Analysis of TiO2 nanoparticles accumulation in vitro
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Abstract
The physicochemical properties of titanium dioxide (TiO2) in nanoforms is often exploited as colorant in food, pharmaceuticals and other consumer products. However, the current evidence of potential hazards associated with titanium dioxide (TiO2) in nanoforms led to a ban of TiO2 as food additive in Europe. This regulatory decision has also an impact on thousands of pharmaceuticals.
In the present study, we tested the internalisation, accumulation and resulting biological effects of different types of TiO2 nanomaterial in short and long-term vitro cultures. Even if we could demonstrate that all tested cell lines were able to take up and accumulate nanomaterial for a period of up to 30 days, the cellular responses using conventional in vitro tests were limited in all tested cell lines. Nevertheless, a transcriptomics study revealed that that the response to the accumulated material differed between two selected cell types. A keratinocyte like cell line reacted with a modified rate of keratinogenesis whereas the enterocyte like cell demonstrated mainly interactions with cell homeostasis. To further clarify possible harmful effects of TiO2, the study suggests analyzing cell/tissue type specific effects of TiO2.
Keywords:
TiO2 nanoparticle, accumulation, radioactivity, transcriptomics, Caco-2, HaCaT, Balb/3T3 cells
Article Details
How to Cite
BOGNI, Alessia et al.
Analysis of TiO2 nanoparticles accumulation in vitro.
Medical Research Archives, [S.l.], v. 12, n. 3, apr. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5272>. Date accessed: 30 apr. 2024.
doi: https://doi.org/10.18103/mra.v12i3.5272.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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21. Gunduz N, Ceylan H, Guler MO, Tekinay AB. Intracellular Accumulation of Gold Nanoparticles Leads to Inhibition of Macropinocytosis to Reduce the Endoplasmic Reticulum Stress. Sci Rep. 2017;7(1):40493. doi:10.1038/srep40493
22. Khlebtsov N, Dykman L. Biodistribution and toxicity of engineered gold nanoparticles: a review of in vitro and in vivo studies. Chem Soc Rev. 2011;40(3):1647-1671. doi:10.1039/ c0cs00018c
23. Kirkland D, Aardema MJ, Battersby R V, et al. A weight of evidence review of the genotoxicity of titanium dioxide (TiO2). Regul Toxicol Pharmacol. 2022;136:105263. doi: https://doi.org/10.1016/j.yrtph.2022.105263
24. Cao X, Han Y, Gu M, et al. Foodborne Titanium Dioxide Nanoparticles Induce Stronger Adverse Effects in Obese Mice than Non-Obese Mice: Gut Microbiota Dysbiosis, Colonic Inflammation, and Proteome Alterations. Small. 2020;16(36):e2001858. Doi :10.1002/smll.202001858
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26. Bettini S, Boutet-Robinet E, Cartier C, et al. Food-grade TiO(2) impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon. Sci Rep. 2017;7:40373. doi:10.1038/srep40373
27. Crosera M, Prodi A, Mauro M, et al. Titanium Dioxide Nanoparticle Penetration into the Skin and Effects on HaCaT Cells. Int J Environ Res Public Health. 2015;12(8):9282-9297. doi:10.3390/ijerph120809282
28. Baroni A, Buommino E, Gregorio V De, Ruocco E, Ruocco V, Wolf R. Structure and function of the epidermis related to barrier properties. Clin Dermatol. 2012;30 3:257-262.
29. Tricarico PM, Mentino D, De Marco A, et al. Aquaporins Are One of the Critical Factors in the Disruption of the Skin Barrier in Inflammatory Skin Diseases. Int J Mol Sci. 2022;23(7). doi:10.3390/ijms23074020
30. Khan A. Aziz, Ham S., Yen L., Lee H. Lim, Huh J., Jeon H., Kim M. Hee RT. A novel role of metal response element binding transcription factor 2 at the Hox gene cluster in the regulation of H3K27me3 by polycomb repressive complex 2. Oncotarget. 2018;9:26 572-26585.
