Biological Trace Element Research

, Volume 176, Issue 2, pp 374–383 | Cite as

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

Article

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.

Keywords

TPEN Progesterone Ovary 

Notes

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.

Compliance with Ethical Standards

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.

Conflict of Interest

The authors declare that they have no conflict of interest.

Funding

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

Research Involving Animal Use

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

References

  1. 1.
    Park JY, YQ S, Ariga M, Law E, Jin SL, Conti M (2004) EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 303(5658):682–684CrossRefPubMedGoogle Scholar
  2. 2.
    Hsieh M, Lee D, Panigone S, Horner K, Chen R, Theologis A, Lee DC, Threadgill DW, Conti M (2007) Luteinizing hormone-dependent activation of the epidermal growth factor network is essential for ovulation. Mol Cell Biol 27(5):1914–1924. doi: 10.1128/mcb.01919-06 CrossRefPubMedGoogle Scholar
  3. 3.
    Y-Q S, Nyegaard M, Overgaard MT, Qiao J, Giudice LC (2006) Participation of mitogen-activated protein kinase in luteinizing hormone-induced differential regulation of steroidogenesis and steroidogenic gene expression in mural and cumulus granulosa cells of mouse preovulatory follicles. Biol Reprod 75(6):859–867. doi: 10.1095/biolreprod.106.052613 CrossRefGoogle Scholar
  4. 4.
    Panigone S, Hsieh M, Fu M, Persani L, Conti M (2008) Luteinizing hormone signaling in preovulatory follicles involves early activation of the epidermal growth factor receptor pathway. Mol Endocrinol 22(4):924–936. doi: 10.1210/me.2007-0246 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Diaz F, Wigglesworth K, Eppig J (2007) Oocytes determine cumulus cell lineage in mouse ovarian follicles. J Cell Sci 120(8):1330–1340CrossRefPubMedGoogle Scholar
  6. 6.
    Eppig JJ, Pendola FL, Wigglesworth K (1998) Mouse oocytes suppress cAMP-induced expression of LH receptor messenger RNA by granulosa cells in vitro. Mol Reprod Dev 49:327–332CrossRefPubMedGoogle Scholar
  7. 7.
    Y-Q S, Wigglesworth K, Pendola FL, O'Brien MJ, Eppig JJ (2002) Mitogen-activated protein kinase activity in cumulus cells is essential for gonadotropin-induced oocyte meiotic resumption and cumulus expansion in the mouse. Endocrinology 143(6):2221–2232CrossRefGoogle Scholar
  8. 8.
    Y-Q S, Denegre JM, Wigglesworth K, Pendola FL, O'Brien MJ, Eppig JJ (2003) Oocyte-dependent activation of mitogen-activated protein kinase (ERK1/2) in cumulus cells is required for the maturation of the mouse oocyte-cumulus cell complex. Dev Biol 263(1):126–138CrossRefGoogle Scholar
  9. 9.
    Diaz FJ, O'Brien MJ, Wigglesworth K, Eppig JJ (2006) The preantral granulosa cell to cumulus cell transition in the mouse ovary: development of competence to undergo expansion. Dev Biol 299(1):91–104CrossRefPubMedGoogle Scholar
  10. 10.
    Jamnongjit M, Gill A, Hammes SR (2005) Epidermal growth factor receptor signaling is required for normal ovarian steroidogenesis and oocyte maturation. Proc Natl Acad Sci U S A 102(45):16257–16262CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Norris RP, Freudzon M, Mehlmann LM, Cowan AE, Simon AM, Paul DL, Lampe PD, Jaffe LA (2008) Luteinizing hormone causes MAP kinase-dependent phosphorylation and closure of connexin 43 gap junctions in mouse ovarian follicles: one of two paths to meiotic resumption. Development 135(19):3229–3238. doi: 10.1242/dev.025494 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Diaz FJ, Anderson LE, YL W, Rabot A, Tsai SJ, Wiltbank MC (2002) Regulation of progesterone and prostaglandin F2alpha production in the CL. Mol Cell Endocrinol 191(1):65–80CrossRefPubMedGoogle Scholar
  13. 13.
    Kim AM, Vogt S, O'Halloran TV, Woodruff TK (2010) Zinc availability regulates exit from meiosis in maturing mammalian oocytes. Nat Chem Biol 6(9):674–681. doi: 10.1038/nchembio.419 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Tian X, Diaz FJ (2012) Zinc depletion causes multiple defects in ovarian function during the periovulatory period in mice. Endocrinology 153(2):873–886CrossRefPubMedGoogle Scholar
  15. 15.
    Bernhardt ML, Kim AM, O'Halloran TV, Woodruff TK (2011) Zinc requirement during meiosis I–meiosis II transition in mouse oocytes is independent of the MOS-MAPK pathway. Biol Reprod 84(3):526–536. doi: 10.1095/biolreprod.110.086488 CrossRefPubMedGoogle Scholar
