Abstract
In vitro fertilization (IVF) increases the risk of tumorigenesis in offspring. The increased oxidative damage during IVF may be involved in tumor formation. However, the molecular mechanisms underlying this phenomenon remain largely unclear. Using a well-established model of oxidatively damaged IVF mouse embryos, we applied the iTRAQ method to identify proteins differentially expressed between control and oxidatively damaged zygotes and explored the possible tumorigenic mechanisms, especially with regard to the effects of oxidative damage on ribosome biogenesis closely related to tumorigenesis. The iTRAQ results revealed that ribosomal proteins were upregulated by oxidative stress through the Nucleolin/β-Catenin/n-Myc pathway, which stimulated ribosomes to synthesize an abundance of repair proteins to correct the damaged DNA/chromosomes in IVF-derived embryos. However, the increased percentages of γH2AX-positive cells and apoptotic cells in the blastocyst suggested that DNA repair was insufficient, resulting in aberrant ribosome biogenesis. Overexpression of ribosomal proteins, particularly Rpl15, which gradually increased from the 1-cell to 8-cell stages, indicated persistent hyperactivation of ribosome biogenesis, which promoted tumorigenesis in offspring derived from oxidatively damaged IVF embryos by selectively enhancing the translation of β-Catenin and TGF-β1. The antioxidant epigallocatechin-3-gallate (EGCG) was added to the in vitro culture medium to protect embryos from oxidative damage, and the expression of ribosome-/tumor-related proteins returned to normal after EGCG treatment. This study suggests that regulation of ribosome biogenesis by EGCG may be a means of preventing tumor formation in human IVF-derived offspring, providing a scientific basis for optimizing in vitro culture conditions and improving human-assisted reproductive technology.
Highlights
In vitro fertilization (IVF) involves the manipulation of early embryos at a time when they may be vulnerable to external disturbances
In this study, using a well-established model of oxidatively damaged IVF mouse embryos, we aimed to explore the relevant mechanisms of tumorigenesis in IVF-derived offspring, especially the effects of reactive oxygen species (ROS) on ribosome biogenesis closely related to tumorigenesis
We used Isobaric tags for relative and absolute quantification (iTRAQ) labeling to identify proteins differentially expressed between the control and H2O2-treated zygotes and successfully found 93 upregulated and 147 downregulated proteins among 1464 total identified proteins, providing a powerful platform for us to study the possible mechanisms of tumorigenesis in IVF-derived offspring
Summary
In vitro fertilization (IVF) involves the manipulation of early embryos at a time when they may be vulnerable to external disturbances. Environmental influences during embryonic development in vitro affect an individual′s susceptibility to epigenetic alterations and diseases such as cardiovascular disease, raising concerns about the potential consequences of IVF on the long-term health of offspring. The influence of IVF on tumor formation in offspring has been a topic of great concern for many researchers. There is increasing evidence that children who are born after IVF treatment have an increased risk of cancer[1,2]. A large registry-based study found a 42% higher risk of cancer in children conceived through IVF3. A 10-year follow-up study demonstrated that the total incidence of neoplasms was higher among IVF-conceived children (1.5/1000 person-years) than among naturally conceived children
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