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Developing a materials perspective of how to control the degradation and negative impact of complex metal oxides requires an integrated understanding of how these nanomaterials transform in the environment and interact with biological systems. Doping with aluminum is known to stabilize oxide materials, but has not been assessed cohesively from synthesis to environmental fate and biological impact. In the present study, the influence of aluminum doping on metal ion release from transition metal oxides was investigated by comparing aqueous transformations of lithium nickel cobalt aluminum oxide (LiNi0.82Co0.15Al0.03O2; NCA) and lithium nickel cobalt oxide (LiNi0.80Co0.20O2; NC) nanoparticles and by calculating the energetics of metal release using a density functional theory (DFT) and thermodynamics method. Two model environmental organisms were used to assess biological impact, and metal ion release was compared for NCA and NC nanoparticles incubated in their respective growth media: moderately hard reconstituted water (MHRW) for the freshwater invertebrate Daphnia magna (D. magna) and minimal growth medium for the Gram-negative bacterium Shewanella oneidensis MR-1 (S. oneidensis). The amount of metal ions released was reduced for NCA compared to NC in MHRW, which correlated to changes in the modeled energetics of release upon Al substitution in the lattice. In minimal medium, metal ion release was approximately an order of magnitude higher compared to MHRW and was similar to the stoichiometry of the bulk nanoparticles for both NCA and NC. Interpretation of the release profiles and modeling indicated that the increase in total metal ion release and the reduced influence of Al doping arises from lactate complexation of metal ions in solution. The relative biological impacts of NC and NCA exposure for both S. oneidensis and D. magna were consistent with the metal release trends observed for minimal medium and MHRW, respectively. Together, these results demonstrate how a combined experimental and computational approach provides valuable insight into the aqueous transformations and biological impacts of complex metal oxide nanoparticles. 

High-valent metal oxides such as LiCoO2 and related materials are of increasing environmental concern due to the large-scale use in lithium-ion batteries and potential for metal ion release into aqueous systems. A key aspect of the environmental chemistry of these materials is the potential role redox chemistry plays in their transformations as well as their influence on the surrounding environment (i.e., biomolecules, organisms etc.). In recent work, we showed that LiCoO2(a common lithium-ion battery cathode material) oxidizes nicotinamide adenine dinucleotide (NADH), an essential molecule for electron transport, and enhances Co release from LiCoO2. In the present work, we investigated the mechanism of interaction by examining the role of the ribose, phosphate, adenosine, and the nicotinamide components of NADH in the transformation of LiCoO2 nanoparticles. To build an understanding of the interaction mechanism, we used fluorescence spectroscopy to measure the changes in redox state and inductively coupled plasma-mass spectrometry (ICP-MS) to measure the changes in dissolved Co. Our results reveal the importance of surface binding, via the phosphate functionality, in initiating the redox transformation of both the LiCoO2 and the NADH. Observations from X-ray photoelectron spectroscopy (XPS) data show that molecules containing phosphate were bound to the surface of the nanoparticles and those without that functionality were not. We further established the generality of the results with LiCoO2 by examining other high-valent transition metal oxides. This surface binding effect has implications for understanding how other phosphorylated species can be transformed directly in the presence of high-valent metal oxide nanomaterials. 

Physico-chemical characteristics of engineered nanomaterials are known to be important in determining the impact on organisms but effects are equally dependent upon the characteristics of the organism exposed. Species sensitivity may vary by orders of magnitude, which could be due to differences in the type or magnitude of the biochemical response, exposure or uptake of nanomaterials. Synthesizing conclusions across studies and species is difficult as multiple species are not often included in a study, and differences in batches of nanomaterials, the exposure duration and media across experiments confound comparisons. Here three model species, Danio rerio, Daphnia magna and Chironomus riparius, that differ in sensitivity to lithium cobalt oxide nanosheets are found to differ in immune-response, iron–sulfur protein and central nervous system pathways, among others. Nanomaterial uptake and dissolution does not fully explain cross-species differences. This comparison provides insight into how biomolecular responses across species relate to the varying sensitivity to nanomaterials. 