31. Zhu P, Zhou W, Wang J, et al. A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation. Mol Cell. 2007;27( 4):609-621. doi:10.1016/j.molcel.2007.07.024
32. Stoccoro A, Di Bucchianico S, Coppedè F, et al. Multiple endpoints to evaluate pristine and remediated titanium dioxide nanoparticles genotoxicity in lung epithelial A549 cells. Toxicol Lett. 2017;276:48-61. doi:10.1016/j.toxlet.2017.05.016
33. Pogribna M, Koonce NA, Mathew A, et al. Effect of titanium dioxide nanoparticles on DNA methylation in multiple human cell lines. Nanotoxicology. 2020;14(4):534-553. doi:10. 1080/17435390.2020.1723730
34. Pogribna M, Hammons G. Epigenetic Effects of Nanomaterials and Nanoparticles. J Nanobiotechnology. 2021;19(1):2. doi:10.118 6/s12951-020-00740-0
35. Hu H, Li L, Guo Q, et al. RNA sequencing analysis shows that titanium dioxide nanoparticles induce endoplasmic reticulum stress, which has a central role in mediating plasma glucose in mice. Nanotoxicology. 2018;12(4):341-356. doi:10.1080/17435390.2018.1446560
36. Ong G, Logue SE. Unfolding the Interactions between Endoplasmic Reticulum Stress and Oxidative Stress. Antioxidants (Basel, Switzerland). 2023;12(5). doi:10.3390/ antiox12050981
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38. Pihán P, Carreras-Sureda A, Hetz C. BCL-2 family: integrating stress responses at the ER to control cell demise. Cell Death Differ. 2017;24(9):1478-1487. doi:10.1038/cdd.2017.82
39. Cui Y, Zhou X, Chen L, et al. Crosstalk between Endoplasmic Reticulum Stress and Oxidative Stress in Heat Exposure-Induced Apoptosis Is Dependent on the ATF4–CHOP–CHAC1 Signal Pathway in IPEC-J2 Cells. J Agric Food Chem. 2021;69(51):15495-15511. doi:10.1021/acs.jafc.1c03361
40. Fattahi F, Saeednejad Zanjani L, Habibi Shams Z, et al. High expression of DNA damage-inducible transcript 4 (DDIT4) is associated with advanced pathological features in the patients with colorectal cancer. Sci Rep. 2021;11(1):13626. doi:10.1038/s415 98-021-92720-z
41. Paredes F, Parra V, Torrealba N, et al. HERPUD1 protects against oxidative stress-induced apoptosis through downregulation of the inositol 1,4,5-trisphosphate receptor. Free Radic Biol Med. 2016;90:206-218. doi:https://doi.org/10.1016/j.freeradbiomed.2015.11.024
42. Luo H, Chiang HH, Louw M, Susanto A, Chen D. Nutrient Sensing and the Oxidative Stress Response. Trends Endocrinol Metab. 2017;28(6):449-460. doi:10.1016/j.tem.2017.02.008
43. Ramachandran A, Madesh M, Balasubramanian KA. Apoptosis in the intestinal epithelium: its relevance in normal and pathophysiological conditions. J Gastroenterol Hepatol. 2000;15(2):109-120. doi:10.1046/j.1440-1746.2000.02059.x
44. Nishito Y, Kambe T. Absorption Mechanisms of Iron, Copper, and Zinc: An Overview. J Nutr Sci Vitaminol (Tokyo). 2018;6 4(1):1-7. doi:10.3177/jnsv.64.1
45. Fan W, Cui M, Liu H, et al. Nano-TiO2 enhances the toxicity of copper in natural water to Daphnia magna. Environ Pollut. 2011;159(3):729-734. doi:10.1016/j.envpol.2010.11.030
46. Stern ST, Adiseshaiah PP, Crist RM. Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Part Fibre Toxicol. 2012;9(1):20. doi: 10.1186/1743-8977-9-20
47. Popp L, Tran V, Patel R, Segatori L. Autophagic response to cellular exposure to titanium dioxide nanoparticles. Acta Biomater. 2018;79:354-363. doi:https://doi.org/10.1016/j.actbio.2018.08.021
2. Baranowska-Wójcik E, Szwajgier D, Oleszczuk P, Winiarska-Mieczan A. Effects of Titanium Dioxide Nanoparticles Exposure on Human Health-a Review. Biol Trace Elem Res. 2020;193(1):118-129. doi:10.1007/s12011-01 9-01706-6
3. Commission Delegated Regulation (EU) 2020/217 of 4 October 2019. Published 2020. https://www.legislation.gov.uk/eur/2020/217/contents
4. Final feedback from European Medicine Agency (EMA) to the EU Commission request to evaluate the impact of the removal of titanium dioxide from the list of authorised food additives on medicinal products. EMA. 2021;(504010).
