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In vitro cytotoxicity of Cu2+, Zn2+, Ag+ and their mixtures on primary human endometrial epithelial cells

  • Jing Wu
    Affiliations
    Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
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  • Luyao Wang
    Affiliations
    Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
    Search for articles by this author
  • Jing He
    Affiliations
    Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
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  • Changhong Zhu
    Correspondence
    Corresponding author. Tel.: +86 027 8369 2651; fax: +86 027 83637374.
    Affiliations
    Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
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      Abstract

      Background

      To avoid the inherent disadvantages of copper-containing intrauterine device (Cu-IUD) induced by free Cu2+, two other well-performing metal ions, namely, Ag+, with long-effective antimicrobial properties, and Zn2+, as an essential trace element, are being considered for use in the future as multifunctional IUDs. The purpose of this study was to assess the cytotoxicity of these metal ions and their mixtures on primary human endometrial epithelial cells (HEECs) cultured in vitro and to provide several choices of alternative potential materials for creating excellent IUDs in the future.

      Study Design

      With the use of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-formazan (MTT-f) production, the cytotoxic effects of single metal ions (Cu2+, Zn2+, Ag+) on HEECs after exposure for 24, 48 or 72 h were investigated, and the synergistic and antagonistic effects of two ions applied simultaneously were also assessed.

      Results

      The cytotoxicity of the metal ions on HEECs ranked as follows: Ag+>Cu2+>Zn2+. All combinations of those tested indicated that the Cu2++Zn2+ system exhibited an antagonistic effect absolutely, the Zn2++Ag+ system showed both antagonism and slight synergism, and asynergistic effect was observed in the Cu2++Ag+ system.

      Conclusion

      From a perspective of favorable biocompatibility, Zn2+ and the Cu2++Zn2+ mixture showed evidence of potential components for use in future IUDs. Although having strong cytotoxicity, Ag+ with its low release rate and broad-spectrum antibiotic activity may also be considered. The study also demonstrated the relative stability of Cu2+ as a classic material of IUD.