Lithium cobalt oxide (LiCoO 2 ), an example of nanoscale transition metal oxide and a widely commercialized cathode material in lithium ion batteries, has been shown to induce oxidative stress and generate intracellular reactive oxygen species (ROS) in model organisms. In this study, we aimed to understand the time-dependent roles of abiotic ROS generation and Co ions released in aqueous medium by LiCoO 2 NPs, and examined the induced biological responses in model bacterium, B. subtilis upon exposure. We found that the redox-active LiCoO 2 NPs produced abiotic ROS primarily through H 2 O 2 generation when freshly suspended. Subsequently, the freshly-suspended LiCoO 2 NPs induced additional DNA breakage, and changes in expression of oxidative stress genes in B. subtilis that could not be accounted for by the released Co ions alone. Notably, in 48 hour old LiCoO 2 suspensions, H 2 O 2 generation subsided while higher concentrations of Co ions were released. The biological responses in DNA damage and gene expression to the aged LiCoO 2 NPs recapitulated those induced by the released Co ions. Our results demonstrated oxidative stress mechanisms for bacteria exposed to LiCoO 2 NPs were mediated by the generation of distinct biotic and abiotic ROS species, which depended on the aqueous transformation state of the NPs. This study revealed the interdependent and dynamic nature of NP transformation and their biological consequences where the state of NPs resulted in distinct NP-specific mechanisms of oxidative injury. Our work highlights the need to capture the dynamic transformation of NPs that may activate the multiple routes of oxidative stress responses in cells. 

Growing evidence across organisms points to altered energy metabolism as an adverse outcome of metal oxide nanomaterial toxicity, with a mechanism of toxicity potentially related to the redox chemistry of processes involved in energy production. Despite this evidence, the significance of this mechanism has gone unrecognized in nanotoxicology due to the field’s focus on oxidative stress as a universal—but non-specific—nanotoxicity mechanism. To further explore metabolic impacts, we determined LCO’s effects on these pathways in the model organism Daphnia magna through global gene expression analysis using RNA-Seq and untargeted metabolomics by direct-injection mass spectrometry. Our results show a sublethal 1 mg/L 48 h exposure of D. magna to LCO nanosheets causes significant impacts on metabolic pathways versus untreated controls, while exposure to ions released over 48 hr does not. Specifically, transcriptomic analysis using DAVID indicated significant enrichment (Benjamini-adjusted p ≤0.0.5) in LCO-exposed animals for changes in pathways involved in the cellular response to starvation (25 genes), mitochondrial function (70 genes), ATP-binding (70 genes), oxidative phosphorylation (53 genes), NADH dehydrogenase activity (12 genes), and protein biosynthesis (40 genes). Metabolomic analysis using MetaboAnalyst indicated significant enrichment (gamma-adjusted p < 0.1) for changes in amino acid metabolism (19 metabolites) and starch, sucrose, and galactose metabolism (7 metabolites). Overlap of significantly impacted pathways by RNA-Seq and metabolomics suggests amino acid breakdown and increased sugar import for energy production. Results indicate that LCO-exposed Daphnia are responding to energy starvation by altering metabolic pathways, both at the gene expression and metabolite level. These results support altered energy production as a sensitive nanotoxicity adverse outcome for LCO exposure and suggest negative impacts on energy metabolism as an important avenue for future studies of nanotoxicity, including for other biological systems and for metal oxide nanomaterials more broadly. 

The initial interactions of engineered nanoparticles (NPs) with living cells are governed by physicochemical properties of the NP and the molecular composition and structure of the cell membrane. Eukaryotic cell membranes contain lipid rafts – liquid-ordered nanodomains involved in membrane trafficking and molecular signaling. However, the impact of these membrane structures on cellular interactions of NPs remains unclear. Here we investigate the role of membrane domains in the interactions of primary amine-terminated quantum dots (Qdots) with liquid-ordered domains or lipid rafts in model membranes and intact cells, respectively. Using correlative atomic force and fluorescence microscopy, we found that the Qdots preferentially localized to boundaries between liquid-ordered and liquid-disordered phases in supported bilayers. The Qdots also induced holes at these phase boundaries. Using super resolution fluorescence microscopy (STORM), we found that the Qdots preferentially co-localized with lipid rafts in the membrane of intact trout gill epithelial cells – a model cell type for environmental exposures. Our observations uncovered preferential interactions of amine-terminated Qdots with liquid-ordered domains and their boundaries, possibly due to membrane curvature at phase boundaries creating energetically favorable sites for NP interactions. The preferential interaction of the Qdots with lipid rafts supports their potential internalization via lipid raft-mediated endocytosis and interactions with raft-resident signaling molecules.