5. SCIENTIFIC COMMITTEE ON CONSUMER SAFETY (SCCS) Request for a scientific opinion on the safety of Titanium dioxide (TiO2) (CAS/EC numbers 13463-67-7/236-675-5, 1317-70-0/215-280- 1, 1317-80-2/215-282-2) in cosmetic products.
6. European Commission (2020a) Chemicals – Strategy for Sustainability (Toxic-Free EU Environment).2021. https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/12264-Chemicals-strategy-forsustainability-toxic-free-EU-environment-_en
7. Food Directorate HC. State of the science of titanium dioxide (TiO₂) as a food additive. Published online 2022. https://publications.gc.ca/site/eng/9.912399/publication.html
8. Kreyling WG, Holzwarth U, Haberl N, et al. Quantitative biokinetics of titanium dioxide nanoparticles after intravenous injection in rats: Part 1. Nanotoxicology. 2017;11(4):434-442. doi:10.1080/17435390.2017.1306892
9. Geraets L, Oomen AG, Krystek P, et al. Tissue distribution and elimination after oral and intravenous administration of different titanium dioxide nanoparticles in rats. Part Fibre Toxicol. 2014;11(1):30. doi:10.1186/174 3-8977-11-30
10. Disdier C, Devoy J, Cosnefroy A, et al. Tissue biodistribution of intravenously administrated titanium dioxide nanoparticles revealed blood-brain barrier clearance and brain inflammation in rat. Part Fibre Toxicol. 2015;12(1):27. doi:10.1186/s12989-015-0102-8
11. Coméra C, Cartier C, Gaultier E, et al. Jejunal villus absorption and paracellular tight junction permeability are major routes for early intestinal uptake of food-grade TiO2 particles: an in vivo and ex vivo study in mice. Part Fibre Toxicol. 2020;17(1):26. doi:10.1186 /s12989-020-00357-z
12. Riedle S, Wills JW, Miniter M, et al. A Murine Oral-Exposure Model for Nano- and Micro-Particulates: Demonstrating Human Relevance with Food-Grade Titanium Dioxide. Small. 2020;16(21):2000486. doi: https://doi.org/10.1002/smll.202000486
13. Winkler HC, Notter T, Meyer U, Naegeli H. Critical review of the safety assessment of titanium dioxide additives in food. J Nanobiotechnology. 2018;16(1):51. doi:10.11 86/s12951-018-0376-8
14. Berggren E, White A, Ouedraogo G, et al. Ab initio chemical safety assessment: A workflow based on exposure considerations and non-animal methods. Comput Toxicol (Amsterdam, Netherlands). 2017;4:31-44. doi: 10.1016/j.comtox.2017.10.001
15. Geiss O, Ponti J, Senaldi C, et al. Characterisation of food grade titania with respect to nanoparticle content in pristine additives and in their related food products. Food Addit Contam Part A. 2020;37(2):239-253. doi:10.1080/19440049.2019.1695067
16. OECD. Study Report and Preliminary Guidance on the Adaptation of the In Vitro Micronucleus Assay (OECD TG 487) for Testing of Manufactured. Series on Testing and Assessment No. 359 Nanomaterials.; 2022. https://one.oecd.org/document/env/cbc/mono(2022)15/en/pdf
17. Forcella M, Lau P, Oldani M, et al. Neuronal specific and non-specific responses to cadmium possibly involved in neurodegeneration: A toxicogenomics study in a human neuronal cell model. Neurotoxicology. 2020;76:162-173. doi:10.10 16/j.neuro.2019.11.002
18. Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523. doi:10.1038/s414 67-019-09234-6
19. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.; 2006.