      Keywords

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      References

        • American College of Obstetricians and Gynecologists Committee on Practice Bulletins���Gynecology
        Clinical management guidelines for obstetrician gynecologists. Intrauterine device.
        Obstet Gynecol. 2005; 105: 223-232
        • Stanford J.B.
        • Mikolajczyk R.T.
        Mechanisms of action of intrauterine devices: update and estimation of postfertilization effects.
        Am J Obstet Gynecol. 2002; 187: 1699-1708
        • Colli E.
        • Tong D.
        • Penhallegon R.
        • Parazzini F.
        Reasons for contraceptive discontinuation in women 20���39 years old in New Zealand.
        Contraception. 1999; 59: 227-231
        • Andersson K.
        • Ryde-Blomqvist E.
        • Lindell K.
        • Odlind V.
        • Milsom I.
        Perforations with intrauterine devices: report from a Swedish survey.
        Contraception. 1998; 57: 251-255
        • Xu T.
        • Lei H.
        • Cai S.Z.
        • Xia X.P.
        • Xie C.S.
        The release of cupric ion in simulated uterine: Material nano-Cu/low-density polyethylene used for intrauterine devices.
        Contraception. 2004; 70: 153-157
        • Xia X.P.
        • Xie C.S.
        • Cai S.Z.
        • Wen F.
        • Zhu C.H.
        • Yang X.L.
        Effect of the loading and size of copper particles on the mechanical properties of novel Cu/LDPE composites for use in intrauterine devices.
        Mater Sci Eng, A. 2006; 429: 329-333
        • Wen F.
        • Xie C.S.
        • Cai S.Z.
        • Gui Y.H.
        Electrochemical behaviour of copper/LDPE composites in the simulated uterine solution.
        Electrochim Acta. 2006; 51: 5606-5611
        • Cai S.Z.
        • Xia X.P.
        • Xie C.S.
        Corrosion behavior of Copper/LDPE nanocomposites in simulated uterine solution.
        Biomaterials. 2005; 26: 2671-2676
        • Yu J.
        • Li J.
        • Li H.G.
        • Li J.X.
        • Xie C.S.
        • Zhu C.H.
        Comparative study on contraceptive efficacy and clinical performance of the copper/low-density polyethylene nanocomposite IUD and the copper T220C IUD.
        Contraception. 2008; 78: 319-323
        • Liu H.F.
        • Liu Z.L.
        • Xie C.S.
        • Yu J.
        • Zhu C.H.
        The antifertility effectiveness of copper/low-density polyethylene nanocomposite and its influence on the endometrial environment in rats.
        Contraception. 2007; 75: 157-161
        • Balazs D.J.
        • Triandafillu K.
        • Wood P.
        • et al.
        Inhibition of bacterial adhesion on PVC endotracheal tubes by RF-oxygen glow discharge, sodium hydroxide and silver nitrate treatments.
        Biomaterials. 2004; 25: 2139-2151
        • Stobie N.
        • Duffy B.
        • McCormack D.E.
        • et al.
        Prevention of Staphylococcus epidermidis biofilm formation using a low-temperature processed silver-doped phenyltriethoxysilane sol���gel coating.
        Biomaterials. 2008; 29: 963-969
        • Melaiye A.
        • Youngs W.J.
        Silver and its application as an antimicrobial agent.
        Expert Opin Ther Pat. 2005; 15: 125-130
        • Vallee B.L.
        • Falchuk K.H.
        The biochemical basis of zinc physiology.
        Physiol Rev. 1993; 73: 79-118
        • Fosmire G.J.
        Zinc toxicity.
        Am J Clin Nutr. 1990; 51: 225-227
        • Braydich-Stolle L.
        • Hussain S.
        • Schlager J.J.
        • Hofmann M.C.
        In vitro cytotoxicity of nanoparticles in mammalian germline stem cells.
        Toxicol Sci. 2005; 88: 412-419
        • Sadovsky E.
        • Polishuk W.Z.
        • Anteby S.O.
        • Yarkoni S.
        • Aboulafa Y.
        Report on the use of the new Andersoon-Ansell ���Latex Leaf��� IUD containing copper and zinc.
        Contraception. 1975; 12: 541-547
        • Thiery M.
        Intrauterine contraception: From silver ring to intrauterine contraceptive implant.
        Eur J Obstet Gyecol Reprod Biol. 2000; 90: 145-152
        • Bat��r I.
        • Kuukankorpi A.
        • Rauramo I.
        • Siljander M.
        Two-year clinical experience with Nova-T 380, a novel copper-silver IUD.
        Adv Contracept. 1999; 15: 37-48
        • Bongso A.
        • Gajra B.
        • Lian N.P.
        • Wong P.C.
        • Soon-Chye N.
        • Ratnam S.
        Establishment of human endometrial cell cultures.
        Hum Reprod. 1988; 3: 705-713
        • Cork B.A.
        • Tuckerman E.M.
        • Li T.C.
        • Laird SM
