Nano Research

, Volume 11, Issue 6, pp 3419–3433 | Cite as

Gold nanoparticles cause size-dependent inhibition of embryonic development during murine pregnancy

  • Xiaowei Ma
  • Xiaolong Yang
  • Yufei Wang
  • Juan Liu
  • Shubin Jin
  • Shuyi Li
  • Xing-Jie LiangEmail author
Research Article


Gold nanoparticles (Au NPs) have been widely utilized in biomedical applications owing to their attractive features and biocompatibility, which greatly increase the risk of humans’ being exposed to Au NPs, including pregnant women. In contrast to mature cells, embryos are more susceptible to outside disruptive stimuli. Nonetheless, a possible inhibitory effect of nanomaterials on embryonic development is usually ignored as long as the NPs do not have significant cytotoxic effects. According to our results, a minimal “nontoxic” concentration of Au NPs during early pregnancy can have lethal inhibitory effects on embryos in vivo and in vitro. We conducted important experiments on the influence of Au NPs on embryonic development and found that Au NPs can disturb embryonic development in a size- and concentration-dependent manner. Au NPs of 15 nm in diameter downregulated the expression pattern of distinct germ layer markers both at mRNA and protein levels; this action prevented differentiation of all three embryonic germ layers. Consequently, fetal resorption was observed. Our work reveals the impact of Au NPs on embryonic development and will provide an important guidance and serve as a reference for biomedical applications of Au NPs with minimal side effects.


gold nanoparticles embryonic development fetal resorption differentiation 


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This work was supported by the National Natural Science Foundation of China (No. 31600808), the Beijing Natural Science Foundation (No. 7164316). This work was supported in part by Chinese Natural Science Foundation key projects (Nos. 31630027 and 31430031). The authors also appreciate the support of the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA09030301).

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Gold nanoparticles cause size-dependent inhibition of embryonic development during murine pregnancy