  16. 16.
    Tian X, Anthony K, Neuberger T, Diaz FJ (2014) Preconception zinc deficiency disrupts postimplantation fetal and placental development in mice. Biol Reprod 90(4):83. doi: 10.1095/biolreprod.113.113910 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tian X, Diaz FJ (2013) Acute dietary zinc deficiency before conception compromises oocyte epigenetic programming and disrupts embryonic development: preconception zinc and oocyte quality. Dev Biol 376(1):51–61. doi: 10.1016/j.ydbio.2013.01.015 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Diaz FJ, Luo W, Wiltbank MC (2011) Effect of decreasing intraluteal progesterone on sensitivity of the early porcine corpus luteum to the luteolytic actions of prostaglandin F2alpha. Biol Reprod 84(1):26–33. doi: 10.1095/biolreprod.110.084368 CrossRefPubMedGoogle Scholar
  19. 19.
    Clegg M, Keen C, Lönnerdal B, Hurley L (1981) Influence of ashing techniques on the analysis of trace elements in animal tissue. Biol Trace Elem Res 3(2):107–115. doi: 10.1007/BF02990451 CrossRefPubMedGoogle Scholar
  20. 20.
    Diaz FJ, Wiltbank MC (2004) Acquisition of luteolytic capacity: changes in prostaglandin F 2alpha regulation of steroid hormone receptors and estradiol biosynthesis in pig corpora lutea. Biol Reprod 70(5):1333–1339CrossRefPubMedGoogle Scholar
  21. 21.
    Diaz FJ, Crenshaw TD, Wiltbank MC (2000) Prostaglandin f(2alpha) induces distinct physiological responses in porcine corpora lutea after acquisition of luteolytic capacity. Biol Reprod 63(5):1504–1512CrossRefPubMedGoogle Scholar
  22. 22.
    Diaz FJ, Wigglesworth K, Eppig JJ (2007) Oocytes are required for the preantral granulosa cell to cumulus cell transition in mice. Dev Biol 305(1):300–311CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-[Delta][Delta]CT method. Methods 25(4):402–408CrossRefPubMedGoogle Scholar
  24. 24.
    Graham JD, Clarke CL (1997) Physiological action of progesterone in target tissues. Endocr Rev 18(4):502–519PubMedGoogle Scholar
  25. 25.
    Conneely OM, Mulac-Jericevic B, Lydon JP (2003) Progesterone-dependent regulation of female reproductive activity by two distinct progesterone receptor isoforms. Steroids 68(10–13):771–778. doi: 10.1016/S0039-128X(03)00126-0 CrossRefPubMedGoogle Scholar
  26. 26.
    Li R, Norman RJ, Armstrong DT, Gilchrist RB (2000) Oocyte-secreted factor(s) determine functional differences between bovine mural granulosa cells and cumulus cells. Biol Reprod 63(3):839–845CrossRefPubMedGoogle Scholar
  27. 27.
    Motola S, Popliker M, Tsafriri A (2007) Are steroids obligatory mediators of luteinizing hormone/human chorionic gonadotropin-triggered resumption of meiosis in mammals? Endocrinology 148(9):4458–4465. doi: 10.1210/en.2007-0445 CrossRefPubMedGoogle Scholar
  28. 28.
    Zheng P, Si W, Bavister BD, Yang J, Ding C, Ji W (2003) 17{beta}-Estradiol and progesterone improve in-vitro cytoplasmic maturation of oocytes from unstimulated prepubertal and adult rhesus monkeys. Hum Reprod 18(10):2137–2144. doi: 10.1093/humrep/deg410 CrossRefPubMedGoogle Scholar
  29. 29.
    Flores-Herrera H, Díaz-Cervantes P, De la Mora G, Zaga-Clavellina V, Uribe-Salas F, Castro I (2008) A possible role of progesterone receptor in mouse oocyte in vitro fertilization regulated by norethisterone and its reduced metabolite. Contraception 78(6):507–512CrossRefPubMedGoogle Scholar
  30. 30.
    Park OK, Mayo KE (1991) Transient expression of progesterone receptor messenger RNA in ovarian granulosa cells after the preovulatory luteinizing hormone surge. Mol Endocrinol 5(7):967–978CrossRefPubMedGoogle Scholar
  31. 31.
    Natraj U, Richards JS (1993) Hormonal regulation, localization, and functional activity of the progesterone receptor in granulosa cells of rat preovulatory follicles. Endocrinology 133(2):761–769PubMedGoogle Scholar
  32. 32.
    Robker RL, Russell DL, Espey LL, Lydon JP, O'Malley BW, Richards JS (2000) Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases. Proc Natl Acad Sci U S A 97(9):4689–4694CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Peluso JJ (2006) Multiplicity of progesterone’s actions and receptors in the mammalian ovary. Biol Reprod 75(1):2–8. doi: 10.1095/biolreprod.105.049924 CrossRefPubMedGoogle Scholar
  34. 34.
    Peluso JJ (2007) Non-genomic actions of progesterone in the normal and neoplastic mammalian ovary. Semin Reprod Med 25(03):198–207CrossRefPubMedGoogle Scholar
  35. 35.