        Expression of IL11 receptor by the human endometrium in vivo and effects of IL11, IL6 and LIF on the production of MMPs and cytokines by human endometrial cells in vitro.
        Mol Hum Reprod. 2002; 8: 841-848
        • Ver��nica A.
        • Claudia P.
        • Herbert E.
        Characterization of copper in uterine fluids of patients who use the copper T-380A intrauterine device.
        Clin Chim Acta. 2003; 332: 69-78
        • Mossman T.
        Rapid colorimetric assay for cellular growth and survival; application to proliferation and cytotoxicity assay.
        J Immunol Meth. 1983; 65: 55-63
        • Seth R.
        • Yang S.
        • Choi S.
        • Sabean M.
        • Roberts E.A.
        In vitro assessment of copper-induced toxicity in the human hepatoma line, Hep G2.
        Toxicol In Vitro. 2004; 18: 501-509
        • Chakrabarti R.
        • Kundu S.
        • Kumar S.
        • Chakrabarti R.
        Vitamin A as an enzyme that catalyzes the reduction of MTT to formazan by vitamin C.
        J Cell Biochem. 2000; 80: 133-138
        • Ioannis M.
        • Runa S.
        • Josef M.
        • et al.
        Immunohistochemical analysis of steroid receptors and glycodelin A (PP14) in isolated glandular epithelial cells of normal human endometrium.
        Histochem Cell Biol. 2000; 114: 405-411
        • Schmalz G.
        • Langer H.
        • Schweikl H.
        Cytotoxicity of dental alloy extracts and corresponding metal salt solutions.
        J Dent Res. 1998; 77: 1772-1778
        • Wataha J.C.
        • Hanks C.T.
        • Craig R.G.
        The in vitro effects of metal cations on eukaryotic cell metabolism.
        J Biomed Mater Res. 1991; 25: 1133-1149
        • Schmalz G.
        • Arenholt-Bindslev D.
        • Pfuller S.
        • Schweikl H.
        Cytotoxicity of metal cations used in dental cast alloys.
        Altern L Anim. 1997; 25: 323-330
        • Satyaswaroop P.G.
        • Bressler R.S.
        • Pena M.M.
        • Gurpide E.
        Isolation and culture of human endometrial glands.
        J Clin Endocrinol Metab. 1979; 48: 639-641
        • Vigano P.
        • Di Blasio A.M.
        • Dell'Antonio G.
        • Vignali M.
        Culture of human endometrial cells: a new simple technique to completely separate epithelial glands.
        Acta Obstet Gynecol Scand. 1993; 72: 87-92
        • Schedle A.
        • Samorapoompichit P.
        • Rausch-Fan X.H.
        • et al.
        Response of L-929 fibroblasts, human gingival fibroblasts, and human tissue mast cells to various metal cations.
        J Dent Res. 1995; 74: 1513-1520
        • Wataha J.C.
        • Malcolm C.T.
        • Hanks C.T.
        Correlation between cytotoxicity and the elements released by dental casting alloys.
        Int J Prosthodont. 1995; 8: 9-14
        • Bumgardnerl J.D.
        • Lucas L.C.
        Cellular response to metallic ions released from nickel-chromium dental alloys.
        J Dent Res. 1995; 74: 1521-1527
        • Paul B.T.
        • Cecilia N.
        • Joyce W.
        • Glass K.
        Copper-induced cytotoxicity and transcriptional activation of stress genes in human liver carcinoma (HepG2) cells.
        Met Ions Biol Med. 2008; 10: 285-290
        • Yamaguchi M.
        • Inamoto K.
        • Suketa Y.
        Effect of essential trace metals on bone metabolism in weanling rats: comparison with zinc and other metals' actions.
        Res Exp Med. 1986; 186: 337-342
        • Song W.
        • Zhang J.
        • Guo J.
        • Zhang J.
        • Ding F.
        • Li L.
        • Sun Z.
        Role of the dissolved zinc ion and reactive oxygen species in cytotoxicity of ZnO nanoparticles.
        Toxicol Lett. 2010; 199: 389-397
        • Shelton J.D.
        Risk of clinical pelvic inflammatory disease attributable to an intrauterine device.
        Lancet. 2001; 357: 443
        • Anshu P.
        • Kathryn M.
        • Herbert B.
        Does insertion and use of an intrauterine device increase the risk of pelvic inflammatory disease among women with sexually transmitted infection? A systematic review.
        Contraception. 2006; 73: 145-153
        • Sinei S.K.
        • Morrison C.S.
        • Sekadde-Kigondu C.
        Complications of use of intrauterine devices among HIV-1-infected women.
        Lancet. 1998; 351: 1238-1241
        • Timonen H.
        Copper release from copper-T intrauterine devices.
        Contraception. 1976; 14: 25-38
        • Francisca M.
        • Eduardolo P.
        Infection risk and intrauterine devices.