  1. [1]
    El-Sayed, I. H.; Huang, X. H.; El-Sayed, M. A. Surface plasmon resonance scattering and absorption of anti-egfr antibody conjugated gold nanoparticles in cancer diagnostics: Applications in oral cancer. Nano Lett. 2005, 5, 829–834.CrossRefGoogle Scholar
  2. [2]
    Lin, C. A. J.; Yang, T. Y.; Lee, C. H.; Huang, S. H.; Sperling, R. A.; Zanella, M.; Li, J. K.; Shen, J. L.; Wang, H. H.; Yeh, H.-I. et al. Synthesis, characterization, and bioconjugation of fluor-escent gold nanoclusters toward biological labeling applications. ACS Nano 2009, 3, 395–401.CrossRefGoogle Scholar
  3. [3]
    Wu, X.; He, X. X.; Wang, K. M.; Xie, C.; Zhou, B.; Qing, Z. H. Ultrasmall near-infrared gold nanoclusters for tumor fluorescence imaging in vivo. Nanoscale 2010, 2, 2244–2249.CrossRefGoogle Scholar
  4. [4]
    Leuvering, J. H. W.; Thal, P. J. M.; Schuurs, A. H. W. M. Optimization of a sandwich sol particle immunoassay for human chorionic gonadotrophin. J. Immunol. Methods 1983, 62, 175–184.CrossRefGoogle Scholar
  5. [5]
    Liu, X.; Dai, Q.; Austin, L.; Coutts, J.; Knowles, G.; Zou, J. H.; Chen, H.; Huo, Q. A one-step homogeneous immunoassay for cancer biomarker detection using gold nanoparticle probes coupled with dynamic light scattering. J. Am. Chem. Soc. 2008, 130, 2780–2782.CrossRefGoogle Scholar
  6. [6]
    Cheng, Z. L.; Al Zaki, A.; Hui, J. Z.; Muzykantov, V. R.; Tsourkas, A. Multifunctional nanoparticles: Cost versus benefit of adding targeting and imaging capabilities. Science 2012, 338, 903–910.CrossRefGoogle Scholar
  7. [7]
    Keelan, J. A. Nanotoxicology: Nanoparticles versus the placenta. Nat. Nanotechnol. 2011, 6, 263–264.CrossRefGoogle Scholar
  8. [8]
    Li, P. W.; Kuo, T. H.; Chang, J. H.; Yeh, J. M.; Chan, W. H. Induction of cytotoxicity and apoptosis in mouse blastocysts by silver nanoparticles. Toxicol. Lett. 2010, 197, 82–87.CrossRefGoogle Scholar
  9. [9]
    Takeda, K.; Suzuki, K. I.; Ishihara, A.; Kubo-Irie, M.; Fujimoto, R.; Tabata, M.; Oshio, S.; Nihei, Y.; Ihara, T.; Sugamata, M. Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J. Health Sci. 2009, 55, 95–102.CrossRefGoogle Scholar
  10. [10]
    Philbrook, N. A.; Winn, L. M.; Afrooz, A. R. M. N.; Saleh, N. B.; Walker, V. K. The effect of TiO2 and Ag nanoparticles on reproduction and development of Drosophila melanogaster and CD-1 mice. Toxicol. Appl. Pharmacol. 2011, 257, 429–436.CrossRefGoogle Scholar
  11. [11]
    Hougaard, K. S.; Jackson, P.; Jensen, K. A.; Sloth, J. J.; Löschner, K.; Larsen, E. H.; Birkedal, R. K.; Vibenholt, A.; Boisen, A. M. Z.; Wallin, H. et al. Effects of prenatal exposure to surface-coated nanosized titanium dioxide (Uv-Titan). A study in mice. Part. Fibre Toxicol. 2010, 7, 16.CrossRefGoogle Scholar
  12. [12]
    Yamashita, K.; Yoshioka, Y.; Higashisaka, K.; Mimura, K.; Morishita, Y.; Nozaki, M.; Yoshida, T.; Ogura, T.; Nabeshi, H.; Nagano, K. et al. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat. Nanotechnol. 2011, 6, 321–328.CrossRefGoogle Scholar
  13. [13]
    Qi, L. F.; Xu, Z. R.; Jiang, X.; Li, Y.; Wang, M. Q. Cytotoxic activities of chitosan nanoparticles and copper-loaded nanoparticles. Bioorg. Med. Chem. Lett. 2005, 15, 1397–1399.CrossRefGoogle Scholar
  14. [14]
    Lim, J. H.; Kim, S. H.; Shin, I. S.; Park, N. H.; Moon, C.; Kang, S. S.; Kim, S. H.; Park, S. C.; Kim, J. C. Maternal exposure to multi-wall carbon nanotubes does not induce embryo-fetal developmental toxicity in rats. Birth Defects Res. Part B: Dev. Reprod. Toxicol. 2011, 92, 69–76.CrossRefGoogle Scholar
  15. [15]
    Campagnolo, L.; Massimiani, M.; Palmieri, G.; Bernardini, R.; Sacchetti, C.; Bergamaschi, A.; Vecchione, L.; Magrini, A.; Bottini, M.; Pietroiusti, A. Biodistribution and toxicity of pegylated single wall carbon nanotubes in pregnant mice. Part. Fibre Toxicol. 2013, 10, 21–33.CrossRefGoogle Scholar
  16. [16]
