Predictive Biomarkers for the Ranking of Pulmonary Toxicity of Nanomaterials
Abstract
:1. Introduction
2. Materials and Methods
2.1. Sample Nanomaterials
2.2. Animals
2.3. Intratracheal Instillation
2.4. Animals Following Intratracheal Instillation
2.5. Total RNA Extraction
2.6. Microarray Analysis
2.7. Validation of Gene Expression Data Using Quantitative Real-Time Polymerase Chain Reaction
2.8. Statistical Analysis
2.9. Histopathology and Immunohistochemistry
3. Results
3.1. Gene Expression Analysis
3.2. Assessment of the Accuracy of Gene Expression of the Toxicity of Chemicals
3.3. CXCL5, CCL2 and CCL7 Immunostaining
3.4. Pathological Features in the Rat Lungs
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
(A) Confusion matrix | |||
Pulmonary Toxicity | |||
High | Low | ||
Gene expression level (fold of control) | ≧Cut off value | a (True positives) | b (False positives) |
<Cut off value | c (False negatives) | d (True negatives) | |
a + c | b + d | ||
Sensitivity = = Specificity = = False positive = = False negative = = a: The number of true positives, b: The number of false positives. c: The number of false negatives, d: The number of true negatives. | |||
(B) Example of confusion matrix. | |||
CXCL5 at 1 week | Pulmonary Toxicity | ||
High | Low | ||
Gene expression level (fold of control) | ≧Cut off value | 19 | 0 |
<Cut off value | 1 | 20 | |
20 | 20 | ||
For example, in CXCL5 at 1 week after instillation. Sensitivity = = 0.95, Specificity = = 1.00, False positive = = 0.00, False negative = = 0.05. |
CXCL5 | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
---|---|---|---|---|---|
Low Dose Group | |||||
NiO | 0.0037 ** | 0.0008 ** | 0.0134 * | 0.0056 ** | 0.1862 |
CeO2 | 0.0002 ** | <0.0001 ** | 0.0003 ** | 0.0302 ** | 0.3518 |
TiO2 | 0.4254 | 0.4474 | 0.9 | 0.2214 | 0.8551 |
ZnO | 0.1483 | 0.6346 | 0.7478 | 0.3446 | 0.1679 |
CCL2 | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
Low Dose Group | |||||
NiO | 0.5879 | 0.0017 ** | 0.8141 | 0.8456 | 0.4627 |
CeO2 | 0.0170 * | 0.1357 | 0.2553 | 0.5301 | 0.9883 |
TiO2 | 0.9217 | 0.9928 | 0.737 | 0.1995 | 0.5812 |
ZnO | 0.0011 ** | 0.926 | 0.6449 | 0.358 | 0.2674 |
CCL7 | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
Low Dose Group | |||||
NiO | 0.8425 | 0.0018 ** | 0.8701 | 0.9175 | 0.608 |
CeO2 | 0.1495 | 0.3895 | 0.4254 | 0.8892 | 1 |
TiO2 | 0.9424 | 0.9997 | 0.9087 | 0.2562 | 0.6004 |
ZnO | 0.0019 ** | 0.5976 | 0.6198 | 0.3636 | 0.1821 |
CXCL10 | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
Low Dose Group | |||||
NiO | 0.9877 | 0.0053 ** | 0.9959 | 0.8678 | 0.3692 |
