Gorka DE et al. (2015) Environ Sci Technol "Reducing Environmental Toxicity of Silver Nanoparticles through Shape Control."

Osterberg JS, Gunsch CK, Colman BP, Liu J, Meyer J, Di Giulio RT, Berhardt ES, Gorka DE, Gwin C

[Environ Sci Technol, 2015]

The use of antibacterial silver nanomaterials in consumer products ranging from textiles to toys has given rise to concerns over their environmental toxicity. These materials, primarily nanoparticles, have been shown to be toxic to a wide range of organisms; thus methods and materials that reduce their environmental toxicity while retaining their useful antibacterial properties can potentially solve this problem. Here we demonstrate that silver nanocubes display a lower toxicity toward the model plant species Lolium multiflorum while showing similar toxicity toward other environmentally relevant and model organisms (Danio rerio and Caenorhabditis elegans) and bacterial species (Esherichia coli, Bacillus cereus, and Pseudomonas aeruginosa) compared to quasi-spherical silver nanoparticles and silver nanowires. More specifically, in the L. multiflorum experiments, the roots of silver nanocube treated plants were 5.3% shorter than the control, while silver nanoparticle treated plant roots were 39.6% shorter than the control. The findings here could assist in the future development of new antibacterial products that cause less environmental toxicity after their intended use.

Yang X et al. (2012) Environ Sci Technol "Mechanism of silver nanoparticle toxicity is dependent on dissolved silver and surface coating in Caenorhabditis elegans."

Marinakos SM, Hsu-Kim H, Yang X, Liu J, Meyer J, Gondikas A, Auffan M

[Environ Sci Technol, 2012]

The rapidly increasing use of silver nanoparticles (Ag NPs) in consumer products and medical applications has raised ecological and human health concerns. A key question for addressing these concerns is whether Ag NP toxicity is mechanistically unique to nanoparticulate silver, or if it is a result of the release of silver ions. Furthermore, since Ag NPs are produced in a large variety of monomer sizes and coatings, and since their physicochemical behavior depends on the media composition, it is important to understand how these variables modulate toxicity. We found that a lower ionic strength medium resulted in greater toxicity (measured as growth inhibition) of all tested Ag NPs to Caenorhabditis elegans and that both dissolved silver and coating influenced Ag NP toxicity. We found a linear correlation between Ag NP toxicity and dissolved silver, but no correlation between size and toxicity. We used three independent and complementary approaches to investigate the mechanisms of toxicity of differentially coated and sized Ag NPs: pharmacological (rescue with trolox and N-acetylcysteine), genetic (analysis of metal-sensitive and oxidative stress-sensitive mutants), and physicochemical (including analysis of dissolution of Ag NPs). Oxidative dissolution was limited in our experimental conditions (maximally 15% in 24 h) yet was key to the toxicity of most Ag NPs, highlighting a critical role for dissolved silver complexed with thiols in the toxicity of all tested Ag NPs. Some Ag NPs (typically less soluble due to size or coating) also acted via oxidative stress, an effect specific to nanoparticulate silver. However, in no case studied here was the toxicity of a Ag NP greater than would be predicted by complete dissolution of the same mass of silver as silver ions.

Tyne W et al. (2013) Environ Toxicol Chem "A new medium for Caenorhabditis elegans toxicology and nanotoxicology studies designed to better reflect natural soil solution conditions."

Lofts S, Spurgeon DJ, Tyne W, Svendsen C, Jurkschat K

[Environ Toxicol Chem, 2013]

A new toxicity test medium for Caenorhabditis elegans is presented. The test solution is designed to provide a better representation of natural soil pore water conditions than currently available test media. The medium has a composition that can readily be modified to allow for studies of the influences of a range of environmentally relevant parameters on nematode biology and toxicology. Tests conducted in the new medium confirmed that nematodes' reproduction was possible at a range of solution pH levels, offering the potential to conduct toxicity studies under a variety of conditions. A test to establish silver nanoparticle and dissolved silver nitrate toxicity, a study type not feasible in M9 or agar media due to precipitation and nanoparticle agglomeration, indicated lower silver nanoparticle (median effective concentration [EC50] of 6.5mg Ag/L) than silver nitrate (EC50 0.28mg Ag/L) toxicity. Characterization identified stable nanoparticle behavior in the new test medium.

Hunt PR et al. (2013) J Appl Toxicol "Nanosilver suppresses growth and induces oxidative damage to DNA in Caenorhabditis elegans."

