Murine blastocysts generated by in vitro fertilization show increased Warburg metabolism and altered lactate production

Abstract
Data availability
Article and author information
Metrics

Abstract

In vitro fertilization (IVF) has resulted in the birth of over 8 million children. Although most of IVF-conceived children are healthy, several studies suggest an increased risk of altered growth rate, cardiovascular dysfunction, and glucose intolerance in this population compared to naturally conceived children. However, a clear understanding of how embryonic metabolism is affected by culture condition and how embryos reprogram their metabolism is unknown. Here, we studied oxidative stress and metabolic alteration in blastocysts conceived by natural mating or by IVF and culture in physiologic (5%) or atmospheric (20%) oxygen. We found that IVF-generated blastocyst manifest increased reactive oxygen species, oxidative damage to DNA/lipid/proteins, and reduction in glutathione. Metabolic analysis revealed IVF-generated blastocysts display decreased mitochondria respiration and increased glycolytic activity suggestive of enhanced Warburg metabolism. These findings were corroborated by altered intracellular and extracellular pH and increased intracellular lactate levels in IVF-generated embryos. Comprehensive proteomic analysis and targeted immunofluorescence showed reduction of LDH-B and MCT1, enzymes involved in lactate metabolism. Importantly, these enzymes remained downregulated in tissues of adult IVF-conceived mice, suggesting that metabolic alterations in IVF-generated embryos may result in alteration in lactate metabolism. These findings suggest that alterations in lactate metabolism is a likely mechanism involved in genomic reprogramming and could be involved in the developmental origin of health and disease.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file;

Article and author information

Author details

Seok Hee Lee

Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Xiaowei Liu

Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
David Jimenez-Morales

Department of Medicine, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Paolo F Rinaudo

Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, United States

For correspondence
rinaudop@obgyn.ucsf.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6528-6009

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 R01HD092267)

Paolo F Rinaudo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments were approved by the Institutional Animal Care and Use Committee (#AN181614-03) of the University of California, San Francisco,

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.