Noli_et_al-2019-STEM_CELLS.pdf (3.3 MB)

Effects of thyroid hormone on mitochondria and metabolism of human preimplantation embryos.

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posted on 22.01.2020 by Laila Noli, Shirin E Khorsandi, Angela Pyle, Gnanaratnam Giritharan, Norah Fogarty, Antonio Capalbo, Liani Devito, Vladimir M Jovanovic, Preeti Khurana, Hannah Rosa, Nikola Kolundzic, Aleksandra Cvoro, Kathy K Niakan, Afshan Malik, Russell Foulk, Nigel Heaton, Mohammad Saleh Ardawi, Patrick F Chinnery, Caroline Ogilvie, Yacoub Khalaf, Dusko Ilic
Thyroid hormones are regarded as the major controllers of metabolic rate and oxygen consumption in mammals. Although it has been demonstrated that thyroid hormone supplementation improves bovine embryo development in vitro, the cellular mechanisms underlying these effects are so far unknown. In this study, we investigated the role of thyroid hormone in development of human preimplantation embryos. Embryos were cultured in the presence or absence of 10-7  M triiodothyronine (T3) till blastocyst stage. Inner cell mass (ICM) and trophectoderm (TE) were separated mechanically and subjected to RNAseq or quantification of mitochondrial DNA copy number. Analyses were performed using DESeq (v1.16.0 on R v3.1.3), MeV4.9 and MitoMiner 4.0v2018 JUN platforms. We found that the exposure of human preimplantation embryos to T3 had a profound impact on nuclear gene transcription only in the cells of ICM (1178 regulated genes - 10.5% of 11 196 expressed genes) and almost no effect on cells of TE (38 regulated genes - 0.3% of expressed genes). The analyses suggest that T3 induces in ICM a shift in OXPHOS activity, as the upregulated genes are contributing to the composition and organization of the respiratory chain and associated co-factors involved in mitoribosome assembly and stability. Furthermore, a number of genes affecting the citric acid cycle energy production have reduced expression. Our findings might explain why thyroid disorders in women have been associated with reduced fertility and adverse pregnancy outcome. Our data also raise a possibility that supplementation of culture media with T3 may improve outcomes for women undergoing in vitro fertilization. © AlphaMed Press 2019 SIGNIFICANCE STATEMENT: Thyroid hormones are regarded as the major controllers of metabolic rate and oxygen consumption in mammals. Little is known about the effects of the thyroid hormones in the earliest stages of human development. Our results suggest that thyroid hormones affect mitochondrial function in human embryos: stimulate mitochondrial replication and energy production within mitochondria by switching metabolism from glycolytic pathway to more efficient oxidative phosphorylation. Our findings shed a light on metabolic switch in early embryo development and might explain why thyroid disorders in women have been associated with reduced fertility and adverse pregnancy outcome. Our data also suggest that supplementation of culture media with T3 may improve outcomes for women undergoing IVF.

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Crick (Grant ID: 10120, Grant title: Niakan FC001120)

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