Boron Oxide Nanoparticles Exhibit Minor, Species-Specific Acute Toxicity to North-Temperate and Amazonian Freshwater Fishes.

Boron oxide nanoparticles (nB2O3) are manufactured for structural, propellant, and clinical applications and also form spontaneously through the degradation of bulk boron compounds. Bulk boron is not toxic to vertebrates but the distinctive properties of its nanostructured equivalent may alter its biocompatibility. Few studies have addressed this possibility, thus our goal was to gain an initial understanding of the potential acute toxicity of nB2O3 to freshwater fish and we used a variety of model systems to achieve this. Bioactivity was investigated in rainbow trout (Oncorhynchus mykiss) hepatocytes and at the whole animal level in three other North and South American fish species using indicators of aerobic metabolism, behavior, oxidative stress, neurotoxicity, and ionoregulation. nB2O3 reduced O. mykiss hepatocyte oxygen consumption (MO2) by 35% at high doses but whole animal MO2 was not affected in any species. Spontaneous activity was assessed using MO2 frequency distribution plots from live fish. nB2O3 increased the frequency of high MO2 events in the Amazonian fish Paracheirodon axelrodi, suggesting exposure enhanced spontaneous aerobic activity. MO2 frequency distributions were not affected in the other species examined. Liver lactate accumulation and significant changes in cardiac acetylcholinesterase and gill Na+/K+-ATPase activity were noted in the north-temperate Fundulus diaphanus exposed to nB2O3, but not in the Amazonian Apistogramma agassizii or P. axelrodi. nB2O3 did not induce oxidative stress in any of the species studied. Overall, nB2O3 exhibited modest, species-specific bioactivity but only at doses exceeding predicted environmental relevance. Chronic, low dose exposure studies are required for confirmation, but our data suggest that, like bulk boron, nB2O3 is relatively non-toxic to aquatic vertebrates and thus represents a promising formulation for further development.

Assessment of the toxic potential of engineered metal oxide nanomaterials using an acellular model: citrated rat blood plasma.

Citrated Sprague-Dawley rat blood plasma was used as a biologically relevant exposure medium to assess the acellular toxic potential of two metal oxide engineered nanomaterials (ENMs), zinc oxide (nZnO), and cerium oxide (nCeO2). Plasma was incubated at 37 °C for up to 48 h with ENM concentrations ranging between 0 and 200 mg/L. The degree of ENM-induced oxidation was assessed by assaying for reactive oxygen species (ROS) levels using dichlorofluorescein (DCF), pH, ferric reducing ability of plasma (FRAP), lipase activity, malondialdehyde (MDA), and protein carbonyls (PC). Whereas previous in vitro studies showed linear-positive correlations between ENM concentration and oxidative damage, our results suggested that low concentrations were generally pro-oxidant and higher concentrations appeared antioxidant or protective, as indicated by DCF fluorescence trends. nZnO and nCeO2 also affected pH in a manner dependent on concentration and elemental composition; higher nZnO concentrations maintained a more alkaline pH, while nCeO2 tended to decrease pH. No other biomarkers of oxidative damage (FRAP, MDA, PC, lipase activity) showed changes at any ENM concentration or time-point tested. Differential dissolution of the two ENMs was also observed, where as much as ∼31.3% of nZnO was instantaneously dissolved to Zn2+ and only negligible nCeO2 was degraded. The results suggest that the direct oxidative potential of nZnO and nCeO2 in citrated rat blood plasma is low, and that a physiological or immune response is needed to generate appreciable damage biomarkers. The data also highlight the need for careful consideration when selecting a model for assessing ENM toxicity.

Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer's disease.

The discovery that the apolipoprotein E (apoE) ε4 allele is genetically linked to both sporadic and familial late-onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain of AD subjects. The presence of the ε4 allele has been associated with lower levels of apoE in both serum and brain tissues of normal and AD subjects. In an attempt to reverse the apoE deficit in AD, we identified and characterized several apoE inducer agents using a low-throughput in vitro screening assay. The most promising of these compounds is called probucol. Administration of probucol, an old cholesterol-lowering drug, in a pilot trial in mild-to-moderate sporadic AD led to a significant increase in cerebrospinal fluid (CSF) apoE levels and a decrease in CSF in both phosphorylated tau 181 and beta-amyloid 1-42 concentrations without significant modifications of lipid hydroperoxide levels.

Multistage screening reveals chameleon ligands of the human farnesyl pyrophosphate synthase: implications to drug discovery for neurodegenerative diseases.

Human farnesyl pyrophosphate synthase (hFPPS) is the gate-keeper of mammalian isoprenoids and the key target of bisphosphonate drugs. Bisphosphonates suffer from poor "drug-like" properties and are mainly effective in treating skeletal diseases. Recent investigations have implicated hFPPS in various nonskeletal diseases, including Alzheimer's disease (AD). Analysis of single nucleotide polymorphisms in the hFPPS gene and mRNA levels in autopsy-confirmed AD subjects was undertaken, and a genetic link between hFPPS and phosphorylated tau (P-Tau) levels in the human brain was identified. Elevated P-Tau levels are strongly implicated in AD progression. The development of nonbisphosphonate inhibitors can provide molecular tools for validating hFPPS as a therapeutic target for tauopathy-associated neurodegeneration. A multistage screening protocol led to the identification of a new monophosphonate chemotype that bind in an allosteric pocket of hFPPS. Optimization of these compounds could lead to human therapeutics that block tau metabolism and arrest the progression of neurodegeneration.

Physiological hepatic response to zinc oxide nanoparticle exposure in the white sucker, Catostomus commersonii.

Liver toxicity of commercially relevant zinc oxide nanoparticles (nZnO) was assessed in a benthic freshwater cypriniform, the white sucker (Catostomus commersonii). Exposure to nZnO caused several changes in levels of liver enzyme activity, antioxidants, and lipid peroxidation end products consistent with an oxidative stress response. Aconitase activity decreased by ~65% but tended to be restored to original levels upon supplementation with Fe(2+), indicating oxidative inactivation of the 4Fe-4S cluster. Furthermore, glucose-6-phosphate dehydrogenase activity decreased by ~29%, and glutathione levels increased by ~56%. Taken together, these suggest that nZnO induces hepatic physiological stress. Each assay was then validated by using a single liver homogenate or plasma sample that was partitioned and treated with nZnO or Zn(2+), the breakdown product of nZnO. It was found that Zn(2+), but not nZnO, increased detected glutathione reductase activity by ~14% and decreased detected malondialdehyde by ~39%. This indicates that if appreciable nZnO dissolution occurs in liver samples during processing and assay, it may skew results, with implications not only for this study, but also for a wide range of nanotoxicology studies focusing on nZnO. Finally, in vitro incubations of cell-free rat blood plasma with nZnO failed to generate any significant increase in malondialdehyde or protein carbonyl levels, or any significant decrease in ferric reducing ability of plasma. This suggests that at the level tested, any oxidative stress caused by nZnO is the result of a coordinated physiological response by the liver.