Abstract
Accumulating evidence indicates that ferroptosis is an iron-dependent form of regulated cell death. This type of iron-dependent programmed cell death is different from traditional forms of regulated cell death, such as apoptosis and autophagy. However, the role of ferroptosis in porcine oocyte maturation and the associated mechanism remain unclear. In the present research, we investigated the effects of ferric ammonium citrate (FAC), a specific ferroptosis inducer, on porcine oocyte meiotic maturation and quality and subsequent embryonic developmental competence. FAC treatment caused obvious accumulation of intracellular ferrous ions in porcine oocytes. At the end of the in vitro maturation (IVM) period, there was a significant decrease in the polar body (PB) extrusion rate and an increase in the percentage of abnormal oocytes in the FAC treatment groups, indicating that iron overload-induced ferroptosis may suppress the meiotic process during porcine oocyte maturation. We also found that after FAC treatment, the subsequent two-cell rate, four-cell rate and blastocyst formation rate were significantly decreased in porcine parthenogenetic activation (PA) embryos, indicating that iron overload-induced ferroptosis decreased porcine oocyte quality. Further analysis revealed that FAC treatment not only enhanced intracellular reactive oxygen species (ROS) generation, decreased intracellular free thiol levels and induced mitochondrial dysfunction but also triggered autophagy in porcine oocytes. Taken together, these findings suggest that iron overload-induced ferroptosis impairs porcine oocyte meiosis and decreases porcine oocyte quality, possibly by increasing oxidative stress, inducing mitochondrial dysfunction and triggering autophagy.
Highlights
With the development of livestock husbandry, an increasing number of assisted reproduction technologies, such as in vitro fertilization (IVF), somatic cell nuclear transfer (SCNT), and intracytoplasmic sperm injection (ICSI), have been widely used in the production of domestic animals
To investigate the potential involvement of ferroptosis in oocyte quality during in vitro maturation (IVM), porcine oocytes were treated with increasing concentrations of ferric ammonium citrate (FAC) (5 μM, 10 μM, and 20 μM), and intracellular Fe2+ levels, the rate of polar body (PB) extrusion and the percentage of abnormal oocytes (Supplementary Figure 1) were analyzed
Western blotting analysis showed that the expression of the key ferroptosis factor GPX4 was upregulated, but there was no statistical significance in the expression of the apoptosisrelated factors cleaved-caspase-3, BCL-2 and BAX in oocytes treated with FAC compared with oocytes in the control group (Supplementary Figures 3, 4)
Summary
With the development of livestock husbandry, an increasing number of assisted reproduction technologies, such as in vitro fertilization (IVF), somatic cell nuclear transfer (SCNT), and intracytoplasmic sperm injection (ICSI), have been widely used in the production of domestic animals The implementation of these techniques needs to be accompanied by the use of highquality in vitro- or in vivo-derived oocytes to be fully effective. Oocyte in vitro maturation (IVM) is a complex process regulated by a large number of internal and external factors (Grupen, 2014) Any changes in this process lead to changes in oocyte quality, which affect the subsequent developmental capacity of preimplantation embryos (Koyama et al, 2014; Ahmed et al, 2017; Ferrer-Vaquer et al, 2019). Identifying the changes that occur in oocytes under stress conditions can help find potential solutions to reduce the corresponding negative effects
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