Pro-Inflammatory and Pro-Fibrogenic Effects of Ionic and Particulate Arsenide and Indium-Containing Semiconductor Materials in the Murine Lung
We have recently shown that the toxicological potential of GaAs and InAs particulates in cells is size- and dissolution-dependent, tending to be more pronounced for nano- vs. micron-sized particles. Whether the size-dependent dissolution and shedding of ionic III-V materials also apply to pulmonary exposure is unclear. While has been demonstrated that micron-sized III-V particles, such as GaAs and InAs, are capable of inducing hazardous pulmonary effects in an occupational setting, as well as in animal studies, the effect of sub-micron particles (e.g., the removal of asperities during processing of semiconductor wafers) is unclear. We used cytokine profiling to compare the pro-inflammatory effects of micron- and nanoscale GaAs and InAs particulates in cells as well as murine lung 40 h and 21 days (D) after oropharyngeal aspiration. Use of cytokine array technology in macrophage and epithelial cell cultures demonstrated a proportionally higher increase in the levels of matrix metalloproteinase inducer (EMMPRIN), macrophage migration inhibitory factor (MIF), and Interleukin IL-1β by nano-sized (n) GaAs and n-InAs as well as As(III). n-GaAs and n-InAs also triggered higher neutrophil counts in the bronchoalveolar lavage fluid (BALF) of mice than micronscale particles 40 h post-aspiration, along with increased production of EMMPRIN and MIF. In contrast, in animals sacrificed 21 D after exposure, only n-InAs induced fibrotic lung changes as determined by increased lung collagen as well as increased levels of TGF-β1 and PDGF-AA in the BALF. A similar trend was seen for EMMPRIN and matrix metallopeptidase (MMP-9) levels in the BALF. Nano- and micron-GaAs had negligible sub-acute effects. Importantly, the difference between the 40 h and 21 D data appears to be biopersistence of n-InAs, as demonstrated by ICP-OES analysis of lung tissue. Interestingly, an ionic form of In, InCl3, also showed pro-fibrogenic effects due to the formation of insoluble In(OH)3 nanostructures. All considered, these data indicate that while nanoscale particles exhibit increased pro-inflammatory effects in the lung, most effects are transient, except for n-InAs and insoluble InCl3 species that are biopersistent and trigger pro-fibrotic effects. These results are of potential importance for the understanding the occupational health effects of III-V particulates.