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Dynamic comparisons of high-resolution expression profiles highlighting mitochondria-related genes between in vivo and in vitro fertilized early mouse embryos.
Hum Reprod. 2015 Dec; 30(12):2892-911.HR

Abstract

STUDY QUESTION

Does in vitro fertilization (IVF) induce comprehensive and consistent changes in gene expression associated with mitochondrial biogenesis and function in mouse embryos from the pre- to post-implantation stage?

SUMMARY ANSWER

IVF-induced consistent mitochondrial dysfunction in early mouse embryos by altering the expression of a number of mitochondria-related genes.

WHAT IS KNOWN ALREADY

Although IVF is generally safe and successful for the treatment of human infertility, there is increasing evidence that those conceived by IVF suffer increased health risks. The mitochondrion is a multifunctional organelle that plays a crucial role in early development. We hypothesized that mitochondrial dysfunction is associated with increased IVF-induced embryonic defects and risks in offspring.

STUDY DESIGN, SIZE, DURATION

After either IVF and development (IVO groups as control) or IVF and culture (IVF groups), blastocysts were collected and transferred to pseudo-pregnant recipient mice. Both IVO and IVF embryos were sampled at E3.5, E7.5 and E10.5, and the expression profiles of mitochondria-related genes from the pre- to post-implantation stage were compared.

PARTICIPANTS/MATERIALS, SETTING, METHODS

ICR mice (5- to 6-week-old males and 8- to 9-week-old females) were used to generate IVO and IVF blastocysts. Embryo day (E) 3.5 blastocysts were transferred to pseudo-pregnant recipient mice. Both IVO and IVF embryos were sampled at E3.5, E7.5 and E10.5 for generating transcriptome data. Mitochondria-related genes were filtered for dynamic functional profiling. Mitochondrial dysfunctions indicated by bioinformatic analysis were further validated using cytological and molecular detection, morphometric and phenotypic analysis and integrated analysis with other high-throughput data.

MAIN RESULTS AND THE ROLE OF CHANCE

A total of 806, 795 and 753 mitochondria-related genes were significantly (P < 0.05) dysregulated in IVF embryos at E3.5, E7.5 and E10.5, respectively. Dynamic functional profiling, together with cytological and molecular investigations, indicated that IVF-induced mitochondrial dysfunctions mainly included: (i) inhibited mitochondrial biogenesis and impaired maintenance of DNA methylation of mitochondria-related genes during the post-implantation stage; (ii) dysregulated glutathione/glutathione peroxidase (GSH/Gpx) system and increased mitochondria-mediated apoptosis; (iii) disturbed mitochondrial β-oxidation, oxidative phosphorylation and amino acid metabolism; and (iv) disrupted mitochondrial transmembrane transport and membrane organization. We also demonstrated that some mitochondrial dysfunctions in IVF embryos, including impaired mitochondrial biogenesis, dysregulated GSH homeostasis and reactive oxygen species-induced apoptosis, can be rescued by treatment with melatonin, a mitochondria-targeted antioxidant, during in vitro culture.

LIMITATIONS, REASONS FOR CAUTION

Findings in mouse embryos and fetuses may not be fully transferable to humans. Further studies are needed to confirm these findings and to determine their clinical significance better.

WIDER IMPLICATIONS OF THE FINDINGS

The present study provides a new insight in understanding the mechanism of IVF-induced aberrations during embryonic development and the increased health risks in the offspring. In addition, we highlighted the possibility of improving existing IVF systems by modulating mitochondrial functions.

Authors+Show Affiliations

Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China wuzhh@cau.edu.cn tianjh@cau.edu.cn.Ministry of Agriculture Key Laboratory of Animal Genetics, Breeding and Reproduction, National Engineering Laboratory for Animal Breeding, College of Animal Sciences and Technology, China Agricultural University, Haidian District, Beijing 100193, China wuzhh@cau.edu.cn tianjh@cau.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26385791