Tyner KM, Conklin S, Nelson BC, Sprando RL, Marquis BJ, Hunt PR, Olejnik N

[J Appl Toxicol, 2013]

Studies on the effects of nanomaterial exposure in mammals are limited, and new methods for rapid risk assessment of nanomaterials are urgently required. The utility of Caenorhabditis elegans cultured in axenic liquid media was evaluated as an alternative in vivo model for the purpose of screening nanomaterials for toxic effects. Spherical silver nanoparticles of 10nm diameter (10nmAg) were used as a test material, and ionic silver from silver acetate as a positive control. Silver uptake and localization, larval growth, morphology and DNA damage were utilized as endpoints for toxicity evaluation. Confocal reflection analysis indicated that 10nmAg localized to the lumen and tissues of the digestive tract of C. elegans. 10nmAg at 10gml(-1) reduced the growth of C. elegans larvae, and induced oxidative damage to DNA as measured by 8-OH guanine levels. Consistent with previously published studies using mammalian models, ionic silver suppressed growth in C. elegans larvae to a greater extent than 10nmAg. Our data suggest that medium-throughput growth screening and DNA damage analysis along with morphology assessments in C. elegans could together provide powerful tools for rapid toxicity screening of nanomaterials.

Moon J et al. (2018) Chemosphere "The effects of silver nanomaterial shape and size on toxicity to Caenorhabditis elegans in soil media."

An YJ, Kwak JI, Moon J

[Chemosphere, 2018]

Silver nanomaterials (AgNMs) of various shapes and sizes are manufactured for different purposes and used as ingredients in a wide variety of products and applications. Recently, the toxicity of AgNMs has attracted significant attention. However, the effect of the shape of AgNMs (particles, wires, plates) on their toxicity in soil ecosystems remains poorly understood. In this study, we added AgNMs of different shapes and sizes (silver nanoparticles, AgNPs; 10m silver nanowires, 10-AgNWs; 20m silver nanowires, 20-AgNWs; silver nanoplates, AgPLs) to natural soil and determined their effect on the growth and reproduction of the free-living nematode, Caenorhabditis elegans. AgNPs and AgPLs were found to inhibit the growth and reproduction of C.elegans, whereas AgNWs had a negligible effect. Among these AgNMs, the results of this study suggest AgNPs are the most toxic. This confirms that the shape of AgNPs plays a significant role in their toxicity level. To the best of our knowledge, this is the first comparative analysis of the shape-dependent toxicity of AgNMs in the soil using nematode C.elegans. This study provides a scientific reference for assessing shape-dependent soil nanotoxicity.

Hunt PR et al. (2014) Toxicol Rep "Bioactivity of nanosilver in Caenorhabditis elegans: Effects of size, coat, and shape."

Gao X, Sprando RL, Oldenburg SJ, Bushana P, Hunt PR, Olejnik N, Keltner Z

[Toxicol Rep, 2014]

The in vivo toxicity to eukaryotes of nanosilver (AgNP) spheres and plates in two sizes each was assessed using the simple model organism Caenorhabditis elegans. For each shape, smaller AgNP size correlated with higher toxicity, as indicated by reduced larval growth. Smaller size also correlated with significant increases in silver uptake for silver nanospheres. Citrate coated silver spheres of 20 nm diameter induced an innate immune response that increased or held steady over 24 h, while regulation of genes involved in metal metabolism peaked at 4 h and subsequently decreased. For AgNP spheres, coating altered bioactivity, with a toxicity ranking of polyethylene glycol (PEG) > polyvinylpyrrolidone (PVP) branched polyethyleneimine (BPEI) > citrate, but silver uptake ranking of PEG > PVP > citrate > BPEI. Our findings in C. elegans correlate well with findings in rodents for AgNP size vs. uptake and toxicity, as well as for induction of immune effectors, while using methods that are faster and far less expensive, supporting the use of C. elegans as an alternative model for early toxicity screening.

Sakoguchi H et al. (2016) Biosci Biotechnol Biochem "Screening of biologically active monosaccharides: growth inhibitory effects of d-allose, d-talose, and l-idose against the nematode Caenorhabditis elegans."

Izumori K, Yoshihara A, Sakoguchi H, Sato M

[Biosci Biotechnol Biochem, 2016]

We compared the growth inhibitory effects of all aldohexose stereoisomers against the model animal Caenorhabditis elegans. Among the tested compounds, the rare sugars d-allose (d-All), d-talose (d-Tal), and l-idose (l-Ido) showed considerable growth inhibition under both monoxenic and axenic culture conditions. 6-Deoxy-d-All had no effect on growth, which suggests that C6-phosphorylation by hexokinase is essential for inhibition by d-All.

