Iron overload in endometriosis peritoneal fluid induces early embryo ferroptosis mediated by HMOX1

Shishi Li,Zhen Jin,Limei Wu,Jing Shu,Ling Zhang,Qiongxiao Huang,Xiaohua Fu,Yier Zhou,Weihai Xu,Fang Gao,Chongyi Shu,Xirong Zhang

doi:10.1038/s41420-021-00751-2

Shishi Li, Zhen Jin + Show 10 more

Open Access

https://doi.org/10.1038/s41420-021-00751-2

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Abstract

Endometriosis is one of the most common disorders that causes infertility in women. Iron is overloaded in endometriosis peritoneal fluid (PF), with harmful effects on early embryo development. However, the mechanism by which endometriosis peritoneal fluid affects embryonic development remains unclear. Hence, this study investigated the effect of iron overload on mouse embryos and elucidated the molecular mechanism. Iron overload in endometriosis PF disrupted blastocyst formation, decreased GPX4 expression and induced lipid peroxidation, suggesting that iron overload causes embryotoxicity and induces ferroptosis. Moreover, mitochondrial damage occurs in iron overload-treated embryos, presenting as decreased ATP levels, increased ROS levels and MMP hyperpolarization. The cytotoxicity of iron overload is attenuated by the ferroptosis inhibitor Fer-1. Furthermore, Smart-seq analysis revealed that HMOX1 is upregulated in embryo ferroptosis and that HMOX1 suppresses ferroptosis by maintaining mitochondrial function. This study provides new insight into the mechanism of endometriosis infertility and a potential target for future endometriosis infertility treatment efforts.

Highlights

Endometriosis is the presence of endometrial tissue, including both the glandular epithelium and stroma, outside the uterine cavity [1]
By Smart-seq, we identified that HMOX1 is upregulated in embryo ferroptosis and that HMOX1 suppression protects against ferroptosis by maintaining mitochondrial function
Iron overload in the Peritoneal fluid (PF) of endometriosis patients To determine the level of iron in endometriosis PF, we measured the iron, transferrin, and ferritin concentrations in the PF supernatant and calculated the transferrin saturations

Summary

Introduction

Endometriosis is the presence of endometrial tissue, including both the glandular epithelium and stroma, outside the uterine cavity [1]. It is one of the most common benign gynecological disorders, affecting 10–15% of all women of reproductive age and a much higher proportion in infertile women, approximately 25–40% [2]. Endometriosis patients may have an abnormal pelvic environment that affects pregnancy. Patients with endometriosis present significantly lower mature oocyte and fertilization rates [3]. Peritoneal fluid (PF) from endometriosis has harmful effects on early embryo development [4,5,6]. The mechanism by which PF affects embryonic development in endometriosis remains unclear

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