Pulmonary dust foci as rat pneumoconiosis lesion induced by titanium dioxide nanoparticles in 13-week inhalation study

Abstract

Background: Most toxicological studies on titanium dioxide (TiO2) particles to date have concentrated on carcinogenicity and acute toxicity, with few studies focusing of pneumoconiosis, which is a variety of airspace and interstitial lung diseases caused by particle-laden macrophages. The present study examined rat pulmonary lesions associated with pneumoconiosis after inhalation exposure to TiO2 nanoparticles (NPs). Methods: Male and female F344 rats were exposed to 6.3, 12.5, 25, or 50 mg/m3 anatase type TiO2 NPs for 6 hours/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. After the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. Results: Numerous milky white spots were present in the lungs after exposure 25 and 50 mg/m3 TiO2 NPs. Histopathological analysis revealed that the spots were alveolar lesions, characterized predominantly by the agglomeration of particle-laden macrophages and the presence of reactive alveolar epithelial type 2 cell (AEC2) hyperplasia. We defined this characteristic lesion as pulmonary dust foci (PDF). The PDF is an inflammatory niche, with decreased vascular endothelial cells in the interstitium, and proliferating AEC2 transformed into alveolar epithelial progenitor cells. The AEC2 in the PDF had acquired DNA damage. Based on PDF induction, the lowest observed adverse effect concentration for pulmonary disorders in male and female rats in this study was 12.5 mg/m3 and 6.3 mg/m3, respectively. The no observed adverse effect concentration for male rats was 6.3 mg/m3. There was a sex difference in lung lesion development, with females showing more pronounced lesion parameters than males. Conclusions: Inhalation exposure to TiO2 NPs caused PDF, an air-space lesion which is an alveolar inflammatory niche containing particle-laden macrophages and proliferating AEC2. This PDF histopathologically resembles some pneumoconiosis lesions (pulmonary siderosis and hard metal pneumoconiosis) in workers and lung disease in smokers, suggesting that it is an early pneumoconiosis lesion caused by exposure to TiO2 NPs in rats and a common alveolar reaction in mammals.

Mechanisms of pulmonary disease in F344 rats after workplace-relevant inhalation exposure to cross-linked water-soluble acrylic acid polymers

“…It has been reported that AEPs are present in mouse and human lungs to contribute to the activation of regenerative molecular programs [11,12] and that Sox9-positive AEPs also exist [19]. Although in this study, we were not able to identify AEPs in normal rat lungs, consistent with our previous findings in rats [13], AEPs were observed immediately after CWAAP-A exposure and after the 18-week recovery period, suggesting that CWAAP-A induced lung lesions are regenerative changes, consistent with previous reports [11]. Furthermore, a small number of Sox9-positive AEPs were also observed in the lesions after the 18-week recovery period.…”

“…9 right panels). These results are consistent with our previous report [13] and confirm that AEPs are conserved in the rat lung and may be involved in the formation and progression of CWAAP-A induced lung lesions. Furthermore, these results support the premise that AEP expansion in the lesion represents a regenerative change in the alveoli in response to alveolar toxicity caused by exposure to CWAAP-A.…”

“…These results suggest that CWAAP-A exposure induces alveolar collapse Fig. 13 Representative macroscopic and microscopic photographs of rat lungs after intratracheal instillation of CWAAPs. White spots were observed on the caudal side of the right and left lungs (middle panels), and histopathological images of the same areas showed diffuse lesions (lower panels) in rat lungs, but that direct damage to epithelial cells and endothelial cells is minor.…”

“…The possible involvement of alveolar epithelial progenitor cells (AEPs), which have recently attracted attention as a cell type activated during the repair process after lung injury [11,12], is an important issue in CWAAP exposed lung pathology and in elucidating the mechanisms of disease progression. We have previously shown that AEPs are also present in rats [13]. Therefore, in the present study, we investigated the contribution of TGFβ signaling and AEPs in the development and progression of lung disease caused by exposure to CWAAPs.…”

Carcinogenicity and testicular toxicity of 2-bromopropane in a 26-week inhalation study using the rasH2 mouse model

“…We have previously conducted systemic inhalation exposure studies of various chemicals in rodents, including rasH2 mice, and have examined various toxicities, including carcinogenicity and pulmonary fibrosis [25][26][27] . In this study, we conducted a 26-week systemic inhalation exposure study of 2-BP using rasH2 mice and comprehensively evaluated carcinogenicity in each organ and reproductive organ toxicity.…”