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Cite This: Chem. Res. Toxicol. 2018, 31, 641−642
Developmental Toxicity of Nanomaterials: Need for a Better Understanding of Indirect Effects Tina Buerki-Thurnherr,* Kyrena Schaepper, Leonie Aengenheister, and Peter Wick
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Particles-Biology Interactions, Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, 9014 St. Gallen, Switzerland ABSTRACT: While placental translocation and direct toxicity to fetal tissue of traversed nanomaterials has been a key focus of developmental toxicity studies, the release of maternal and fetal mediators that indirectly interfere with fetal development and health later in life lacks systematic insights and deserves special attention.
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circulation, and so far, it is unclear if these low amounts of transferred particles can account for the adverse embryofetotoxic effects. In fact, developmental toxicity can even occur in the absence of apparent placental transfer. It appears that particles can cause adverse effects by inducing the release of mediators in maternal or placental tissue (indirect effects). For instance, pulmonary exposure of pregnant mice to TiO2 and CeO2 nanoparticles induced fetal growth restriction and longlasting lung impairment in the offspring without detectable particles in fetal lung tissue.3 The authors hypothesized that these were due to placental-mediated toxicity since they found accumulation of particles in the placental tissue, a decrease in placental efficiency, and downregulation of critical placental mediators of lung development (e.g., VEGR-α, MMP-9, and FGF-18), but mechanistic support for these conclusions is difficult to attain from such in vivo model studies. Moreover, the placenta is perhaps the most species-specific mammalian organ, which questions the relevance of animal data for gaining insight on human pregnancy. To achieve the most comprehensive insights on placentamediated toxicity, particularly for addressing indirect mechanisms, future studies should exploit advanced human in vitro and ex vivo placenta models to complement in vivo studies in pregnant rodents. These existing and emerging models provide a unique opportunity since the placenta is a rather accessible human organ that provides primary material from different stages of pregnancy. There are a variety of promising models such as the ex vivo placenta perfusion system, placental explants, or primary trophoblast cultures.1,2 In addition, cell line-based in vitro human placenta models such as 3D coculture microtissues4 or BeWo cell transfer models1,5 are
n the last decades, tremendous research activities into new nanomaterial-based solutions for industrial, body care, or medical applications were made. The large-scale production and extensive use of nanomaterials across many industries and fields will inevitably increase human exposure and raise safety concerns in particular for vulnerable populations. Among these, the developing fetus is particularly sensitive to adverse effects of chemicals. Even small amounts of toxic compounds can have a devastating impact on embryo-fetal development and health while being nonhazardous to the adult organism. Because of their small size and unique properties, nanomaterials have the propensity to overcome biological tissue barriers. Translocation has first been described for primary barriers including the lung and gastrointestinal tract. With the realization that nanomaterials can reach systemic circulation, internal protective barriers became increasingly relevant. The placenta is of particular importance since it performs a multitude of functions essential for successful pregnancy, protects the developing fetus from harmful substances, and defines in utero exposure. First indications that nanomaterials can cross the placental barrier and induce developmental toxicity came from animal studies, and transfer was later confirmed in human placenta perfusion studies (reviewed in ref 1). Placental transfer has been shown to depend on many parameters including particle characteristics (e.g., size and surface modification), exposure route, and applied dose as well as the timing and duration of exposure; however, underlying translocation mechanisms are only marginally understood.1,2 For years, the prevailing conception was that translocated particles are responsible for the observed developmental toxicity of nanomaterials through direct interference with embryo/fetal tissue function (direct effects). However, often only few percentages of the applied doses reach the fetal © 2018 American Chemical Society
Published: July 23, 2018 641
DOI: 10.1021/acs.chemrestox.8b00177 Chem. Res. Toxicol. 2018, 31, 641−642
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Chemical Research in Toxicology
metallic nanomaterials during pregnancy irreversibly impairs lung development of the offspring. Nanotoxicology 11, 484−495. (4) Muoth, C., Wichser, A., Monopoli, M., Correia, M., Ehrlich, N., Loeschner, K., Gallud, A., Kucki, M., Diener, L., Manser, P., Jochum, W., Wick, P., and Buerki-Thurnherr, T. (2016) A 3D co-culture microtissue model of the human placenta for nanotoxicity assessment. Nanoscale 8, 17322. (5) Hawkins, S. J., Crompton, L. A., Sood, A., Saunders, M., Boyle, N. T., Buckley, A., Minogue, A. M., McComish, S. F., JimenezMoreno, N., Cordero-Llana, O., Stathakos, P., Gilmore, C. E., Kelly, S., Lane, J. D., Case, C. P., and Caldwell, M. A. (2018) Nanoparticleinduced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes. Nat. Nanotechnol. 13, 427− 433.
