Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Silica and titanium dioxide nanoparticles cause pregnancy complications in mice

Abstract

The increasing use of nanomaterials has raised concerns about their potential risks to human health. Recent studies have shown that nanoparticles can cross the placenta barrier in pregnant mice and cause neurotoxicity in their offspring, but a more detailed understanding of the effects of nanoparticles on pregnant animals remains elusive. Here, we show that silica and titanium dioxide nanoparticles with diameters of 70 nm and 35 nm, respectively, can cause pregnancy complications when injected intravenously into pregnant mice. The silica and titanium dioxide nanoparticles were found in the placenta, fetal liver and fetal brain. Mice treated with these nanoparticles had smaller uteri and smaller fetuses than untreated controls. Fullerene molecules and larger (300 and 1,000 nm) silica particles did not induce these complications. These detrimental effects are linked to structural and functional abnormalities in the placenta on the maternal side, and are abolished when the surfaces of the silica nanoparticles are modified with carboxyl and amine groups.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Biodistribution of nanoparticles in pregnant mice.
Figure 2: Pregnancy complications in nSP70- or nano-TiO2-treated mice.
Figure 3: Pathological examination of placenta.
Figure 4: Dysfunction of placentae.
Figure 5: Prevention of nSP70-induced pregnancy complications with heparin.

References

  1. Konstantatos, G. & Sargent, E. H. Nanostructured materials for photon detection. Nature Nanotech. 5, 391–400 (2010).

    Article  CAS  Google Scholar 

  2. Augustin, M. A. & Sanguansri, P. Nanostructured materials in the food industry. Adv. Food. Nutr. Res. 58, 183–213 (2009).

    Article  CAS  Google Scholar 

  3. Bowman, D. M., van Calster, G. & Friedrichs, S. Nanomaterials and regulation of cosmetics. Nature Nanotech. 5, 92 (2010).

    Article  CAS  Google Scholar 

  4. Petros, R. A. & DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nature Rev. Drug Discov. 9, 615–627 (2010).

    Article  CAS  Google Scholar 

  5. Martin, K. R. The chemistry of silica and its potential health benefits. J. Nutr. Health Aging. 11, 94–97 (2007).

    CAS  Google Scholar 

  6. Knopp, D., Tang, D. & Niessner, R. Review: bioanalytical applications of biomolecule-functionalized nanometer-sized doped silica particles. Anal. Chim. Acta. 647, 14–30 (2009).

    Article  CAS  Google Scholar 

  7. Kagan, V. E., Bayir, H. & Shvedova, A. A. Nanomedicine and nanotoxicology: two sides of the same coin. Nanomedicine 1, 313–316 (2005).

    Article  CAS  Google Scholar 

  8. Nel, A., Xia, T., Madler, L. & Li, N. Toxic potential of materials at the nanolevel. Science 311, 622–627 (2006).

    Article  CAS  Google Scholar 

  9. Fadeel, B. & Garcia-Bennett, A. E. Better safe than sorry: understanding the toxicological properties of inorganic nanoparticles manufactured for biomedical applications. Adv. Drug. Deliv. Rev. 62, 362–374 (2010).

    Article  CAS  Google Scholar 

  10. Poland, C. A. et al. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nature Nanotech. 3, 423–428 (2008).

    Article  CAS  Google Scholar 

  11. Donaldson, K., Murphy, F. A., Duffin, R. & Poland, C. A. Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. Part. Fibre Toxicol. 7, 5 (2010).

    Article  Google Scholar 

  12. Nabeshi, H. et al. Systemic distribution, nuclear entry and cytotoxicity of amorphous nanosilica following topical application. Biomaterials 32, 2713–2724 (2011).

    Article  CAS  Google Scholar 

  13. Nabeshi, H. et al. Amorphous nanosilica induce endocytosis-dependent ROS generation and DNA damage in human keratinocytes. Part. Fibre Toxicol. 8, 1 (2011).

    Article  CAS  Google Scholar 

  14. Koren, G., Pastuszak, A. & Ito, S. Drugs in pregnancy. N. Engl. J. Med. 338, 1128–1137 (1998).

    Article  CAS  Google Scholar 

  15. Tardiff, R. G., Carson, M. L. & Ginevan, M. E. Updated weight of evidence for an association between adverse reproductive and developmental effects and exposure to disinfection by-products. Regul. Toxicol. Pharmacol. 45, 185–205 (2006).

