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ResearchIn-Press PreviewDevelopmentReproductive biology Open Access | 10.1172/JCI201633

Mouse offspring conceived by in vitro fertilization exhibit accelerated reproductive aging through early ovarian failure

Eric A. Rhon-Calderon,1 Cassidy N. Hemphill,1 Alexandra J. Savage,1 Ana Domingo-Muelas,2 Zhengfeng Liu,1 Christopher J. Krapp,1 Laren Riesche,1 Nicolas Plachta,2 Richard M. Schultz,3 and Marisa S. Bartolomei1

1Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, United States of America

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1Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, United States of America

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1Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, United States of America

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1Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, United States of America

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1Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, United States of America

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1Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, United States of America

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1Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, United States of America

Find articles by Riesche, L. in: PubMed | Google Scholar

1Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, United States of America

Find articles by Plachta, N. in: PubMed | Google Scholar

1Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, United States of America

Find articles by Schultz, R. in: PubMed | Google Scholar

1Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

2Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

3Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, United States of America

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Published June 30, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI201633.
Copyright © 2026, Rhon-Calderon et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 30, 2026 - Version history
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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 (ART), can accelerate reproductive aging by promoting premature ovarian failure 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 accelerates reproductive aging in female offspring by inducing premature ovarian failure. IVF-conceived females 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.

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  • Version 1 (June 30, 2026): In-Press Preview
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