20. Akram MW, Raziq F, Fakhar-e-Alam M, et al. Tailoring of Au-TiO2 nanoparticles conjugated with doxorubicin for their synergistic response and photodynamic therapy applications. J Photochem Photobiol A Chem. Published online 2019.
21. Gunduz N, Ceylan H, Guler MO, Tekinay AB. Intracellular Accumulation of Gold Nanoparticles Leads to Inhibition of Macropinocytosis to Reduce the Endoplasmic Reticulum Stress. Sci Rep. 2017;7(1):40493. doi:10.1038/srep40493
22. Khlebtsov N, Dykman L. Biodistribution and toxicity of engineered gold nanoparticles: a review of in vitro and in vivo studies. Chem Soc Rev. 2011;40(3):1647-1671. doi:10.1039/ c0cs00018c
23. Kirkland D, Aardema MJ, Battersby R V, et al. A weight of evidence review of the genotoxicity of titanium dioxide (TiO2). Regul Toxicol Pharmacol. 2022;136:105263. doi: https://doi.org/10.1016/j.yrtph.2022.105263
24. Cao X, Han Y, Gu M, et al. Foodborne Titanium Dioxide Nanoparticles Induce Stronger Adverse Effects in Obese Mice than Non-Obese Mice: Gut Microbiota Dysbiosis, Colonic Inflammation, and Proteome Alterations. Small. 2020;16(36):e2001858. Doi :10.1002/smll.202001858
25. Nogueira CM, de Azevedo WM, Dagli MLZ, et al. Titanium dioxide induced inflammation in the small intestine. World J Gastroenterol. 2012;18(34):4729-4735. doi:10 .3748/wjg.v18.i34.4729
26. Bettini S, Boutet-Robinet E, Cartier C, et al. Food-grade TiO(2) impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon. Sci Rep. 2017;7:40373. doi:10.1038/srep40373
27. Crosera M, Prodi A, Mauro M, et al. Titanium Dioxide Nanoparticle Penetration into the Skin and Effects on HaCaT Cells. Int J Environ Res Public Health. 2015;12(8):9282-9297. doi:10.3390/ijerph120809282
28. Baroni A, Buommino E, Gregorio V De, Ruocco E, Ruocco V, Wolf R. Structure and function of the epidermis related to barrier properties. Clin Dermatol. 2012;30 3:257-262.
29. Tricarico PM, Mentino D, De Marco A, et al. Aquaporins Are One of the Critical Factors in the Disruption of the Skin Barrier in Inflammatory Skin Diseases. Int J Mol Sci. 2022;23(7). doi:10.3390/ijms23074020
30. Khan A. Aziz, Ham S., Yen L., Lee H. Lim, Huh J., Jeon H., Kim M. Hee RT. A novel role of metal response element binding transcription factor 2 at the Hox gene cluster in the regulation of H3K27me3 by polycomb repressive complex 2. Oncotarget. 2018;9:26 572-26585.