    Article  CAS  Google Scholar 

  16. Wigle, D. T. et al. Epidemiologic evidence of relationships between reproductive and child health outcomes and environmental chemical contaminants. J. Toxicol. Environ. Health. B. Crit. Rev. 11, 373–517 (2008).

    Article  CAS  Google Scholar 

  17. Mills, J. L. et al. Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. N. Engl. J. Med. 319, 1617–1623 (1988).

    Article  CAS  Google Scholar 

  18. Cetin, I. & Alvino, G. Intrauterine growth restriction: implications for placental metabolism and transport. A review. Placenta 30(Suppl. A), S77–S82 (2009).

    Article  Google Scholar 

  19. Godfrey, K. M. & Barker, D. J. Fetal nutrition and adult disease. Am. J. Clin. Nutr. 71, 1344S–1352S (2000).

    Article  CAS  Google Scholar 

  20. Barker, D. J. Adult consequences of fetal growth restriction. Clin. Obstet. Gynecol. 49, 270–283 (2006).

    Article  Google Scholar 

  21. Takeda, K. et al. Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J. Health Sci. 55, 95–102 (2009).

    Article  CAS  Google Scholar 

  22. Shimizu, M. et al. Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse. Part. Fibre Toxicol. 6, 20 (2009).

    Article  Google Scholar 

  23. Tian, F. et al. Surface modification and size dependence in particle translocation during early embryonic development. Inhal. Toxicol. 21(Suppl. 1), 92–96 (2009).

    Article  CAS  Google Scholar 

  24. Saunders, M. Transplacental transport of nanomaterials. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 1, 671–684 (2009).

    Article  CAS  Google Scholar 

  25. Chu, M. et al. Transfer of quantum dots from pregnant mice to pups across the placental barrier. Small 6, 670–678 (2010).

    Article  CAS  Google Scholar 

  26. Hougaard, K. S. et al. Effects of prenatal exposure to surface-coated nanosized titanium dioxide (UV-Titan). A study in mice. Part. Fibre Toxicol. 7, 16 (2010).

    Article  Google Scholar 

  27. He, X. et al. In vivo study of biodistribution and urinary excretion of surface-modified silica nanoparticles. Anal. Chem. 80, 9597–9603 (2008).

    Article  CAS  Google Scholar 

  28. Wick, P. et al. Barrier capacity of human placenta for nanosized materials. Environ. Health Perspect. 118, 432–436 (2010).

    Article  CAS  Google Scholar 

  29. Watson, R. E., Desesso, J. M., Hurtt, M. E. & Cappon, G. D. Postnatal growth and morphological development of the brain: a species comparison. Birth Defects Res. B. Dev. Reprod. Toxicol. 77, 471–484 (2006).

    Article  CAS  Google Scholar 

  30. Li, L. et al. In vivo delivery of silica nanorattle encapsulated docetaxel for liver cancer therapy with low toxicity and high efficacy. ACS Nano. 4, 6874–6882 (2010).

    Article  CAS  Google Scholar 

  31. Filipe, P. et al. Stratum corneum is an effective barrier to TiO2 and ZnO nanoparticle percutaneous absorption. Skin Pharmacol. Physiol. 22, 266–275 (2009).

    Article  CAS  Google Scholar 

  32. Sadrieh, N. et al. Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles. Toxicol. Sci. 115, 156–166 (2010).

    Article  CAS  Google Scholar 

  33. Albrecht, C. et al. Inflammatory time course after quartz instillation: role of tumor necrosis factor-alpha and particle surface. Am. J. Respir. Cell. Mol. Biol. 31, 292–301 (2004).

    Article  CAS  Google Scholar 

  34. Kibschull, M., Gellhaus, A. & Winterhager, E. Analogous and unique functions of connexins in mouse and human placental development. Placenta 29, 848–854 (2008).

    Article  CAS  Google Scholar 

  35. Gasperowicz, M. & Otto, F. The notch signalling pathway in the development of the mouse placenta. Placenta 29, 651–659 (2008).

    Article  CAS  Google Scholar 

  36. Lam, C., Lim, K. H. & Karumanchi, S. A. Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia. Hypertension 46, 1077–1085 (2005).