    Chan, W. H.; Shiao, N. H. Cytotoxic effect of cdse quantum dots on mouse embryonic development. Acta Pharmacol. Sin. 2008, 29, 259–266.CrossRefGoogle Scholar
  17. [17]
    Hsieh, M. S.; Shiao, N. H.; Chan, W. H. Cytotoxic effects of CdSe quantum dots on maturation of mouse oocytes, fertilization, and fetal development. Int. J. Mol. Sci. 2009, 10, 2122–2135.CrossRefGoogle Scholar
  18. [18]
    Chu, M. Q.; Wu, Q.; Yang, H.; Yuan, R. Q.; Hou, S. K.; Yang, Y. F.; Zou, Y. J.; Xu, S.; Xu, K. Y.; Ji, A. L. et al. Transfer of quantum dots from pregnant mice to pups across the placental barrier. Small 2010, 6, 670–678.CrossRefGoogle Scholar
  19. [19]
    Wiwanitkit, V.; Sereemaspun, A.; Rojanathanes, R. Effect of gold nanoparticles on spermatozoa: The first world report. Fertil. Steril. 2009, 91, e7–e8.CrossRefGoogle Scholar
  20. [20]
    Taylor, U.; Barchanski, A.; Petersen, S.; Kues, W. A.; Baulain, U.; Gamrad, L.; Sajti, L.; Barcikowski, S.; Rath, D. Gold nanoparticles interfere with sperm functionality by membrane adsorption without penetration. Nanotoxicology 2014, 8, 118–127.CrossRefGoogle Scholar
  21. [21]
    Tiedemann, D.; Taylor, U.; Rehbock, C.; Jakobi, J.; Klein, S.; Kues, W. A.; Barcikowski, S.; Rath, D. Reprotoxicity of gold, silver, and gold-silver alloy nanoparticles on mammalian gametes. Analyst 2014, 139, 931–942.CrossRefGoogle Scholar
  22. [22]
    Yang, H.; Sun, C. J.; Fan, Z. L.; Tian, X.; Yan, L.; Du, L.; Liu, Y.; Chen, C. Y.; Liang, X. J.; Anderson, G. J. et al. Effects of gestational age and surface modification on materno-fetal transfer of nanoparticles in murine pregnancy. Sci. Rep. 2012, 2, 847.CrossRefGoogle Scholar
  23. [23]
    Hui, Y.; Du, L. B.; Xin, T.; Fan, Z. L.; Sun, C. J.; Yang, L.; Keelan, J. A.; Nie, G. J. Effects of nanoparticle size and gestational age on maternal biodistribution and toxicity of gold nanoparticles in pregnant mice. Toxicol. Lett. 2014, 230, 10–18.CrossRefGoogle Scholar
  24. [24]
    Xin, T.; Zhu, M. T.; Du, L. B.; Jing, W.; Fan, Z. L.; Liu, J.; Zhao, Y. L.; Nie, G. J. Intrauterine inflammation increases materno-fetal transfer of gold nanoparticles in a size-dependent manner in murine pregnancy. Small 2013, 9, 2432–2439.CrossRefGoogle Scholar
  25. [25]
    Tsyganova, N. A.; Khairullin, R. M.; Terentyuk, G. S.; Khlebtsov, B. N.; Bogatyrev, V. A.; Dykman, L. A.; Erykov, S. N.; Khlebtsov, N. G. Penetration of pegylated gold nanoparticles through rat placental barrier. Bull. Exp. Biol. Med. 2014, 157, 383–385.CrossRefGoogle Scholar
  26. [26]
    Semmler-Behnke, M.; Lipka, J.; Wenk, A.; Hirn, S.; Schäffler, M.; Tian, F. R.; Schmid, G.; Oberdörster, G.; Kreyling, W. G. Size dependent translocation and fetal accumulation of gold nanoparticles from maternal blood in the rat. Part. Fibre Toxicol. 2014, 11, 33.CrossRefGoogle Scholar
  27. [27]
    Huo, S. D.; Jin, S. B.; Ma, X. W.; Xue, X. D.; Yang, K. N.; Kumar, A.; Wang, P. C.; Zhang, J. C.; Hu, Z. B.; Liang, X. J. Ultrasmall gold nanoparticles as carriers for nucleus-based gene therapy due to size-dependent nuclear entry. ACS Nano 2014, 8, 5852–5862.CrossRefGoogle Scholar
  28. [28]
    Huang, K. Y.; Ma, H. L.; Liu, J.; Huo, S. D.; Kumar, A.; Wei, T.; Zhang, X.; Jin, S. B.; Gan, Y. L.; Wang, P. C. et al. Size-dependent localization and penetration of ultrasmall gold nanoparticles in cancer cells, multicellular spheroids, and tumors in vivo. ACS Nano 2012, 6, 4483–4493.CrossRefGoogle Scholar
  29. [29]
    Huo, S. D.; Ma, H. L.; Huang, K. Y.; Liu, J.; Wei, T.; Jin, S. B.; Zhang, J. C.; He, S. T.; Liang, X. J. Superior penetration and retention behavior of 50 nm gold nanoparticles in tumors. Cancer Res. 2013, 73, 319–330.CrossRefGoogle Scholar
  30. [30]
    Jiang, W.; Kim, B. Y. S.; Rutka, J. T.; Chan, W. C. W. Nanoparticle-mediated cellular response is size-dependent. Nat. Nanotechnol. 2008, 3, 145–150.CrossRefGoogle Scholar