CeO2 | 0.161 | 0.4941 | 0.5374 | 0.9784 | 0.3855 |
TiO2 | 0.9956 | 0.9929 | 0.7097 | 0.212 | 0.592 |
ZnO | <0.0001 ** | 0.0002 ** | 0.4146 | 0.3867 | 0.3168 |
CXCL11 | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
Low Dose Group | |||||
NiO | 0.9995 | 0.0289 * | 0.9985 | 0.8235 | 0.4274 |
CeO2 | 0.2719 | 0.5391 | 0.5132 | 0.9954 | 0.6872 |
TiO2 | 0.9996 | 0.9982 | 0.7218 | 0.2127 | 0.2207 |
ZnO | <0.0001 ** | 0.0038 ** | 0.7349 | 0.3887 | 0.1187 |
CXCL5 | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
High dose group | |||||
NiO | 0.0063 ** | 0.0003 ** | <0.0001 ** | <0.0001 ** | <0.0001 ** |
CeO2 | 0.0004 ** | <0.0001 ** | <0.0001 ** | <0.0301 * | 0.0020 ** |
TiO2 | <0.0001 ** | 0.0053 ** | 0.0133 * | 0.7013 | 0.4984 |
ZnO | 0.1626 | 0.6737 | 0.6125 | 0.4968 | 0.0405 * |
CCL2 | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
High Dose Group | |||||
NiO | <0.0001 ** | 0.0022 ** | 0.0003 ** | 0.0025 ** | <0.0001 ** |
CeO2 | <0.0001 ** | 0.0156 * | 0.0130 * | 0.0004 ** | 0.0177 * |
TiO2 | <0.0001 ** | 0.1091 | 0.0267 * | 0.8836 | 0.9128 |
ZnO | 0.0020 ** | 0.6238 | 0.9559 | 0.4076 | 0.3763 |
CCL7 | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
High Dose Group | |||||
NiO | <0.0001 ** | 0.0031 ** | 0.0004 ** | 0.0064 ** | <0.0001 ** |
CeO2 | <0.0001 ** | 0.0889 | 0.0782 | 0.0141 * | 0.0327 * |
TiO2 | 0.0008 ** | 0.2082 | 0.0651 | 0.9479 | 0.8681 |
ZnO | 0.0110 * | 0.5797 | 0.9974 | 0.4146 | 0.8918 |
CXCL10 | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
High Dose Group | |||||
NiO | 0.0004 ** | 0.2108 | 0.0081 ** | 0.1018 | 0.9967 |
CeO2 | 0.3798 | 0.5606 | 0.4095 | 0.1205 | 0.5615 |
TiO2 | 0.0613 | 0.2908 | 0.9398 | 0.9278 | 0.3888 |
ZnO | 0.0011 ** | 0.0655 | 0.54 | 0.4204 | 0.659 |
CXCL11 | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
High Dose Group | |||||
NiO | 0.0014 ** | 0.6045 | 0.0277 * | 0.097 | 0.2332 |
CeO2 | 0.2058 | 0.5708 | 0.4182 | 0.1515 | 0.2836 |
TiO2 | 0.1343 | 0.3348 | 0.7182 | 0.9359 | 0.2013 |
ZnO | <0.0001 ** | 0.0672 | 0.4405 | 0.3996 | 0.4958 |
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Nanomaterials | NiO | CeO2 | TiO2 | ZnO |
---|---|---|---|---|
Pulmonary toxicity | High | High | Low | Low |
Primary diameter | 19 nm | 7.8 nm | Short 12 nm Long 55 nm | 35 nm |
Specific surface area | 57 m2/g | 101 m2/g | 111 m2/g | 31 m2/g |
Shape | Sphere | Irregular shape | Spindle-shaped | Sphere like |
Secondary diameter (DLS) | 39.8–47.1 nm | 2.6–9.3 nm | 20–80 nm | 17–37 nm |
Purity | More than 99.5% | 99.9% | 99.5% | 99.9% |
Bulk density | 6.72 g/cm3 | 7.22 g/cm3 | 4.17 g/cm3 | 5.60 g/cm3 |