        Acta Obstet Gyn Scan. 2009; 88: 246-250
        • Kumar R.
        • M��nstedt H.
        Silver ion release from antimicrobial polyamide/silver composites.
        Biomaterials. 2005; 26: 2081-2088
        • Parikh D.V.
        • Fink T.
        • Rajasekharan K.
        • Sachinvala N.D.
        • Sawhney A.P.S.
        Antimicrobial silver/sodium carboxymethyl cotton dressings for burn wounds.
        Text Res J. 2005; 5: 134-138
        • Ulkur E.
        • Oncul O.
        • Karagoz H.
        • Yeniz E.
        • Celikoz B.
        Comparison of silver-coated dressing (Acticoat), chlorhexidine acetate 0.5% (Bactigrass), and fusidic acid 2% (Fucidin) for topical antibacterial effect in methicillin-resistant staphylococci contaminated, full-skin thickness rat burn wounds.
        Burns. 2005; 31: 874-877
        • Pan��cek A.
        • Kv��tek L.
        • Prucek R.
        • Kol��r M.
        Silver colloid nanoparticles: synthesis, characterization, and their antibacterial activity.
        J Phys Chem B. 2006; 110: 16248-16253
        • Chou W.L.
        • Yu D.G.
        • Yang M.C.
        The preparation and characterization of silver loading cellulose acetate hollow fiber membrane for water treatment.
        Polym Adv Technol. 2005; 16: 600-607
        • Gibbins B.
        • Warner L.
        The role of antimicrobial silver nanotechnology.
        Medical Device & Diagnostic Industry. August 2005; : 26
        • Taylor P.L.
        • Ussher A.L.
        • Burrell R.E.
        Impact of heat on nanocrystalline silver dressings: Part I. Chemical and biological properties.
        Biomaterials. 2005; 26: 7221-7229
        • Valappil S.P.
        • Pickup D.M.
        • Carroll D.L.
        • Hope C.K.
        Effect of silver content on the structure and antibacterial activity of silver-doped phosphate-based glasses.
        Antimicrob Agents Chemother. 2007; 51: 4453-4461
        • Franck F.
        • Kelly S.M.
        • Ben W.
        Silver nanoparticles and polymeric medical devices: a new approach to prevention of infection?.
        J Antimicrob Chemother. 2004; 54: 1019-1024
        • Saravanapavan P.
        • Gough J.E.
        • Jones J.R.
        • Hench L.L.
        Antimicrobial macroporous gel glasses: dissolution and cytotoxicity.
        in: Proceedings of the 16th International Symposium on Ceramics in Medicine (BIOCERAMICS-16). Trans Tech Publications Ltd, Zurich, Switzerland2004: 1087-1090
        • Baker C.
        • Pradhan A.
        • Pakstis L.
        • Pochan D.J.
        • Shah S.I.
        Synthesis and antibacterial properties of silver nanoparticles.
        J Nanosci Nanotechnol. 2005; 5: 244-249
        • Pal S.
        • Tak Y.K.
        • Song J.M.
        Does the antibacterial activity of silver nanoparticles depend on the shape of the nanoparticle? A study of the Gram-negative bacterium Escherichia coli.
        Appl Environ Microbiol. 2007; 73: 1712-1720
        • Balan L.
        • Schneider R.
        • Lougnot D.J.
        A new and convenient route to polyacrylate/silver nanocomposites by light-induced cross-linking polymerization.
        Prog Org Coat. 2008; 62: 351-357
        • Magee A.C.
        • Matrone G.
        Studies on growth, copper metabolism of rats fed high levels of zinc.
        J Nutr. 1960; 72: 233-242
        • Ogiso T.
        • Moriyama K.
        • Sasaki S.
        Inhibitory effect of high dietary zinc on copper absorption in rats.
        Chem Pharm Bull (Tokyo). 1974; 22: 55-60
        • Van Campen D.R.
        Copper interference with the intestinal absorption of zinc-65 by rats.
        J Nutr. 1969; 97: 104-108
        • Okerete T.
        • Strenlib I.
        • Morell A.
        • Sheinberg I.
        Systemic absorption of intrauterine copper.
        Science. 1972; 177: 358-361
        • Brewer G.J.
        Zinc acetate for the treatment of Wilson's disease.
        Expert Op Pharmacother. 2001; 2: 1473-1477
        • Singh R.P.
        • Kumar S.
        • Nada R.
        • Prasad R.
        Evaluation of copper toxicity in isolated human peripheral blood mononuclear cells and its attenuation by zinc: ex vivo.
        Mol Cell Biochem. 2006; 282: 13-21
        • Li J.D.
        • Li Y.B.
        • Wang X.J.
        • Wang W.H.
        • Zhou G.
        Antibacterial effect and the mechanism of Cu2+ Zn2+ bearing nano-hydroxyapatite.
        J Inorg Mater. 2006; 21: 162-168
        • Tang X.N.
        • Xiue G.
        • Zhang B.
        Inorganic material contains copper and zinc ion.
        J Chin Rare Earth Soc. 2004; 22: 576-578