Abstract
Amorphous silica nanoparticles are widely used as pharmaceutical excipients and food additive (E551). Despite the potential human health risks of mineral nanoparticles, very few data regarding their oral toxicity are currently available. This study aims to evaluate and to understand the interactions of silica particles at 1 and 10 mg mL−1 with the intestinal barrier using a Caco-2 monolayer and a Caco-2/HT29-MTX co-culture. A size- and concentration-dependent reversible increase of the paracellular permeability is identified after a short-term exposure to silica nanoparticles. Nanoparticles of 30 nm induce the highest transepithelial electrical resistance drop whereas no effect is observed with 200 nm particles. Additive E551 affect the Caco-2 monolayer permeability. Mucus layer reduces the permeability modulation by limiting the cellular uptake of silica. After nanoparticle exposure, tight junction expression including Zonula occludens 1 (ZO-1) and Claudin 2 is not affected, whereas the actin cytoskeleton disruption of enterocytes and the widening of ZO-1 staining bands are observed. A complete permeability recovery is concomitant with the de novo filament actin assembly and the reduction of ZO-1 bands. These findings suggest the paracellular modulation by small silica particles is directly correlated to the alteration of the ZO-actin binding strongly involved in the stability of the tight junction network.
Similar content being viewed by others
References
Athinarayanan J, Periasamy VS, Alsaif MA et al (2014) Presence of nanosilica (E551) in commercial food products: TNF-mediated oxidative stress and altered cell cycle progression in human lung fibroblast cells. Cell Biol Toxicol 30:89–100. https://doi.org/10.1007/s10565-014-9271-8
Barahona F, Ojea-Jimenez I, Geiss O et al (2016) Multimethod approach for the detection and characterisation of food-grade synthetic amorphous silica nanoparticles. J Chromatogr A 1432:92–100. https://doi.org/10.1016/j.chroma.2015.12.058
Billat P-A, Roger E, Faure S, Lagarce F (2017) Models for drug absorption from the small intestine: where are we and where are we going? Drug Discov Today 22:761–775. https://doi.org/10.1016/j.drudis.2017.01.007
Brun E, Barreau F, Veronesi G et al (2014) Titanium dioxide nanoparticle impact and translocation through ex vivo, in vivo and in vitro gut epithelia. Part Fibre Toxicol 11:13. https://doi.org/10.1186/1743-8977-11-13
Christen V, Camenzind M, Fent K (2014) Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway. Toxicol Rep 1:1143–1151. https://doi.org/10.1016/j.toxrep.2014.10.023
EFSA Panel on Food Additivies, and Nutrient Sources added to Food (ANS), Younes M, Aggett P et al (2018) Re-evaluation of silicon dioxide (E 551) as a food additive. EFSA J. https://doi.org/10.2903/j.efsa.2018.5088
He X, Deng H, Hwang H (2019) The current application of nanotechnology in food and agriculture. J Food Drug Anal 27:1–21. https://doi.org/10.1016/j.jfda.2018.12.002
Ispanixtlahuatl-Meráz O, Schins RPF, Chirino YI (2018) Cell type specific cytoskeleton disruption induced by engineered nanoparticles. Environ Sci Nano 5:228–245. https://doi.org/10.1039/C7EN00704C
Jackson TC, Patani BO, Israel MB (2017) Nanomaterials and cell interactions: a review. JBNB 08:220–228. https://doi.org/10.4236/jbnb.2017.84015
Kirby R, Linklater AKJ (eds) (2016) Monitoring and intervention for the critically ill small animal: the rule of 20. Wiley Blackwell, Ames
Kleiveland CR (2015) Co-cultivation of Caco-2 and HT-29MTX. In: Verhoeckx K, Cotter P, López-Expósito I, et al. (eds) The impact of food bioactives on health: in vitro and ex vivo models. Springer International Publishing, Cham, pp 135–140
Lee SH (2015) Intestinal permeability regulation by tight junction: implication on inflammatory bowel diseases. Intest Res 13:11–18. https://doi.org/10.5217/ir.2015.13.1.11
Lemmer HJR, Hamman JH (2013) Paracellular drug absorption enhancement through tight junction modulation. Expert Opin Drug Deliv 10:103–114. https://doi.org/10.1517/17425247.2013.745509
Li C-H, Shyu M-K, Jhan C et al (2015) Gold nanoparticles increase endothelial paracellular permeability by altering components of endothelial tight junctions, and increase blood–brain barrier permeability in mice. Toxicol Sci 148:192–203. https://doi.org/10.1093/toxsci/kfv176
