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Transition Metal Chelator Induces Progesterone Production in Mouse Cumulus-Oocyte Complexes and Corpora Lutea

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Abstract

Progesterone production is upregulated in granulosa cells (cumulus and mural) after the LH surge, but the intra-follicular mechanisms regulating this transition are not completely known. Recent findings show that the transition metal chelator, N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN), impairs ovarian function. In this study, we provide evidence that chelating transition metals, including zinc, enhances progesterone production. The findings show that TPEN (transition metal chelator) increases abundance of Cyp11a1 and Star messenger RNA (mRNA) between 8- and 20-fold and progesterone production more than 3-fold in cultured cumulus-oocyte complexes (COC). Feeding a zinc-deficient diet for 10 days, but not 3 days, increased Star, Hsd3b, and prostaglandin F2 alpha receptor (Ptgfr) mRNA ~2.5-fold, suggesting that the effect of TPEN is through modulation of zinc availability. Progesterone from cumulus cells promotes oocyte developmental potential. Blocking progesterone production with epostane during maturation reduced subsequent blastocyst formation from 89 % in control to 18 % in epostane-treated complexes, but supplementation with progesterone restored blastocyst developmental potential to 94 %. Feeding a zinc-deficient diet for 5 days before ovulation did not affect the number of CL, STAR protein, or serum progesterone. However, incubating luteal tissue with TPEN increased abundance of Star, Hsd3b, and Ptgfr mRNA 2–3-fold and increased progesterone production 3-fold. TPEN is known to abolish SMAD2/3 signaling in cumulus cells. However, treatment of COC with the SMAD2/3 phosphorylation inhibitor, SB421542, did not by itself induce steroidogenic transcripts but did potentiate EGF-induced Star mRNA expression. Collectively, the results show that depletion of transition metals with TPEN acutely enhances progesterone biosynthesis in COC and luteal tissue.

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Acknowledgments

We thank Dr. Doug Stocco for providing STAR antibody and to Nick McCormick, Tom Croxford, and Shannon Kelleher for help with tissue zinc analyses.

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Author notes

  1. X. Tian

    Present address: Department of Radiation Oncology, University of North Carolina at Chapel Hill, 2236 Marsico Hall, 125 Mason Farm Road, Chapel Hill, NC, 27599, USA

Authors and Affiliations

  1. Center for Reproductive Biology and Health and Department of Animal Science, Pennsylvania State University, 206 Henning Building, University Park, PA, 16802, USA

    X. Tian, K. Anthony & Francisco J. Diaz

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  1. X. Tian
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  2. K. Anthony
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  3. Francisco J. Diaz
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Correspondence to Francisco J. Diaz.

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Animals were maintained according to the Guide for the Care and Use of Laboratory Animals (Institute for Learning and Animal Research). All animal use was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at the Pennsylvania State University.

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The authors declare that they have no conflict of interest.

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This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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All procedures used on animals were approved by the Animal Care and Use Committee of the Pennsylvania State University.

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Tian, X., Anthony, K. & Diaz, F.J. Transition Metal Chelator Induces Progesterone Production in Mouse Cumulus-Oocyte Complexes and Corpora Lutea. Biol Trace Elem Res 176, 374–383 (2017). https://doi.org/10.1007/s12011-016-0841-x

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