    Robker RL, Richards JS (2000) Progesterone: lessons from the progesterone receptor knockout. In: Adashi E, Stouffer R (eds) Ovulation: evolving scientific and clinical concepts. Springer, New York, pp. 121–129CrossRefGoogle Scholar
  36. 36.
    Qiu HB, SS L, Ji KL, Song XM, YQ L, Zhang M, KH L (2008) Membrane progestin receptor beta (mPR-[beta]): a protein related to cumulus expansion that is involved in in vitro maturation of pig cumulus-oocyte complexes. Steroids 73(14):1416–1423CrossRefPubMedGoogle Scholar
  37. 37.
    Peluso JJ, Pappalardo A, Losel R, Wehling M (2006) Progesterone membrane receptor component 1 expression in the immature rat ovary and its role in mediating progesterone’s antiapoptotic action. Endocrinology 147(6):3133–3140. doi: 10.1210/en.2006-0114 CrossRefPubMedGoogle Scholar
  38. 38.
    Luciano AM, Lodde V, Franciosi F, Ceciliani F, Peluso JJ (2010) Progesterone receptor membrane component 1 expression and putative function in bovine oocyte maturation, fertilization, and early embryonic development. Reproduction 140(5):663–672. doi: 10.1530/rep-10-0218 CrossRefPubMedGoogle Scholar
  39. 39.
    Sugiura K, Su YQ, Diaz FJ, Pangas SA, Sharma S, Wigglesworth K, O’Brien MJ, Matzuk MM, Shimasaki S, Eppig JJ (2007) Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in companion cumulus cells. Development 134(14):2593–2603CrossRefPubMedGoogle Scholar
  40. 40.
    Chang H-M, Cheng J-C, Klausen C, Leung PCK (2013) BMP15 suppresses progesterone production by down-regulating StAR via ALK3 in human granulosa cells. Mol Endocrinol 27(12):2093–2104. doi: 10.1210/me.2013-1233 CrossRefPubMedGoogle Scholar
  41. 41.
    Fang L, Chang H-M, Cheng J-C, Leung PC, Sun Y-P (2014) TGF-β1 downregulates StAR expression and decreases progesterone production through Smad3 and ERK1/2 signaling pathways in human granulosa cells. The Journal of Clinical Endocrinology & Metabolism 99(11):E2234–E2243. doi: 10.1210/jc.2014-1930 CrossRefGoogle Scholar
  42. 42.
    Miro F, Smyth CD, Hillier SG (1991) Development-related effects of recombinant activin on steroid synthesis in rat granulosa cells. Endocrinology 129(6):3388–3394. doi: 10.1210/endo-129-6-3388 CrossRefPubMedGoogle Scholar
  43. 43.
    Clem BF, Clark BJ (2006) Association of the mSin3A-histone deacetylase 1/2 corepressor complex with the mouse steroidogenic acute regulatory protein gene. Mol Endocrinol 20(1):100–113. doi: 10.1210/me.2004-0495 CrossRefPubMedGoogle Scholar
  44. 44.
    Kuo F-T, Fan K, Bentsi-Barnes I, Barlow GM, Pisarska MD (2012) Mouse forkhead L2 maintains repression of FSH-dependent genes in the granulosa cell. Reproduction 144(4):485–494. doi: 10.1530/rep-11-0259 CrossRefPubMedGoogle Scholar
  45. 45.
    Lisle R, Anthony K, Randall M, Diaz F (2013) Oocyte-cumulus cell interactions regulate free intracellular zinc in mouse oocytes. Reproduction 145:381–390CrossRefPubMedGoogle Scholar
  46. 46.
    Arslan P, Di Virgilio F, Beltrame M, Tsien RY, Pozzan T (1985) Cytosolic Ca2+ homeostasis in Ehrlich and Yoshida carcinomas. A new, membrane-permeant chelator of heavy metals reveals that these ascites tumor cell lines have normal cytosolic free Ca2+. J Biol Chem 260(5):2719–2727PubMedGoogle Scholar
  47. 47.
    Martell A, Smith R (2004) NIST critical stability constants of metal complexes (, 1998). NIST Standard Reference Database 46, v80 Gaithersburg, MD: Standard Reference Data Program, National Institute of Standards and Technology, U.S. Dept. of CommerceGoogle Scholar
  48. 48.
    Kolesarova A, Capcarova M, Medvedova M, Sirotkin AV, Kovacik J (2011) In vitro assessment of iron effect on porcine ovarian granulosa cells: secretory activity, markers of proliferation and apoptosis. Physiol Res 60(3):503–510PubMedGoogle Scholar
  49. 49.
    Strushkevich N, MacKenzie F, Cherkesova T, Grabovec I, Usanov S, Park H-W (2011) Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Proc Natl Acad Sci 108(25):10139–10143. doi: 10.1073/pnas.1019441108 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Roychoudhury S, Bulla J, Sirotkin AV, Kolesarova A (2014) In vitro changes in porcine ovarian granulosa cells induced by copper. J Environ Sci Health, Part A: Tox Hazard Subst Environ Eng 49(6):625–633. doi: 10.1080/10934529.2014.865404 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Center for Reproductive Biology and Health and Department of Animal SciencePennsylvania State UniversityUniversity ParkUSA
  2. 2.Department of Radiation OncologyUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations