Toxicity of TiO2 Nanoparticles: Validation of Alternative Models
Abstract
:1. Introduction
2. Results
2.1. TiO2 Nanoparticles Characterization
2.2. In Vitro Cytotoxicity Study
2.3. Transcriptomic Analysis of Dysregulated Genes Following In Vivo, In Vitro Submerged, and ALI Vitrocell Cloud ® Exposure (ALI) to NM-105 TiO2 NP
2.4. Common Dysregulated Genes between In Vivo, In Vitro, and ALI Exposures to TiO2 NP
2.5. Comparison of Functional Annotations of Dysregulated Genes In Vivo, In Vitro, and ALI after Exposition to TiO2 NP
2.6. Functional Analysis of Common Dysregulated Genes between In Vivo, In Vitro, and ALI Expositions to TiO2 NP
3. Discussion
3.1. Methodology
3.2. Viability of NR8383 Cells Exposed to TiO2
3.3. Number of DEGs in Each Exposure Method
3.4. Transcriptomic Study
4. Materials and Methods
4.1. TiO2 NP Characterization
4.2. Cell Culture
4.3. In Vitro Cytotoxicity Study
4.4. In Vivo Exposure
4.5. Exposure at the Air–liquid Interface
4.6. Transcriptomic Study
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Nanoparticle | Primary Size (nm) | Secondary Size (nm) | Zeta Potential (mV) | Specific Surface Aera (m2/g) | Provider |
---|---|---|---|---|---|
TiO2 (NM-105) | 21.5 ± 7.2 | 170 ± 1.5 | 11.1 ± 0.7 | 51 | Joint Research Center |
Groups | FC 1.3 | FC 1.5 | FC3 | ||||||
---|---|---|---|---|---|---|---|---|---|
Up | Down | Total | Up | Down | Total | Up | Down | Total | |
in vitro submerged | 4612 | 5224 | 9836 | 3939 | 3956 | 7895 | 345 | 1376 | 1721 |
in vitro ALI | 439 | 412 | 851 | 108 | 94 | 202 | 0 | 1 | 1 |
lung | 898 | 579 | 1477 | 559 | 221 | 780 | 64 | 5 | 69 |
Gene Set | p-Value in vivo Lung | p-Value in vitro ALI | p-Value in vitro Submerged |
---|---|---|---|
Common gene sets between the three exposures | |||
IL6_JAK_STAT3_SIGNALING | 1.25 × 10−7 | 7.42 × 10−2 | 3.82 × 10−2 |
MYC_TARGETS_V2 | 4.30 × 10−6 | 7.42 × 10−2 | 3.65 × 10−2 |
Common gene sets between in vivo and ALI exposures | |||
E2F_TARGETS | 1.04 × 10−14 | 8.40 × 10−7 | – |
G2M_CHECKPOINT | 7.96 × 10−11 | 7.00 × 10−3 | – |
MYC_TARGETS_V1 | 1.08 × 10−4 | 7.00 × 10−3 | – |
EPITHELIAL_MESENCHYMAL_TRANSITION | 9.03 × 10−2 | 3.84 × 10−2 | – |
Common gene sets between in vivo and in vitro submerged exposures | |||
UV_RESPONSE_DN | 6.21 × 10−3 | – | 6.73 × 10−2 |
TNFA_SIGNALING_VIA_NFKB | 9.43 × 10−3 | – | 1.46 × 10−3 |
Non common gene sets | |||
ALLOGRAFT_REJECTION | 1.25 × 10−7 | – | – |
MTORC1_SIGNALING | 5.73 × 10−7 | – | – |
INFLAMMATORY_RESPONSE | 1.48 × 10−6 | – | – |
MYOGENESIS | 4.30 × 10−6 | – | – |
INTERFERON_GAMMA_RESPONSE | 8.61 × 10−4 | – | – |
COMPLEMENT | 5.05 × 10−3 | – | – |
ANGIOGENESIS | 5.82 × 10−3 | – | – |
IL2_STAT5_SIGNALING | 2.32 × 10−2 | – | – |
CHOLESTEROL_HOMEOSTASIS | 3.89 × 10−2 | – | – |
APICAL_JUNCTION | 4.49 × 10−2 | – | – |
GLYCOLYSIS | 6.27 × 10−2 | – | – |
HEDGEHOG_SIGNALING | 6.27 × 10−2 | – | – |
WNT_BETA_CATENIN_SIGNALING | 8.13 × 10−2 | – | – |
COAGULATION | 8.89 × 10−2 | – | – |
TGF_BETA_SIGNALING | 9.03 × 10−2 | – | – |
OXIDATIVE_PHOSPHORYLATION | 9.03 × 10−2 | – | – |
UNFOLDED_PROTEIN_RESPONSE | 9.55 × 10−2 | – | – |
UV_RESPONSE_UP | – | 7.42 × 10−2 | – |
MITOTIC_SPINDLE | – | – | 9.38 × 10−3 |
DNA_REPAIR | – | – | 3.65 × 10−2 |
PROTEIN_SECRETION | – | – | 4.11 × 10−2 |
Name Gene Protein | FC | Protein Function | Function Group *KEGG Pathway | Pathologies Associated | ||
---|---|---|---|---|---|---|
Vivo | Vitro | ALI | ||||
Cenpf Centromere protein F | 1.97 | −8.43 | −1.33 | The CENPF protein is a part of the corona of kinetochore complex which interacts with microtubules and participate to a precise and rapid chromosome segregation. [23] | Mitosis kinetochore–centromere complex | |
Nuf2 kinetochore protein Nuf2 | 2.66 | −4.05 | −1.31 | Component of the essential kinetochore-associated NDC80 complex, required for chromosome segregation and spindle checkpoint activity, required for kinetochore integrity. [24] | Mitosis kinetochore–centromere complex | |
Kif15 kinesin-like protein KIF15 | 2.11 | −3.35 | −1.38 | Plus-end directed kinesin-like motor enzyme involved in mitotic spindle assembly [25] | Mitosis kinetochore–centromere complex | |
Kif20b kinesin family member 20B | 2.50 | −8.91 | −1.39 | Belongs to the TRAFAC class myosin–kinesin ATPase superfamily. kinesin family (String DB) | Mitosis kinetochore–centromere complex | |
Plk4 serine/threonine protein kinase | 1.67 | −4.64 | −1.36 | serine/threonine–protein kinase that plays a central role in centriole duplication; (UniProt) | Mitosis kinetochore–centromere complex | |
Depdc1 DEP domain containing 1 | 3.31 | −4.45 | −1.33 | DEP domain containing 1 (DEPDC1) is a highly conserved protein among many species. DEPDC1 was overexpressed in different types of cancers. [26] | Mitosis regulation [26] | Cancer [26] |
Hmgb2 high mobility group box 2 | 1.46 | −3.59 | −1.44 | Multifunctional protein with various roles in different cellular compartments. May act in a redox sensitive manner. In the nucleus is an abundant chromatin-associated non-histone protein involved in transcription, chromatin remodeling and V(D)J recombination. HMGBs act as architectural facilitators in the assembly of nucleoprotein complexes. [27] | Mitosis chromatin remodeling T cells differentiation | Cancer [28] [29] |
P2ry12 P2Y purinoceptor 12 | 1.43 | −3.54 | −1.58 | Receptor for ADP and ATP coupled to G-proteins. Required for normal platelet aggregation and blood coagulation. [30] | Inflammation: chemotaxis receptor Cell differentiation Macrophages M1/M2 [31] | Cancer [31] |
Ccl4 C–C motif chemokine 4 | 1.71 | 3.72 | 2.15 | Monokine with inflammatory and chemokinetic properties; (UniProt) | Inflammation: chemotaxis *Cytokine–cytokine receptor interaction | Inflammation diseases |
Ccl7 C–C motif chemokine 7 | 5.61 | 3.53 | 1.47 | Chemotactic factor attracts monocytes and eosinophils, but not neutrophils. (String DB) | Inflammation: chemotaxis *Cytokine–cytokine receptor interaction | Inflammation diseases Cancer |
Osm oncostatin-M | 1.38 | 6.84 | 1.41 | Growth regulator. It regulates cytokine production, including IL-6, G-CSF and GM-CSF; (UniProt) | Inflammation: regulation *Cytokine–cytokine receptor interaction | Cancer |
Tfec transcription factor EC | 1.35 | −5.86 | −1.32 | transcriptional regulator that acts as a repressor or an activator; (UniProt) | Cell differentiation Macrophages M2 activation [32] Inflammation [33] | Cancer |
Ogfrl1 opioid growth factor receptor-like 1 | 1.47 | −7.00 | −1.32 | Mobilization and differentiation of bone marrow (BM)-derived cells [34] | Cell differentiation Upregulated in M2 macrophages [35] | Cancer [36] |
Bcl3 B-cell CLL/lymphoma 3 | 1.69 | 4.60 | 1.41 | BCL3 (BCL3 transcription Coactivator) is a proto-oncogene candidate. Its related pathways are Apoptosis-related network and Common cytokine receptor gamma-chain family signaling pathways. Contributes to the regulation of cell proliferation and to the regulation of transcriptional activation of NF-kappa-B target genes. (GeneCards) | Cell proliferation Apoptosis regulation | Cancer |
Osgin1 oxidative stress induced growth inhibitor 1 | −1.38 | 7.10 | 1.74 | This gene encodes an oxidative stress response protein that regulates cell death. Expression regulated by p53 and induced by DNA damage. The protein regulates apoptosis by inducing cytochrome c release from mitochondria. Key regulator of both inflammatory and anti-inflammatory molecules. The loss of this protein correlates with uncontrolled cell growth and tumor formation. (GeneCards) | Inflammation regulation Apoptosis regulation | Cancer |
Ptpn13 protein tyrosine phosphatase non-receptor type 13 | −1.41 | 3.01 | −1.57 | Member of the protein tyrosine phosphatase (PTP) family. PTPs are signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle and oncogenic transformation. Regulates negatively FAS-induced apoptosis and NGFR-mediated pro-apoptotic signaling. (GeneCards) | Cell proliferation and differentiation Apoptosis regulation Mitosis Oncogenic transformation | Amyloidosis Cancer |
Ppp2r5b serine/threonine protein phosphatase regulatory subunit beta isoform | −1.57 | 3.32 | 1.48 | The product of this gene belongs to the phosphatase 2A (PP2A) regulatory subunit B family. PP2A it is implicated in the negative control of cell growth and division. The phosphorylated form mediates the interaction between PP2A and AKT1. (GeneCards) | Cell proliferation | Cancer |
Bcap29 B-cell receptor-associated protein 29 | 1.54 | −2.90 | −1.38 | Among its related pathways are B Cell Receptor Signaling Pathway and AKT Signaling Pathway. May play a role in transport of membrane proteins. May be involved in CASP8-mediated apoptosis. (GeneCards) | Transport of membrane protein Apoptosis |
(A) GO-term | Description | Count in Gene Set | False Discovery Rate |
GO:0071346 | cellular response to interferon-gamma | 2 of 39 | 0.0265 |
GO:0070098 | chemokine-mediated signaling pathway | 2 of 30 | 0.0265 |
GO:0050921 | positive regulation of chemotaxis | 2 of 68 | 0.0265 |
GO:0048522 | positive regulation of cellular process | 7 of 2201 | 0.0265 |
GO:0048247 | lymphocyte chemotaxis | 2 of 20 | 0.0265 |
GO:0045087 | innate immune response | 3 of 217 | 0.0265 |
GO:0044089 | positive regulation of cellular component biogenesis | 3 of 220 | 0.0265 |
GO:0040011 | locomotion | 4 of 404 | 0.0265 |
GO:0030593 | neutrophil chemotaxis | 2 of 23 | 0.0265 |
GO:0016477 | cell migration | 3 of 293 | 0.0265 |
GO:0010469 | regulation of signaling receptor activity | 4 of 325 | 0.0265 |
GO:0009967 | positive regulation of signal transduction | 4 of 638 | 0.0265 |
GO:0006955 | immune response | 4 of 386 | 0.0265 |
GO:0006954 | inflammatory response | 3 of 250 | 0.0265 |
GO:0006935 | chemotaxis | 3 of 172 | 0.0265 |
GO:0006928 | movement of cell or subcellular component | 4 of 486 | 0.0265 |
GO:0002687 | positive regulation of leukocyte migration | 2 of 63 | 0.0265 |
GO:0002548 | monocyte chemotaxis | 2 of 12 | 0.0265 |
GO:0071347 | cellular response to interleukin-1 | 2 of 75 | 0.0267 |
GO:0051173 | positive regulation of nitrogen compound metabolic process | 5 of 1184 | 0.0267 |
(B) KEGG Pathways | Pathway Description | Count in Gene Set | False Discovery Rate |
rno04060 | Cytokine–cytokine receptor interaction | 3 of 217 | 0.0130 |
(C) Reactome Pathways | Pathway Description | Count in Gene Set | False Discovery Rate |
RNO-68877 | Mitotic prometaphase | 4 of 168 | 0.00063 |
RNO-5663220 | RHO GTPases activate formins | 3 of 116 | 0.0013 |
RNO-2500257 | Resolution of sister chromatid cohesion | 3 of 100 | 0.0013 |
RNO-141444 | Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal | 3 of 80 | 0.0013 |
RNO-2467813 | Separation of sister chromatids | 3 of 149 | 0.0019 |
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Leroux, M.M.; Doumandji, Z.; Chézeau, L.; Gaté, L.; Nahle, S.; Hocquel, R.; Zhernovkov, V.; Migot, S.; Ghanbaja, J.; Bonnet, C.; et al. Toxicity of TiO2 Nanoparticles: Validation of Alternative Models. Int. J. Mol. Sci. 2020, 21, 4855. https://doi.org/10.3390/ijms21144855
Leroux MM, Doumandji Z, Chézeau L, Gaté L, Nahle S, Hocquel R, Zhernovkov V, Migot S, Ghanbaja J, Bonnet C, et al. Toxicity of TiO2 Nanoparticles: Validation of Alternative Models. International Journal of Molecular Sciences. 2020; 21(14):4855. https://doi.org/10.3390/ijms21144855
Chicago/Turabian StyleLeroux, Mélanie M., Zahra Doumandji, Laetitia Chézeau, Laurent Gaté, Sara Nahle, Romain Hocquel, Vadim Zhernovkov, Sylvie Migot, Jafar Ghanbaja, Céline Bonnet, and et al. 2020. "Toxicity of TiO2 Nanoparticles: Validation of Alternative Models" International Journal of Molecular Sciences 21, no. 14: 4855. https://doi.org/10.3390/ijms21144855