Toxicity of Metal Oxide Nanoparticles: Looking through the Lens of Toxicogenomics

Abstract

The impact of solubility on the toxicity of metal oxide nanoparticles (MONPs) requires further exploration to ascertain the impact of the dissolved and particulate species on response. In this study, FE1 mouse lung epithelial cells were exposed for 2–48 h to 4 MONPs of varying solubility: zinc oxide, nickel oxide, aluminum oxide, and titanium dioxide, in addition to microparticle analogues and metal chloride equivalents. Previously published data from FE1 cells exposed for 2–48 h to copper oxide and copper chloride were examined in the context of exposures in the present study. Viability was assessed using Trypan Blue staining and transcriptomic responses via microarray analysis. Results indicate material solubility is not the sole property governing MONP toxicity. Transcriptional signaling through the ‘HIF-1α Signaling’ pathway describes the response to hypoxia, which also includes genes associated with processes such as oxidative stress and unfolded protein responses and represents a conserved response across all MONPs tested. The number of differentially expressed genes (DEGs) in this pathway correlated with apical toxicity, and a panel of the top ten ranked DEGs was constructed (Hmox1, Hspa1a, Hspa1b, Mmp10, Adm, Serpine1, Slc2a1, Egln1, Rasd1, Hk2), highlighting mechanistic differences among tested MONPs. The HIF-1α pathway is proposed as a biomarker of MONP exposure and toxicity that can help prioritize MONPs for further evaluation and guide specific testing strategies.

A Systematic Genotoxicity Assessment of a Suite of Metal Oxide Nanoparticles Reveals Their DNA Damaging and Clastogenic Potential

“…Uncoated Fe 2 O 3 NPs (US3160) were 30.95 ± 13.12 nm (Table 3). Almost all MONPs had an aspect ratio spanning from 1.22 ± 0.20 to 1.39 ± 0.39 and showed a spherical morphology, except uncoated MnO 2 NPs (4910DX) and uncoated Al 2 O 3 NPs (544833), which exhibited an aspect ratio of ~2.7 with a rod-like shape (reported previously in Boyadzhiev et al [54] and Figure S4).…”

“…Uncoated CeO 2 NPs (US3136) showed 39.78 ± 14.55 nm, and the rest of the CeO 2 NPs (Uncoated-US3036, PVP-coated and stearic acid-coated [US3037]) exhibited smaller lengths, ranging from 10.61 ± 2.71 to 14.12 ± 4.54 nm. The uncoated TiO 2 NPs were 26.8 ± 8.9 nm in length (reported previously [34,54]). Uncoated Fe 2 O 3 NPs (US3160) were 30.95 ± 13.12 nm (Table 3).…”

“…The Figure S8 shows representative SEM images of MnO 2 MOMPs, CeO 2 MOMPs, and Fe 2 O 3 MPs. The images of the previously reported MONPs and MOMPs can be found in Boyadzhiev et al [34,54]. [54]).…”

“…The images of the previously reported MONPs and MOMPs can be found in Boyadzhiev et al [34,54]. [54]). Uncoated CeO 2 NPs (US3136) showed 39.78 ± 14.55 nm, and the rest of the CeO 2 NPs (Uncoated-US3036, PVP-coated and stearic acid-coated [US3037]) exhibited smaller lengths, ranging from 10.61 ± 2.71 to 14.12 ± 4.54 nm.…”

“…The primary size determined by TEM, the HD, PDI, and ZP in the cell culture medium are summarized in Table 3. Part of the characterization of uncoated ZnO NPs (US3580), uncoated CuO NPs (544868), uncoated NiO NPs (US3355), uncoated Al 2 O 3 NPs (544833), uncoated TiO 2 NPs, ZnO MPs, CuO MPs, NiO MPs, Al 2 O 3 MPs, and TiO 2 MPs were previously reported in Boyadzhiev et al [34,49,54] and are indicated with letters "a", "b", and "c" in Table 3. The characterization of HD, PDI, and ZP in dH 2 O is found in Table S2, and the BET SSA characterization is found in Table S3.…”