available and amenable to high-throughput use. A smart combination of in vitro placenta models, embryo-fetal development models, and in vivo studies can effectively push our knowledge on indirect developmental toxicity mechanisms.5 Using such an approach, it was shown that CoCr nanoparticleinduced indirect neuronal toxicity across the placental barrier was triggered by impairment of autophagic flux and release of interleukin-6.5 There are also hints in literature for potential interference of nanomaterials with endocrine, inflammatory, and vascular signaling from the placental tissue, which needs to be carefully addressed since dysregulation of such mediators has been involved in the pathogenesis of pregnancy disorders including preeclampsia, intrauterine growth restriction, or preterm birth. Nanomaterial contact with maternal tissues is a further mechanism that should be considered during pregnancy. Inflammatory and oxidative stress responses frequently associated with nanomaterial exposure have been postulated as candidates for indirect maternal-mediated developmental toxicity.2 Maternal mediators may either directly pass the placental barrier or affect signaling processes and functions of secondary organs (including the placenta), thereby contributing to the establishment of a hostile gestational environment for fetal development. Clearly, considering the limited available data, there is a tremendous need to better understand mechanisms of developmental toxicity influenced by nanomaterials including direct and indirect maternal- and placental-mediated effects to establish the groundwork for a sound risk assessment of nanomaterials in pregnancy and their safe and sustainable use in industrial, commercial, and potential medical applications. New insights on direct/indirect toxicity mechanisms at the placental barrier may also be relevant for other biological barriers, where access to primary tissue is more limited or not available.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Tina Buerki-Thurnherr: 0000-0003-3723-6562 Peter Wick: 0000-0002-0079-4344 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. The authors declare no competing financial interest.
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REFERENCES
(1) Muoth, C., Aengenheister, L., Kucki, M., Wick, P., and BuerkiThurnherr, T. (2016) Nanoparticle transport across the placental barrier: pushing the field forward! Nanomedicine (London, U. K.) 11, 941−957. (2) Hougaard, K. S., Campagnolo, L., Chavatte-Palmer, P., Tarrade, A., Rousseau-Ralliard, D., Valentino, S., Park, M. V., de Jong, W. H., Wolterink, G., Piersma, A. H., Ross, B. L., Hutchison, G. R., Hansen, J. S., Vogel, U., Jackson, P., Slama, R., Pietroiusti, A., and Cassee, F. R. (2015) A perspective on the developmental toxicity of inhaled nanoparticles. Reprod. Toxicol. 56, 118−140. (3) Paul, E., Franco-Montoya, M.-L., Paineau, E., Angeletti, B., Vibhushan, S., Ridoux, A., Tiendrebeogo, A., Salome, M., Hesse, B., Vantelon, D., Rose, J., Canouï-Poitrine, F., Boczkowski, J., Lanone, S., Delacourt, C., and Pairon, J.-C. (2017) Pulmonary exposure to 642
DOI: 10.1021/acs.chemrestox.8b00177 Chem. Res. Toxicol. 2018, 31, 641−642
