Pro-Inflammatory and Pro-Fibrogenic Effects of Ionic and Particulate Arsenide and Indium-Containing Semiconductor Materials in the Murine Lung

Abstract

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 the murine lung 40 h and 21 days after oropharyngeal aspiration. Use of cytokine array technology in macrophage and epithelial cell cultures demonstrated a proportionally higher increase in the levels of extracellular matrix metalloproteinase inducer (EMMPRIN), macrophage migration inhibitory factor (MIF), and interleukin 1β (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 days 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 days 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.

RNA Sequencing Analyses Reveal the Potential Mechanism of Pulmonary Injury Induced by Gallium Arsenide Particles in Human Bronchial Epithelioid Cells

“…Toxicities of arsenic-induced carcinogenicity, including generation of oxidative stress, altered cell proliferation, changes in DNA methylation and co-carcinogenesis, though the exact molecular mechanism governing this toxicity is not well understood 18,23,24 . The toxicity of GaAs in pulmonary tissue includes inflammation, lung weight increase, fibrosis, seropurulent pneumonia and pneumocyte hyperplasia 18,20,25 .…”

Predictive Metabolomic Signatures for Safety Assessment of Metal Oxide Nanoparticles

“…The test animals (n = 4 mice/per group) were treated with MOx NPs by an oropharyngeal aspiration as described previously. 68,69 Briefly, aesthesia was maintained by intraperitoneal injection of ketamine (100 mg/kg) and xylazine (10 mg/kg). With the anesthetized animals held in a vertical position, 50 μL suspensions containing the MOx NPs at 10 or 40 μg in water (equivalent to 0.5, 2.0 mg/kg) were instilled at the back of the tongue to allow aspiration in the lung.…”

Molecular Mechanisms, Characterization Methods, and Utilities of Nanoparticle Biotransformation in Nanosafety Assessments

“…[16,17] After cellular internalization, NPs either assemble in intracellular vesicles (endosomes or lysosomes) or freely distribute in cytoplasm, [18] and a small portion of them (e.g., La 2 O 3 , CuO) may elicit hazard biochemical signals (e.g., oxygen radical generation, [19] cellular redox changes, [20] enzyme inactivation [21] ) and cytotoxicity. [16] Although there are uncertainties about how to assess the bioeffects, a growing number of studies regarding nanotoxicology in the past 15 years, provided evidences of adverse biological effects, such as generation of reactive oxygen species (ROS), [22][23][24] mitochondrial damage, [25][26][27][28] cytochrome C release, [23,29,30] membrane damage, [29][30][31][32][33] DNA damage, [24,25] inflammatory cytokine release, [7,21,[33][34][35][36][37][38][39][40] cell death, [28,41] etc.…”