Solubility | Low (>CeO2) | Low | Low | High |
(A) | |||
---|---|---|---|
mRNA Level (Fold Change of Control) | Number of Genes | ||
Up regulation | ≧2-fold | 450 | |
2–4-fold | 383 | ||
4–8-fold | 51 | ||
≧8-fold | 16 | ||
Down regulation | ≦-fold | 388 | |
-fold | 359 | ||
-fold | 15 | ||
≦-fold | 14 | ||
(B) | |||
Gene Symbol | Gene Description | Fold Change | |
CXCL5 | Chemokine (C-X-C motif) ligand5 | 12.83 | |
CCL2 | Chemokine (C-C motif) ligand2 | 17.93 | |
CCL7 | Chemokine (C-C motif) ligand7 | 23.44 | |
CXCL10 | Chemokine (C-X-C motif) ligand10 | 16.42 | |
CXCL11 | Chemokine (C-X-C motif) ligand11 | 16.70 |
Observation Time | 3 Days | 1 Week | 1 Month | 3 Months | 6 Months |
---|---|---|---|---|---|
AUC | AUC | AUC | AUC | AUC | |
(95% C.I.) | (95% C.I.) | (95% C.I.) | (95% C.I.) | (95% C.I.) | |
(Cut-off Value) | (Cut-off Value) | (Cut-off Value) | (Cut-off Value) | (Cut-off Value) | |
CXCL5 | 0.990 | 0.998 | 0.995 | 0.983 | 0.928 |
(0.982–0.999) | (0.961–1.000) | (0.948–1.000) | (0.874–0.998) | (0.803–0.976) | |
(10.008) | (10.308) | (9.513) | (3.277) | (1.934)) | |
CCL2 | 0.693 | 0.973 | 0.980 | 0.910 | 0.848 |
(0.501–0.835) | (0.841–0.996) | (0.904–0.996) | (0.753–0.971) | (0.674–0.937) | |
(11.495) | (3.919) | (1.945) | (2.059) | (1.076) | |
CCL7 | 0.680 | 0.968 | 0.993 | 0.898 | 0.893 |
(0.487–0.826) | (0.860–0.993) | (0.933–0.999) | (0.744–0.963) | (0.720–0.964) | |
(12.380) | (5.090) | (1.990) | (2.007) | (1.020) | |
CXCL10 | 0.603 | 0.795 | 0.848 | 0.778 | 0.663 |
(0.415–0.764) | (0.592–0.912) | (0.673–0.974) | (0.593–0.894) | (0.473–0.811) | |
(8.311) | (2.088) | (1.620) | (1.466) | (1.097) | |
CXCL11 | 0.525 | 0.890 | 0.883 | 0.813 | 0.920 |
(0.340–0.704) | (0.744–0.958) | (0.741–0.952) | (0.612–0.922) | (0.798–0.971) | |
(7.843) | (2.790) | (2.073) | (1.025) | (0.706) |
Sensitivity | Specificity | False Positive | False Negative | ||||||
---|---|---|---|---|---|---|---|---|---|
3 days | CXCL5 | 0.95 | (19/20) | 1.00 | (20/20) | 0.00 | (0/20) | 0.05 | (1/20) |
CCL2 | 0.50 | (10/20) | 0.95 | (19/20) | 0.05 | (1/20) | 0.50 | (10/20) | |
CCL7 | 0.50 | (10/20) | 0.95 | (19/20) | 0.05 | (1/20) | 0.50 | (10/20) | |
CXCL10 | 0.30 | (6/20) | 1.00 | (20/20) | 0.00 | (0/20) | 0.70 | (14/20) | |
CXCL11 | 0.35 | (7/20) | 0.95 | (19/20) | 0.05 | (1/20) | 0.65 | (13/20) | |
CXCL5 + CCL2 + CCL7 | 0.90 | (18/20) | 0.05 | (1/20) | 0.95 | (19/20) | 0.10 | (2/20) | |
1 week | CXCL5 | 0.95 | (19/20) | 1.00 | (20/20) | 0.00 | (0/20) | 0.05 | (1/20) |
CCL2 | 1.00 | (20/20) | 0.90 | (18/20) | 0.10 | (2/20) | 0.00 | (0/20) | |
