Sex-specific divergence of antioxidant pathways in fetal brain, liver, and skeletal muscles

Abstract

The sex-specific divergence of antioxidant pathways in fetal organs of opposite-sex twin is unknown and remains urgently in need of investigation. Such study faces many challenges, mainly the ethical impossibility of obtaining human fetal organs. Opposite-sex sheep twins represent a unique model for studying a sex dimorphism for antioxidant systems. The activity of total superoxide dismutase (SOD), SOD1, SOD2, glutathione peroxidase (GPX), glutathione reductase (GR) and catalase (CAT), the content of total glutathione, reduced glutathione (GSH), and oxidized glutathione (GSSG) were measured in brain, lung, liver, kidney, and skeletal muscles of female and male fetuses collected from sheep twin pregnancies at day 65 of gestation. Lipid peroxidation was assessed by measuring melondialdehyde (MDA) tissue content. Male brain has greater total SOD and SOD1 activities than female brain. Female liver has greater SOD2 activity than male liver. Male liver has greater GR activity than female liver. Male liver has higher total GSH and GSSG content than female liver. Male skeletal muscles have higher total GSH, GSH, and GSSG content than female skeletal muscles. Female brain and liver have higher MDA content than male brain and liver. This is the first report of a sex dimorphism for fetal organ antioxidative pathways. Brain, liver, and skeletal muscles of male and female fetuses display distinct antioxidant pathways. Such sexually dimorphic responses to early life oxidative stress might be involved in the sex-related difference in fetal development that may have a long-term effect on offspring. Our study urges researchers to take into consideration the importance of sex as a biologic variable in their investigations.

KEYWORDS:

• Antioxidant pathways
• fetal organs
• opposite-sex twin
• pregnancy
• sex dimorphism

Acknowledgements

We thank Philippe Bolifraud (INRA, France) and Krawiec Angele, Sandra Grange, Laurence Puillet-Anselme (CHU Grenoble, France) for their expert technical assistance. The authors also thank the staff of the sheep sheds of Jouy-en-Josas (INRA, France). The authors would also like to thank the anonymous reviewers for their close examination of this article and their useful comments.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contributions

KHA conceived and designed the study, prepared the animal model, performed tissue collection, acquisition and statistical analysis of data, wrote the manuscript and acted as corresponding author. CG provided reagents and materials and took responsibility for the integrity and the accuracy of the biochemical analysis.