Citation

Ren, Likun, et al. "Dynamic Comparisons of High-resolution Expression Profiles Highlighting Mitochondria-related Genes Between in Vivo and in Vitro Fertilized Early Mouse Embryos." Human Reproduction (Oxford, England), vol. 30, no. 12, 2015, pp. 2892-911.
Ren L, Wang Z, An L, et al. Dynamic comparisons of high-resolution expression profiles highlighting mitochondria-related genes between in vivo and in vitro fertilized early mouse embryos. Hum Reprod. 2015;30(12):2892-911.
Ren, L., Wang, Z., An, L., Zhang, Z., Tan, K., Miao, K., Tao, L., Cheng, L., Zhang, Z., Yang, M., Wu, Z., & Tian, J. (2015). Dynamic comparisons of high-resolution expression profiles highlighting mitochondria-related genes between in vivo and in vitro fertilized early mouse embryos. Human Reproduction (Oxford, England), 30(12), 2892-911. https://doi.org/10.1093/humrep/dev228
Ren L, et al. Dynamic Comparisons of High-resolution Expression Profiles Highlighting Mitochondria-related Genes Between in Vivo and in Vitro Fertilized Early Mouse Embryos. Hum Reprod. 2015;30(12):2892-911. PubMed PMID: 26385791.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dynamic comparisons of high-resolution expression profiles highlighting mitochondria-related genes between in vivo and in vitro fertilized early mouse embryos. AU - Ren,Likun, AU - Wang,Zhuqing, AU - An,Lei, AU - Zhang,Zhennan, AU - Tan,Kun, AU - Miao,Kai, AU - Tao,Li, AU - Cheng,Linghua, AU - Zhang,Zhenni, AU - Yang,Mingyao, AU - Wu,Zhonghong, AU - Tian,Jianhui, Y1 - 2015/09/18/ PY - 2015/04/02/received PY - 2015/08/24/accepted PY - 2015/9/20/entrez PY - 2015/9/20/pubmed PY - 2016/9/10/medline KW - apoptosis KW - embryonic development KW - glutathione (GSH) KW - in vitro fertilization KW - melatonin KW - methylation KW - mitochondria KW - mitochondria-related gene KW - mtDNA replication KW - reactive oxygen species (ROS) SP - 2892 EP - 911 JF - Human reproduction (Oxford, England) JO - Hum. Reprod. VL - 30 IS - 12 N2 - STUDY QUESTION: Does in vitro fertilization (IVF) induce comprehensive and consistent changes in gene expression associated with mitochondrial biogenesis and function in mouse embryos from the pre- to post-implantation stage? SUMMARY ANSWER: IVF-induced consistent mitochondrial dysfunction in early mouse embryos by altering the expression of a number of mitochondria-related genes. WHAT IS KNOWN ALREADY: Although IVF is generally safe and successful for the treatment of human infertility, there is increasing evidence that those conceived by IVF suffer increased health risks. The mitochondrion is a multifunctional organelle that plays a crucial role in early development. We hypothesized that mitochondrial dysfunction is associated with increased IVF-induced embryonic defects and risks in offspring. STUDY DESIGN, SIZE, DURATION: After either IVF and development (IVO groups as control) or IVF and culture (IVF groups), blastocysts were collected and transferred to pseudo-pregnant recipient mice. Both IVO and IVF embryos were sampled at E3.5, E7.5 and E10.5, and the expression profiles of mitochondria-related genes from the pre- to post-implantation stage were compared. PARTICIPANTS/MATERIALS, SETTING, METHODS: ICR mice (5- to 6-week-old males and 8- to 9-week-old females) were used to generate IVO and IVF blastocysts. Embryo day (E) 3.5 blastocysts were transferred to pseudo-pregnant recipient mice. Both IVO and IVF embryos were sampled at E3.5, E7.5 and E10.5 for generating transcriptome data. Mitochondria-related genes were filtered for dynamic functional profiling. Mitochondrial dysfunctions indicated by bioinformatic analysis were further validated using cytological and molecular detection, morphometric and phenotypic analysis and integrated analysis with other high-throughput data. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 806, 795 and 753 mitochondria-related genes were significantly (P < 0.05) dysregulated in IVF embryos at E3.5, E7.5 and E10.5, respectively. Dynamic functional profiling, together with cytological and molecular investigations, indicated that IVF-induced mitochondrial dysfunctions mainly included: (i) inhibited mitochondrial biogenesis and impaired maintenance of DNA methylation of mitochondria-related genes during the post-implantation stage; (ii) dysregulated glutathione/glutathione peroxidase (GSH/Gpx) system and increased mitochondria-mediated apoptosis; (iii) disturbed mitochondrial β-oxidation, oxidative phosphorylation and amino acid metabolism; and (iv) disrupted mitochondrial transmembrane transport and membrane organization. We also demonstrated that some mitochondrial dysfunctions in IVF embryos, including impaired mitochondrial biogenesis, dysregulated GSH homeostasis and reactive oxygen species-induced apoptosis, can be rescued by treatment with melatonin, a mitochondria-targeted antioxidant, during in vitro culture. LIMITATIONS, REASONS FOR CAUTION: Findings in mouse embryos and fetuses may not be fully transferable to humans. Further studies are needed to confirm these findings and to determine their clinical significance better. WIDER IMPLICATIONS OF THE FINDINGS: The present study provides a new insight in understanding the mechanism of IVF-induced aberrations during embryonic development and the increased health risks in the offspring. In addition, we highlighted the possibility of improving existing IVF systems by modulating mitochondrial functions. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/26385791/Dynamic_comparisons_of_high_resolution_expression_profiles_highlighting_mitochondria_related_genes_between_in_vivo_and_in_vitro_fertilized_early_mouse_embryos_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/dev228 DB - PRIME DP - Unbound Medicine ER -