Liu X, Sui B, Sun J (2017) Blood-brain barrier dysfunction induced by silica NPs in vitro and in vivo: Involvement of oxidative stress and Rho-kinase/JNK signaling pathways. Biomaterials 121:64–82. https://doi.org/10.1016/j.biomaterials.2017.01.006
Ma TY, Hoa NT, Tran DD et al (2000) Cytochalasin B modulation of Caco-2 tight junction barrier: role of myosin light chain kinase. Am J Physiol 279:G875–G885. https://doi.org/10.1152/ajpgi.2000.279.5.G875
Madara JL, Barenberg D, Carlson S (1986) Effects of cytochalasin D on occluding junctions of intestinal absorptive cells: further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity. J Cell Biol 102:2125–2136. https://doi.org/10.1083/jcb.102.6.2125
Madara JL, Moore R, Carlson S (1987) Alteration of intestinal tight junction structure and permeability by cytoskeletal contraction. Am J Physiol 253:C854–861. https://doi.org/10.1152/ajpcell.1987.253.6.C854
Pedata P, Ricci G, Malorni L et al (2019) In vitro intestinal epithelium responses to titanium dioxide nanoparticles. Food Res Int 119:634–642. https://doi.org/10.1016/j.foodres.2018.10.041
Pradhan N, Singh S, Ojha N et al (2015) Facets of nanotechnology as seen in food processing, packaging, and preservation industry. Biomed Res Int 2015:1–17. https://doi.org/10.1155/2015/365672
Rao R (2008) Oxidative stress-induced disruption of epithelial and endothelial tight junctions. Front Biosci 13:7210–7226
Rodgers LS, Fanning AS (2011) Regulation of epithelial permeability by the actin cytoskeleton. Cytoskeleton 68:653–660. https://doi.org/10.1002/cm.20547
Sahu SC, Hayes AW (2017) Toxicity of nanomaterials found in human environment: a literature review. Toxicol Res Appl. https://doi.org/10.1177/2397847317726352
Stevenson BR, Begg DA (1994) Concentration-dependent effects of cytochalasin D on tight junctions and actin filaments in MDCK epithelial cells. J Cell Sci 107(Pt 3):367–375
Suzuki T, Yoshinaga N, Tanabe S (2011) Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium. J Biol Chem 286:31263–31271. https://doi.org/10.1074/jbc.M111.238147
Talavera D, Castillo AM, Dominguez MC et al (2004) IL8 release, tight junction and cytoskeleton dynamic reorganization conducive to permeability increase are induced by dengue virus infection of microvascular endothelial monolayers. J Gen Virol 85:1801–1813. https://doi.org/10.1099/vir.0.19652-0
Tarantini A, Lanceleur R, Mourot A et al (2015) Toxicity, genotoxicity and proinflammatory effects of amorphous nanosilica in the human intestinal Caco-2 cell line. Toxicol In Vitro 29:398–407. https://doi.org/10.1016/j.tiv.2014.10.023
Van Itallie CM, Fanning AS, Bridges A, Anderson JM (2009) ZO-1 stabilizes the tight junction solute barrier through coupling to the perijunctional cytoskeleton. Mol Biol Cell 20:3930–3940. https://doi.org/10.1091/mbc.e09-04-0320
Vancamelbeke M, Vermeire S (2017) The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol 11:821–834. https://doi.org/10.1080/17474124.2017.1343143
Weber CR (2012) Dynamic properties of the tight junction barrier: dynamic properties of the tight junction barrier. Ann N Y Acad Sci 1257:77–84. https://doi.org/10.1111/j.1749-6632.2012.06528.x
Ye D, Bramini M, Hristov DR et al (2017) Low uptake of silica nanoparticles in Caco-2 intestinal epithelial barriers. Beilstein J Nanotechnol 8:1396–1406. https://doi.org/10.3762/bjnano.8.141
Zhou Y, Quan G, Wu Q et al (2018) Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceut Sin B 8:165–177. https://doi.org/10.1016/j.apsb.2018.01.007
Acknowledgements
Raphaël Cornu is supported by a fellowship from the “Communauté d’Agglomération du Grand Besançon (CAGB)”. We thank DImaCell microscopy facilities, especially M. Tissot for her technical assistance (Plateforme DImaCell, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France). The authors thank FHU InCREASe for the Oral Communication Award and the financial support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Cornu, R., Chrétien, C., Pellequer, Y. et al. Small silica nanoparticles transiently modulate the intestinal permeability by actin cytoskeleton disruption in both Caco-2 and Caco-2/HT29-MTX models. Arch Toxicol 94, 1191–1202 (2020). https://doi.org/10.1007/s00204-020-02694-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-020-02694-6