Journal
REPRODUCTIVE TOXICOLOGY
Volume 105, Issue -, Pages 156-165Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.reprotox.2021.08.010
Keywords
Endometriosis; Iron overload; Blastocyst; Mitochondria; ROS; Ferroptosis; Apoptosis
Categories
Funding
- National Natural Science Foundation of China [81901452, 81701460]
- Research Program for Medicine and Health of Zhejiang Province [2019KY033, 2020KY414, 2019KY021, 2014KYA235, 2020KY448]
- Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, P. R. China [ZDFY2020-RG-0006]
- Natural Science Foundation of Zhejiang Province [LY17H040014]
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This study found that iron levels significantly impact the development of preimplantation mouse embryos, with excess iron impairing early embryo development and leading to mitochondrial dysfunction, apoptosis, and ferroptosis.
We and others have previously shown that abnormal pelvic environment plays an important role in the unexplained infertility of endometriosis. However, whether iron overload caused by ectopic periodic bleeding found in patients with endometriosis participates in endometriosis-associated reproductive failure is unknown. This study aimed to investigate effects of iron at level relevant to pelvic iron overload on the development of preimplantation mouse embryo. Two-cell embryos were collected, and cultured to blastocysts in G1/G2 medium supplemented with iron alone or in combination with iron chelator. The development rates, ATP level, mitochondrial membrane potential (MMP), reactive oxygen species level (ROS), and apoptotic and ferroptotic indices were compared between control and iron treatments across each specific developmental stage. Prolonged exposure to iron remarkably impaired early embryo development in vitro by hampering blastocyst formation (P < 0.001), which could be partly restored by iron chelator (P < 0.001). The arrest of embryo development was linked with iron-initiated mitochondrial dysfunction with reduction of ATP generation and MMP (P < 0.05 and P < 0.001, respectively). Impaired mitochondria altered ROS accumulation post-iron exposure at morula stage and blastocyst stage (P < 0.05). Moreover, Iron-exposed blastocyst stage embryos showed higher apoptotic and ferroptotic rates (P < 0.001 and P < 0.05, respectively). Our results highlight that pathologically relevant level of iron compromises preimplantation mouse embryo development by disrupting mitochondrial function and triggering both apoptosis and ferroptosis, which implicates that excess iron found in peritoneal fluid of women with endometriosis likely participates in endometriosis-associated reproductive failure.
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