

Ovarian morphology analysis.

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Ovarian morphology analysis. (A) E18.5 natural whole ovarian staining fo...
(A) E18.5 natural whole ovarian staining for GCNA1 (germ cells) and DAPI (nuclei). Scale bars: 100 μm. (B) Quantification of whole ovarian staining at E18.5. (C) Ovarian cross-sections stained with H&E at 12 and 39 weeks. Original magnification, ×40. (D) Total follicle number per ovary at 12 weeks. (E) Total follicle number per ovary at 39 weeks. (F) Ovarian cross-sections stained with PS at 12 and 39 weeks. Original magnification, ×40. (G) Quantification of collagen deposition shown as the percentage of PSR+ area. Each data point represents one biological replicate. Sample sizes are indicated below each panel as the number of animals (litters). Data are presented as the mean ± SEM. Normality was assessed using the Shapiro-Wilk test. Data that did not meet the normality assumption were analyzed using the nonparametric Mann-Whitney U test, whereas normally distributed data were analyzed using an unpaired 2-tailed t test with Welch’s correction. *P < 0.05 compared with Naturals.