  31. [31]
    Giljohann, D. A.; Seferos, D. S.; Daniel, W. L.; Massich, M. D.; Patel, P. C.; Mirkin, C. A. Gold nanoparticles for biology and medicine. Angew. Chem., Int. Ed. 2010, 49, 3280–3294.CrossRefGoogle Scholar
  32. [32]
    Nel, A. E.; Mädler, L.; Velegol, D.; Tian, X.; Hoek, E. M. V.; Somasundaran, P.; Klaessig, F.; Castranova, V.; Thompson, M. Understanding biophysicochemical interactions at the nano-bio interface. Nat. Mater. 2009, 8, 543–557.CrossRefGoogle Scholar
  33. [33]
    Pan, G. J.; Thomson, J. A. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 2007, 17, 42–49.CrossRefGoogle Scholar
  34. [34]
    Kraushaar, D. C.; Yamaguchi, Y.; Wang, L. C. Heparan sulfate is required for embryonic stem cells to exit from self-renewal. J. Biol. Chem. 2010, 285, 5907–5916.CrossRefGoogle Scholar
  35. [35]
    He, S. H.; Nakada, D.; Morrison, S. J. Mechanisms of stem cell self-renewal. Annu. Rev. Cell Dev. Biol. 2009, 25, 377–406.CrossRefGoogle Scholar
  36. [36]
    Conway, A.; Vazin, T.; Spelke, D. P.; Rode, N. A.; Healy, K. E.; Kane, R. S.; Schaffer, D. V. Multivalent ligands control stem cell behaviour in vitro and in vivo. Nat. Nanotechnol. 2013, 8, 831–838.CrossRefGoogle Scholar
  37. [37]
    Ren, M. M.; Han, Z.; Li, J. L.; Feng, G.; Ouyang, S. Y. Ascorbic acid delivered by mesoporous silica nanoparticles induces the differentiation of human embryonic stem cells into cardio-myocytes. Mater. Sci. Eng., C 2015, 56, 348–355.CrossRefGoogle Scholar
  38. [38]
    Smith, L. A.; Liu, X. H.; Hu, J.; Ma, P. X. The enhancement of human embryonic stem cell osteogenic differentiation with nano-fibrous scaffolding. Biomaterials 2010, 31, 5526–5535.CrossRefGoogle Scholar
  39. [39]
    Pelton, T. A.; Bettess, M. D.; Lake, J.; Rathjen, J.; Rathjen, P. D. Developmental complexity of early mammalian pluripotent cell populations in vivo and in vitro. Reprod. Fertil. Dev. 1998, 10, 535–549.CrossRefGoogle Scholar
  40. [40]
    Guo, S. T.; Huang, Y. Y.; Jiang, Q.; Sun, Y.; Deng, L. D.; Liang, Z. C.; Du, Q.; Xing, J. F.; Zhao, Y. L.; Wang, P. C. et al. Enhanced gene delivery and siRNA silencing by gold nano-particles coated with charge-reversal polyelectrolyte. ACS Nano 2010, 4, 5505–5511.CrossRefGoogle Scholar
  41. [41]
    Li, F.; Li, T. Y.; Sun, C. X.; Xia, J. H.; Jiao, Y.; Xu, H. P. Selenium-doped carbon quantum dots for free-radical scav-enging. Angew. Chem., Int. Ed. 2017, 56, 9910–9914.CrossRefGoogle Scholar
  42. [42]
    Chung, M. F.; Liu, H. Y.; Lin, K. J.; Chia, W. T.; Sung, H. W. A Ph-responsive carrier system that generates No bubbles to trigger drug release and reverse P-glycoprotein-mediated multidrug resistance. Angew. Chem., Int. Ed. 2015, 54, 9890–9893.CrossRefGoogle Scholar
  43. [43]
    Cao-Milán, R.; Liz-Marzán, L. M. Gold nanoparticle conjugates: Recent advances toward clinical applications. Expert Opin. Drug Deliv. 2014, 11, 741–752.CrossRefGoogle Scholar
  44. [44]
    Shukla, R.; Bansal, V.; Chaudhary, M.; Basu, A.; Bhonde, R. R.; Sastry, M. Biocompatibility of gold nanoparticles and their endocytotic fate inside the cellular compartment: A microscopic overview. Langmuir 2005, 21, 10644–10654.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Xiaowei Ma
    • 1
    • 2
  • Xiaolong Yang
    • 3
  • Yufei Wang
    • 1
    • 2
  • Juan Liu
    • 4
  • Shubin Jin
    • 5
  • Shuyi Li
    • 1
    • 2
  • Xing-Jie Liang
    • 1
    • 2
    Email author
  1. 1.Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of ChinaBeijingChina
  2. 2.University of Chinese Academy of SciencesBeijingChina
  3. 3.College of BiotechnologyTianjin University of Science & TechnologyTianjinChina
  4. 4.Tissue Engineering LabBeijing Institute of Transfusion MedicineBeijingChina
  5. 5.Beijing Municipal Institute of Labour ProtectionBeijingChina

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