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. 2018 Oct 23;15(1):41.
doi: 10.1186/s12989-018-0277-x.

Usefulness of myeloperoxidase as a biomarker for the ranking of pulmonary toxicity of nanomaterials

Taisuke Tomonaga  1 , Hiroto Izumi  2 , Yukiko Yoshiura  2 , Toshihiko Myojo  2 , Takako Oyabu  2 , Byeong-Woo Lee  2 , Takami Okada  2 , Takashi Marui  2 , Ke-Yong Wang  3 , Masaru Kubo  4 , Manabu Shimada  4 , Shingo Noguchi  5 , Chinatsu Nishida  5 , Kazuhiro Yatera  5 , Yasuo Morimoto  2
Affiliations

Usefulness of myeloperoxidase as a biomarker for the ranking of pulmonary toxicity of nanomaterials

Taisuke Tomonaga et al. Part Fibre Toxicol. .

Abstract

Background: In order to examine whether myeloperoxidase (MPO) can be a useful marker for evaluating the pulmonary toxicity of nanomaterials, we analyzed MPO protein in bronchoalveolar lavage fluid (BALF) samples obtained from previous examinations of a rat model. In those examinations we performed intratracheal instillation exposures (dose: 0.2-1.0 mg) and inhalation exposures (exposure concentration: 0.32-10.4 mg/m3) using 9 and 4 nanomaterials with different toxicities, respectively. Based on those previous studies, we set Nickel oxide nanoparticles (NiO), cerium dioxide nanoparticles (CeO2), multi wall carbon nanotubes with short or long length (MWCNT (S) and MWCNT (L)), and single wall carbon nanotube (SWCNT) as chemicals with high toxicity; and titanium dioxide nanoparticles (TiO2 (P90) and TiO2 (Rutile)), zinc oxide nanoparticles (ZnO), and toner with external additives including nanoparticles as chemicals with low toxicity. We measured the concentration of MPO in BALF samples from rats from 3 days to 6 months following a single intratracheal instillation, and from 3 days to 3 months after the end of inhalation exposure.

Results: Intratracheal instillation of high toxicity NiO, CeO2, MWCNT (S), MWCNT (L), and SWCNT persistently increased the concentration of MPO, and inhalation of NiO and CeO2 increased the MPO in BALF. By contrast, intratracheal instillation of low toxicity TiO2 (P90), TiO2 (Rutile), ZnO, and toner increased the concentration of MPO in BALF only transiently, and inhalation of TiO2 (Rutile) and ZnO induced almost no increase of the MPO. The concentration of MPO correlated with the number of total cells and neutrophils, the concentration of chemokines for neutrophils (cytokine-induced neutrophil chemoattractant (CINC)-1 and heme oxygenase (HO)-1), and the activity of released lactate dehydrogenase (LDH) in BALF. The results from the receiver operating characteristics (ROC) for the toxicity of chemicals by the concentration of MPO proteins in the intratracheal instillation and inhalation exposures showed that the largest areas under the curves (AUC) s in both examinations occurred at 1 month after exposure.

Conclusion: These data suggest that MPO can be a useful biomarker for the ranking of the pulmonary toxicity of nanomaterials, especially at 1 month after exposure, in both intratracheal instillation and inhalation exposure.

Keywords: Biomarker; Inhalation; Intratracheal instillation; Myeloperoxidase; Nanomaterial; Pulmonary toxicity; Rat.

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Conflict of interest statement

Ethics approval and consent to participate

All procedures and animal handling were done according to the guidelines described in the Japanese Guide for the Care and Use of Laboratory Animals as approved by the Animal Care and Use Committee, University of Occupational and Environmental Health, Japan.

Consent for publication

Not required as no human data presented.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Concentration of MPO in BALF exposed to inhaled chemicals. a 0.2 mg exposed chemicals following intratracheal instillation. b 0.4–1.0 mg exposed chemicals following intratracheal instillation. c all of the exposed groups following inhalation. Error bar means standard deviation. Asterisks indicate significant differences compared with each control (Mann-Whitney U test) (*p < 0.05, **p < 0.01)
Fig. 2
Fig. 2
Relationship between MPO and inflammatory markers: a neutrophils, b percent of neutrophils in total cells, c total cell, d CINC-1, e HO-1 and f LDH versus MPO concentration in BALF after inhalation and intratracheal instillation of inhaled chemicals. Values of ρ are Spearman’s rank correlation coefficient for all the data
Fig. 3
Fig. 3
Myeloperoxidase immunostaining of lung sections at 1 month exposure: (a) distilled water as a negative control, (b) 1 mg TiO2 (Rutile)-exposed lung, (c) 1 mg ZnO-exposed lung, (d) 1 mg NiO-exposed lung, (e) 1 mg CeO2-exposed lung, (f) 0.6 mg MWCNT (L)-exposed lung. Positive areas were observed mainly at the gathering sites of inflammatory cells at 1 month in NiO-, CeO2- and MWCNT (L)- exposed groups, and no positive areas were observed in negative control, TiO2 (Rutile) and ZnO- exposed groups
Fig. 4
Fig. 4
The receiver operating characteristics for the toxicity of chemicals by the concentration of MPO proteins. a Intratracheal instillation. b Inhalation exposure. The area under the curves at 1 months after exposure following both of intratracheal instillation and inhalation were larger than the other observation times
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