Abstract
The mechanisms underlying the potential risks of in vitro fertilization and embryo transfer (IVF-ET) have not been fully elucidated. The aim of this study was to explore changes in the complement and coagulation pathways in placentae subjected to IVF-ET in the first trimester compared to placentae from normal pregnancies. Four placenta samples in the first trimester were obtained from patients undergoing IVF-ET owing to oviductal factors only. An additional 4 control placentae were obtained from volunteers with normal pregnancies. A GeneChip Affymetrix HG-U133 Plus 2.0 Array was utilized to analyze the changes in gene expression between the normal and IVF-ET placentae. Differentially expressed genes (DEGs) were analyzed using the Database for Annotation and Visualization and Integrated Discovery bioinformatics resource, and gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted. Using real-time PCR, we confirmed the obtained microarray data in 10 dysregulated genes. Five of the gene products were further analyzed by immunohistochemistry (IHC) to determine their protein expression and localization. A total of fifty DEGs were identified in the complement and coagulation pathways in the IVF-ET treated placentae: 38 upregulated and 12 down-regulated. KEGG pathway analysis indicated that IVF-ET manipulation substantially over-activated the coagulation and complement pathways, while urokinase plasminogen activator- and urokinase plasminogen activator receptor-mediated trophoblastic invasion and tissue remodeling were inhibited. Furthermore, the 5 proteins analyzed by IHC were found to be localized specifically to the placenta. This is the first study to compare DEGs relating to the placental complement and coagulation pathways from patients undergoing IVF-ET treatment compared to those undergoing normal pregnancy. These findings identified valuable biomarkers and potential novel therapeutic targets to combat the unfavorable effects of IVF-ET.
Highlights
Therapeutic strategies against infertility caused by various etiological factors have improved greatly in recent years, in vitro fertilization and embryo transfer (IVFET).[1]
38 transcripts were up-regulated, and 12 transcripts were down-regulated in the placenta during the first trimester between the in vitro fertilization and embryo transfer (IVF-ET) and natural pregnancy samples
Hierarchical clustering was applied to the microarray data and a very clear separation was observed in the gene expression profiles between IVF-ET and natural pregnancy samples in the same period; the 2 groups were distinctly clustered into 2 different groups (Fig. 1A)
Summary
Therapeutic strategies against infertility caused by various etiological factors have improved greatly in recent years, in vitro fertilization and embryo transfer (IVFET).[1]. Increasing research has shown that placental tissues are more sensitive than embryonic tissues to the preimplantation epigenetic dysregulation of imprinted genes.[7,8] This can lead to abnormal placental development and function with possible consequences for the developing fetus Based on this observation, subsequent studies have proposed 2 possible scenarios to explain why these defects appeared to be restricted to the trophectoderm lineage.[9,10] On one hand, trophectoderm cells, which are in contact with the culture medium, are more strongly influenced by in vitro culture, which is responsible for a loss of imprinting in midgestation placenta.[11] On the other hand, they are the first lineage to differentiate in the embryo as trophectoderm stem cells, from which the different cell lines in the future placenta will originate.[12] In addition to the fact that the composition of culture media differs from that of the in vivo natural environment, and despite careful manipulation, in vitro cultured trophectoderm cells are vulnerable to several environmental stressors, such as oxygen tension, pH and temperature variations during manipulation, light exposure, and shear stress linked to repeated pipetting, which may affect placental development and function.[13]
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