Sakoguchi H et al. (2016) Bioorg Med Chem Lett "Growth inhibitory effect of d-arabinose against the nematode Caenorhabditis elegans: Discovery of a novel bioactive monosaccharide."

Shintani T, Izumori K, Sato M, Sakoguchi H, Okuma K, Yoshihara A

[Bioorg Med Chem Lett, 2016]

Biological activities of unusual monosaccharides (rare sugars) have largely remained unstudied until recently. We compared the growth inhibitory effects of aldohexose stereoisomers against the animal model Caenorhabditis elegans cultured in monoxenic conditions with Escherichia coli as food. Among these stereoisomers, the rare sugar d-arabinose (d-Ara) showed particularly strong growth inhibition. The IC50 value for d-Ara was estimated to be 7.5mM, which surpassed that of the potent glycolytic inhibitor 2-deoxy-d-glucose (19.5mM) used as a positive control. The inhibitory effect of d-Ara was also observed in animals cultured in axenic conditions using a chemically defined medium; this excluded the possible influence of E. coli. To our knowledge, this is the first report of biological activity of d-Ara. The d-Ara-induced inhibition was recovered by adding either d-ribose or d-fructose, but not d-glucose. These findings suggest that the inhibition could be induced by multiple mechanisms, for example, disturbance of d-ribose and d-fructose metabolism.

Yoshihara A et al. (2019) Bioorg Med Chem Lett "Growth inhibition by 1-deoxy-d-allulose, a novel bioactive deoxy sugar, screened using Caenorhabditis elegans assay."

Sakoguchi H, Fleet GWJ, Izumori K, Shintani T, Sato M, Yoshihara A

[Bioorg Med Chem Lett, 2019]

The biological activities of deoxy sugars (deoxy monosaccharides) have remained largely unstudied until recently. We compared the growth inhibition by all 1-deoxyketohexoses using the animal model Caenorhabditis elegans. Among the eight stereoisomers, 1-deoxy-d-allulose (1d-d-Alu) showed particularly strong growth inhibition. The 50% inhibition of growth (GI₅₀) concentration by 1d-d-Alu was estimated to be 5.4mM, which is approximately 10 times lower than that of d-allulose (52.7mM), and even lower than that of the potent glycolytic inhibitor, 2-deoxy-d-glucose (19.5mM), implying that 1d-d-Alu has a strong growth inhibition. In contrast, 5-deoxy- and 6-deoxy-d-allulose showed no growth inhibition of C. elegans. The inhibition by 1d-d-Alu was alleviated by the addition of d-ribose or d-fructose. Our findings suggest that 1d-d-Alu-mediated growth inhibition could be induced by the imbalance in d-ribose metabolism. To our knowledge, this is the first report of biological activity of 1d-d-Alu which may be considered as an antimetabolite drug candidate.

Katane M et al. (2020) Biochim Biophys Acta Proteins Proteom "Biochemical characterization of d-aspartate oxidase from Caenorhabditis elegans: Its potential use in the determination of free D-glutamate in biological samples."

Katane M, Sekine M, Nakayama K, Homma H, Kuwabara H, Saitoh Y, Miyamoto T

[Biochim Biophys Acta Proteins Proteom, 2020]

d-Aspartate oxidase (DDO) is a flavin adenine dinucleotide (FAD)-containing flavoprotein that stereospecifically acts on acidic D-amino acids (i.e., free d-aspartate and D-glutamate). Mammalian DDO, which exhibits higher activity toward d-aspartate than D-glutamate, is presumed to regulate levels of d-aspartate in the body and is not thought to degrade D-glutamate in vivo. By contrast, three DDO isoforms are present in the nematode Caenorhabditis elegans, DDO-1, DDO-2, and DDO-3, all of which exhibit substantial activity toward D-glutamate as well as d-aspartate. In this study, we optimized the Escherichia coli culture conditions for production of recombinant C. elegans DDO-1, purified the protein, and showed that it is a flavoprotein with a noncovalently but tightly attached FAD. Furthermore, C. elegans DDO-1, but not mammalian (rat) DDO, efficiently and selectively degraded D-glutamate in addition to d-aspartate, even in the presence of various other amino acids. Thus, C. elegans DDO-1 might be a useful tool for determining these acidic D-amino acids in biological samples.