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Silica and titanium dioxide nanoparticles cause pregnancy complications in mice

Nature Nanotechnology volume 6, pages 321–328 (2011)Cite this article

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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.

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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.

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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.

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Author notes

  1. Kohei Yamashita and Yasuo Yoshioka: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Kohei Yamashita, Yasuo Yoshioka, Kazuma Higashisaka, Yuki Morishita, Tokuyuki Yoshida, Toshinobu Ogura, Hiromi Nabeshi, Norio Itoh, Tomoaki Yoshikawa & Yasuo Tsutsumi

  2. Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8, Saito-Asagi, Ibaraki, 567-0085, Osaka, Japan

    Kohei Yamashita, Yasuo Yoshioka, Kazuma Higashisaka, Yuki Morishita, Tokuyuki Yoshida, Toshinobu Ogura, Hiromi Nabeshi, Kazuya Nagano, Yasuhiro Abe, Haruhiko Kamada, Shin-ichi Tsunoda, Tomoaki Yoshikawa & Yasuo Tsutsumi

  3. The Center for Advanced Medical Engineering and Informatics, Osaka University, 1-6, Yamadaoka, Suita, 565-0871, Osaka, Japan

    Yasuo Yoshioka, Haruhiko Kamada, Shin-ichi Tsunoda & Yasuo Tsutsumi

  4. Department of Developmental Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, 594-1101, Osaka, Japan

    Kazuya Mimura, Masatoshi Nozaki & Itaru Yanagihara

  5. Bioresources Research, Laboratory of Common Apparatus, National Institute of Biomedical Innovation, 7-6-8, Saito-Asagi, Ibaraki, 567-0085, Osaka, Japan

    Youko Monobe & Takayoshi Imazawa

  6. Vitamin C60 BioResearch Corporation, 1-3-19, Yaesu, Chuo-ku, 103-0028, Tokyo, Japan

    Hisae Aoshima

  7. Mitsubishi Corporation, 2-6-1, Marunouchi, Chiyoda-ku, 100-8086, Tokyo, Japan

    Kiyoshi Shishido

  8. Graduate School of Pharmaceutical Sciences, Kobe-Gakuin University, 1-1-3, Minatojima, Chuo-ku, Kobe, 650-8586, Hyogo, Japan

    Yuichi Kawai & Tadanori Mayumi

  9. Department of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, 7-6-8 Saito-asagi, Ibaraki, 567-0085, Osaka, Japan

    Shin-ichi Tsunoda

  10. Department of Obstetrics and Gynecology, University of Toyama, 2630, Sugitani, Toyama, 930-0194, Japan

    Shigeru Saito

Authors
  1. Kohei Yamashita
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  2. Yasuo Yoshioka
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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.

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The authors declare no competing financial interests.

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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

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