CCL7 | 0.95 | (19/20) | 0.90 | (18/20) | 0.10 | (2/20) | 0.05 | (1/20) | |
CXCL10 | 0.75 | (15/20) | 0.90 | (18/20) | 0.10 | (2/20) | 0.25 | (5/20) | |
CXCL11 | 0.75 | (15/20) | 0.95 | (19/20) | 0.05 | (1/20) | 0.25 | (5/20) | |
CXCL5 + CCL2 + CCL7 | 1.00 | (20/20) | 0.90 | (18/20) | 0.10 | (2/20) | 0.00 | (0/20) | |
1 month | CXCL5 | 0.95 | (19/20) | 1.00 | (20/20) | 0.00 | (0/20) | 0.05 | (1/20) |
CCL2 | 1.00 | (20/20) | 0.90 | (18/20) | 0.10 | (2/20) | 0.00 | (0/20) | |
CCL7 | 1.00 | (20/20) | 0.95 | (19/20) | 0.05 | (1/20) | 0.00 | (0/20) | |
CXCL10 | 0.65 | (13/20) | 1.00 | (20/20) | 0.00 | (0/20) | 0.35 | (7/20) | |
CXCL11 | 0.65 | (13/20) | 0.95 | (19/20) | 0.05 | (1/20) | 0.35 | (7/20) | |
CXCL5 + CCL2 + CCL7 | 1.00 | (20/20) | 0.90 | (18/20) | 0.10 | (2/20) | 0.00 | (0/20) | |
3 months | CXCL5 | 1.00 | (20/20) | 0.95 | (19/20) | 0.05 | (1/20) | 0.00 | (0/20) |
CCL2 | 0.95 | (19/20) | 0.80 | (16/20) | 0.20 | (4/20) | 0.50 | (1/20) | |
CCL7 | 0.95 | (19/20) | 0.80 | (16/20) | 0.20 | (4/20) | 0.50 | (1/20) | |
CXCL10 | 0.75 | (15/20) | 0.80 | (16/20) | 0.20 | (4/20) | 0.25 | (5/20) | |
CXCL11 | 0.90 | (18/20) | 0.75 | (15/20) | 0.25 | (5/20) | 0.10 | (2/20) | |
CXCL5 + CCL2 + CCL7 | 1.00 | (20/20) | 0.80 | (16/20) | 0.20 | (4/20) | 0.00 | (0/20) | |
6 months | CXCL5 | 0.95 | (19/20) | 0.80 | (16/20) | 0.20 | (4/20) | 0.05 | (1/20) |
CCL2 | 0.85 | (17/20) | 0.80 | (16/20) | 0.20 | (4/20) | 0.15 | (3/20) | |
CCL7 | 0.85 | (17/20) | 0.85 | (17/20) | 0.15 | (3/20) | 0.15 | (3/20) | |
CXCL10 | 0.55 | (11/20) | 0.80 | (16/20) | 0.20 | (4/20) | 0.45 | (9/20) | |
CXCL11 | 1.00 | (20/20) | 0.70 | (14/20) | 0.30 | (6/20) | 0.00 | (0/20) | |
CXCL5 + CCL2 + CCL7 | 1.00 | (20/20) | 0.30 | (6/20) | 0.70 | (14/20) | 0.00 | (0/20) |
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Nishida, C.; Izumi, H.; Tomonaga, T.; Takeshita, J.-i.; Wang, K.-Y.; Yamasaki, K.; Yatera, K.; Morimoto, Y. Predictive Biomarkers for the Ranking of Pulmonary Toxicity of Nanomaterials. Nanomaterials 2020, 10, 2032. https://doi.org/10.3390/nano10102032
Nishida C, Izumi H, Tomonaga T, Takeshita J-i, Wang K-Y, Yamasaki K, Yatera K, Morimoto Y. Predictive Biomarkers for the Ranking of Pulmonary Toxicity of Nanomaterials. Nanomaterials. 2020; 10(10):2032. https://doi.org/10.3390/nano10102032
Chicago/Turabian StyleNishida, Chinatsu, Hiroto Izumi, Taisuke Tomonaga, Jun-ichi Takeshita, Ke-Yong Wang, Kei Yamasaki, Kazuhiro Yatera, and Yasuo Morimoto. 2020. "Predictive Biomarkers for the Ranking of Pulmonary Toxicity of Nanomaterials" Nanomaterials 10, no. 10: 2032. https://doi.org/10.3390/nano10102032