The role of zinc in ovarian function

Author:

Tian, Xi

Graduate Program:

Animal Science

Degree:

Doctor of Philosophy

Document Type:

Dissertation

Date of Defense:

June 05, 2013

Committee Members:

Francisco Javier Diaz, Dissertation Advisor/Co-Advisor
Francisco Javier Diaz, Committee Chair/Co-Chair
Alan Leslie Johnson, Committee Member
Paul Allen Bartell, Committee Member
Robert Paulson, Committee Member
Shannon Leanne Kelleher, Committee Member

Keywords:

zinc
ovary
follicular development
oocyte
embryonic development
mouse

Abstract:

The ovarian environment is a prime determinant of oocyte quality, which plays a key role in determining the success of fertilization, pregnancy maintenance, embryonic development as well as postnatal health. The essential trace metal zinc has been recently recognized as an important factor that is necessary for completion of progression trhough meiosis I. However, the role of zinc in controlling cumulus cell function, promoting oocyte quality and developmental potential is not known. Using in vitro and in vivo (dietary) zinc deficiency models, current study uncovers effects and mechanisms how zinc is involved in ovarian function and embryonic development. In granulosa cells, TPEN treatment altered cumulus transcripts, blocked cumulus expansion and suppressed expansion-related transcripts Has2, Ptx3, Ptgs2, and Tnfaip6 mRNA, by inhibiting SMAD2/3 signaling. In oocytes, a chelator N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) caused premature germinal vesicle breakdown and associated spindle defects even with the presence of a phosphodiesterase 3A inhibitor. Acute dietary zinc deficiency model confirmed the in vitro observations that oocytes failed to maintain meiotic arrest in the absence of zinc. Longer zinc depletion (10 days) completely blocked ovulation and compromised cumulus expansion. Additionally, preconception dietary zinc depletion (3-5 days) dramatically disrupted histone H3K4 trimethylation and global DNA methylation in oocytes and fertilized eggs, resulting in aberrant gene expression of repetitive elements and oocyte transcripts. Supplementation with the methyl donor S-adenosylmethionine partially rescued the fertilization capability in zinc deficient oocytes by restoring histone methylation. Epigenetic defects in zinc deficient oocytes further impaired fertilization and preimplantation embryonic development. Embryo transfer experiments further confirmed the impact of preconception zinc deficiency on implantation rate, placental and postimplantation development by excluding the effects of zinc deficiency on uterus function. Collectively, these studies show that zinc is an important factor required for regulating ovarian function and promoting oocyte quality and developmental potential, and also provides new insights to better understand the physiological aspects of zinc on female fertility.