31. Zhu P, Zhou W, Wang J, et al. A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation. Mol Cell. 2007;27( 4):609-621. doi:10.1016/j.molcel.2007.07.024
32. Stoccoro A, Di Bucchianico S, Coppedè F, et al. Multiple endpoints to evaluate pristine and remediated titanium dioxide nanoparticles genotoxicity in lung epithelial A549 cells. Toxicol Lett. 2017;276:48-61. doi:10.1016/j.toxlet.2017.05.016
33. Pogribna M, Koonce NA, Mathew A, et al. Effect of titanium dioxide nanoparticles on DNA methylation in multiple human cell lines. Nanotoxicology. 2020;14(4):534-553. doi:10. 1080/17435390.2020.1723730
34. Pogribna M, Hammons G. Epigenetic Effects of Nanomaterials and Nanoparticles. J Nanobiotechnology. 2021;19(1):2. doi:10.118 6/s12951-020-00740-0
35. Hu H, Li L, Guo Q, et al. RNA sequencing analysis shows that titanium dioxide nanoparticles induce endoplasmic reticulum stress, which has a central role in mediating plasma glucose in mice. Nanotoxicology. 2018;12(4):341-356. doi:10.1080/17435390.2018.1446560
36. Ong G, Logue SE. Unfolding the Interactions between Endoplasmic Reticulum Stress and Oxidative Stress. Antioxidants (Basel, Switzerland). 2023;12(5). doi:10.3390/ antiox12050981
37. Liu M qing, Chen Z, Chen L xi. Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases. Acta Pharmacol Sin. 2016;37(4):425-443. doi:10.1038/aps.2015.145
38. Pihán P, Carreras-Sureda A, Hetz C. BCL-2 family: integrating stress responses at the ER to control cell demise. Cell Death Differ. 2017;24(9):1478-1487. doi:10.1038/cdd.2017.82
39. Cui Y, Zhou X, Chen L, et al. Crosstalk between Endoplasmic Reticulum Stress and Oxidative Stress in Heat Exposure-Induced Apoptosis Is Dependent on the ATF4–CHOP–CHAC1 Signal Pathway in IPEC-J2 Cells. J Agric Food Chem. 2021;69(51):15495-15511. doi:10.1021/acs.jafc.1c03361
40. Fattahi F, Saeednejad Zanjani L, Habibi Shams Z, et al. High expression of DNA damage-inducible transcript 4 (DDIT4) is associated with advanced pathological features in the patients with colorectal cancer. Sci Rep. 2021;11(1):13626. doi:10.1038/s415 98-021-92720-z
41. Paredes F, Parra V, Torrealba N, et al. HERPUD1 protects against oxidative stress-induced apoptosis through downregulation of the inositol 1,4,5-trisphosphate receptor. Free Radic Biol Med. 2016;90:206-218. doi:https://doi.org/10.1016/j.freeradbiomed.2015.11.024
42. Luo H, Chiang HH, Louw M, Susanto A, Chen D. Nutrient Sensing and the Oxidative Stress Response. Trends Endocrinol Metab. 2017;28(6):449-460. doi:10.1016/j.tem.2017.02.008
43. Ramachandran A, Madesh M, Balasubramanian KA. Apoptosis in the intestinal epithelium: its relevance in normal and pathophysiological conditions. J Gastroenterol Hepatol. 2000;15(2):109-120. doi:10.1046/j.1440-1746.2000.02059.x
44. Nishito Y, Kambe T. Absorption Mechanisms of Iron, Copper, and Zinc: An Overview. J Nutr Sci Vitaminol (Tokyo). 2018;6 4(1):1-7. doi:10.3177/jnsv.64.1
45. Fan W, Cui M, Liu H, et al. Nano-TiO2 enhances the toxicity of copper in natural water to Daphnia magna. Environ Pollut. 2011;159(3):729-734. doi:10.1016/j.envpol.2010.11.030
46. Stern ST, Adiseshaiah PP, Crist RM. Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Part Fibre Toxicol. 2012;9(1):20. doi: 10.1186/1743-8977-9-20
47. Popp L, Tran V, Patel R, Segatori L. Autophagic response to cellular exposure to titanium dioxide nanoparticles. Acta Biomater. 2018;79:354-363. doi:https://doi.org/10.1016/j.actbio.2018.08.021