title: Dynamic comparisons of high-resolution expression profiles highlighting mitochondria-related genes between in vivo and in vitro fertilized early mouse embryos.
abstract: OBJECTIVE
  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?
  
  
  CONCLUSIONS
  IVF-induced consistent mitochondrial dysfunction in early mouse embryos by altering the expression of a number of mitochondria-related genes.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Likun
authors.initials: L
authors.lastname: Ren
authors.affiliation: 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.
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: An
authors.affiliation: 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.
authors.forename: Zhennan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Kun
authors.initials: K
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Kai
authors.initials: K
authors.lastname: Miao
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.affiliation: 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.
authors.forename: Linghua
authors.initials: L
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: Zhenni
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Zhonghong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Tian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019175:DNA Methylation; D046149:Embryo Culture Techniques; D004624:Embryo Transfer / Q000379:methods; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D001678:Organelle Biogenesis; D018384:Oxidative Stress / Q000235:genetics; D011247:Pregnancy
keywords: apoptosis; embryonic development; glutathione (GSH); in vitro fertilization; melatonin; methylation; mitochondria; mitochondria-related gene; mtDNA replication; reactive oxygen species (ROS)