    Article  CAS  Google Scholar 

  37. Hirashima, M., Lu, Y., Byers, L. & Rossant, J. Trophoblast expression of fms-like tyrosine kinase 1 is not required for the establishment of the maternal–fetal interface in the mouse placenta. Proc. Natl Acad. Sci. USA 100, 15637–15642 (2003).

    Article  CAS  Google Scholar 

  38. Derksen, R. H., Khamashta, M. A. & Branch, D. W. Management of the obstetric antiphospholipid syndrome. Arthritis Rheum. 50, 1028–1039 (2004).

    Article  CAS  Google Scholar 

  39. Li, Y., Wang, H. Y. & Cho, C. H. Association of heparin with basic fibroblast growth factor, epidermal growth factor, and constitutive nitric oxide synthase on healing of gastric ulcer in rats. J. Pharmacol. Exp. Ther. 290, 789–796 (1999).

    CAS  Google Scholar 

  40. Girardi, G., Redecha, P. & Salmon, J. E. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nature Med. 10, 1222–1226 (2004).

    Article  CAS  Google Scholar 

  41. Hills, F. A. et al. Heparin prevents programmed cell death in human trophoblast. Mol. Hum. Reprod. 12, 237–243 (2006).

    Article  CAS  Google Scholar 

  42. Hossain, N., Schatz, F. & Paidas, M. J. Heparin and maternal fetal interface: why should it work to prevent pregnancy complications? Thromb. Res. 124, 653–655 (2009).

    Article  CAS  Google Scholar 

  43. Girardi, G., Yarilin, D., Thurman, J. M., Holers, V. M. & Salmon, J. E. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J. Exp. Med. 203, 2165–2175 (2006).

    Article  CAS  Google Scholar 

  44. Redecha, P., van Rooijen, N., Torry, D. & Girardi, G. Pravastatin prevents miscarriages in mice: role of tissue factor in placental and fetal injury. Blood 113, 4101–4109 (2009).

    Article  CAS  Google Scholar 

  45. Myatt, L. & Cui, X. Oxidative stress in the placenta. Histochem. Cell. Biol. 122, 369–382 (2004).

    Article  CAS  Google Scholar 

  46. Hussain, S. et al. Oxidative stress and proinflammatory effects of carbon black and titanium dioxide nanoparticles: role of particle surface area and internalized amount. Toxicology 260, 142–149 (2009).

    Article  CAS  Google Scholar 

  47. Liu, X. & Sun, J. Endothelial cells dysfunction induced by silica nanoparticles through oxidative stress via JNK/P53 and NF-κB pathways. Biomaterials 31, 8198–8209 (2010).

    Article  CAS  Google Scholar 

  48. Lundqvist, M. et al. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc. Natl Acad. Sci. USA 105, 14265–14270 (2008).

    Article  CAS  Google Scholar 

  49. Enders, A. C. & Blankenship, T. N. Comparative placental structure. Adv. Drug Deliv. Rev. 38, 3–15 (1999).

    Article  CAS  Google Scholar 

  50. Rossant, J. & Cross, J. C. Placental development: lessons from mouse mutants. Nature Rev. Genet. 2, 538–548 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) and from the Japan Society for the Promotion of Science (JSPS) through a Knowledge Cluster Initiative (MEXT). It was also supported by Health Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan (MHLW), by a Global Environment Research Fund from the Minister of the Environment, and by the Food Safety Commission (Cabinet Office), the Cosmetology Research Foundation, the Smoking Research Foundation and the Takeda Science Foundation.

Author information

Authors and Affiliations

Authors

Contributions

K.Y. and Y.Y. designed the study. K.Y., K.H., K.M., Y. Morishita, M.N., T. Yoshida, T.O., H.N., K.N., Y.A., H.K., Y. Monobe and T.I. performed the experiments. K.Y. and Y.Y. collected and analysed the data. K.Y. and Y.Y. wrote the manuscript. H.A., K.S., Y.K., T.M., S.T., N.I., I.Y., S.S. and T. Yoshikawa provided technical support and conceptual advice. Y.T. supervised the project. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Yasuo Yoshioka or Yasuo Tsutsumi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 559 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yamashita, K., Yoshioka, Y., Higashisaka, K. et al. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nature Nanotech 6, 321–328 (2011). https://doi.org/10.1038/nnano.2011.41

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2011.41

This article is cited by

Search

Quick links

Find nanotechnology articles, nanomaterial data and patents all in one place. Visit Nano by Nature Research