There is an emerging literature reporting toxic effects of manufactured nanomaterials (NMs) and nanoparticles (NPs) in fish, but the mechanistic basis of both exposure and effect are poorly understood. This paper critically evaluates some of the founding assumptions in fish toxicology, and likely mechanisms of absorption, distribution, metabolism and excretion (ADME) of NPs in fish compared to other chemicals. Then, using a case study approach, the paper compares these assumptions for two different NPs; TiO2 and C60 fullerenes. Adsorption of NPs onto the gill surface will involve similar processes in the gill microenvironment and mucus layer to other substances, but the uptake mechanisms for NPs by epithelial cells are more likely to occur via vesicular processes (e.g., endocytosis) than uptake on membrane transporters or by diffusion through the cell membranes. Target organs may include the gills, gut, liver and sometimes the brain. Information on metabolism and excretion of NPs in fish is limited; but hepatic excretion into the bile seems a more likely mechanism, rather than mainly by renal or branchial excretion. TiO2 and C60 share some common chemical properties that appear to be associated with some similar toxic effects, but there are also differences, that highlight the notion that chemical reactivity can inform toxic effect of NPs in a fundamentally similar way to other chemicals. In this paper we identify many knowledge gaps including the lack of field observations on fish and other wildlife species for exposure and effects of manufactured NMs. Systematic studies of the abiotic factors that influence bioavailability, and investigation of the cell biology that informs on the mechanisms of metabolism and excretion of NMs, will greatly advance our understanding of the potential for adverse effects. There are also opportunities to apply existing tools and techniques to fundamental studies of fish toxicology with NPs, such as perfused organs and fish cell culture systems.

Gold nanoparticles (AuNP) provide many opportunities in imaging, diagnostics, and therapy in nanomedicine. For the assessment of AuNP biokinetics, we intratracheally instilled into rats a suite of 198Au-radio-labelled monodisperse, well-characterized, negatively-charged AuNP of five different sizes (1.4, 2.8, 5, 18, 80, 200 nm) and 2.8 nm AuNP with positive surface charges. At 1-h, 3-h, and 24-h the biodistribution of the AuNP was quantitatively measured by gamma-spectrometry to be used for comprehensive risk assessment. Our study shows, as AuNP get smaller, they are more likely to cross the air-blood-barrier (ABB) depending strongly on the inverse diameter d−1 of their gold core; i.e. their specific surface area (SSA). So, 1.4 nm AuNP (highest SSA) translocated most while 80 nm AuNP (lowest SSA) translocated least, but 200 nm particles did not follow the d−1 relation translocating significantly higher than 80 nm AuNP. However, relative to the AuNP which had crossed the ABB, their retention in most of the secondary organs and tissues was SSA-independent. Only renal filtration, retention in blood and excretion via urine further declined with d−1 of AuNP core. Translocation of 5, 18 and 80 nm AuNP is virtually complete after 1-h, while 1.4 nm AuNP continue to translocate until 3-h. Translocation of negatively charged 2.8 nm AuNP was significantly higher than for positively charged 2.8 nm AuNP. Our study shows that translocation across the ABB and accumulation and retention in secondary organs and tissues are two distinct processes, both depending specifically on particle characteristics such as SSA and surface charge.

Owing to their antimicrobial properties, silver nanoparticles (NPs) are the most commonly used engineered nanomaterial for use in a wide array of consumer and medical applications. Many discussions are currently ongoing as to whether or not exposure of silver NPs to the ecosystem (i.e. plants and animals) may be conceived as harmful or not. Metallic silver, if released into the environment, can undergo chemical and biochemical conversion which strongly influence its availability towards any biological system. During this process, in the presence of moisture, silver can be oxidized resulting in the release of silver ions. To date, it is still debatable as to whether any biological impact of nanosized silver is relative to either its size, or to its ionic constitution. The aim of this review therefore is to provide a comprehensive, interdisciplinary overview-for biologists, chemists, toxicologists as well as physicists-regarding the production of silver NPs, its (as well as in their ionic form) chemical and biochemical behaviours towards/within a multitude of relative and realistic biological environments and also how such interactions may be correlated across a plethora of different biological organisms.

Despite increasing application of silver nanoparticles (NPs) in industry and consumer products, there is still little known about their potential toxicity, particularly to organisms in aquatic environments. To investigate the fate and effects of silver NPs in fish, rainbow trout (Oncorhynchus mykiss) were exposed via the water to commercial silver particles of three nominal sizes: 10 nm (N(10)), 35 nm (N(35)), and 600-1600 nm (N(Bulk)), and to silver nitrate for 10 days. Uptake into the gills, liver, and kidneys was quantified by inductively coupled plasma-optical emission spectrometry, and levels of lipid peroxidation in gills, liver, and blood were determined by measurements of thiobarbituric acid reactive substances. Expression of a suite of genes, namely cyp1a2, cyp3a45, hsp70a, gpx, and g6pd, known to be involved in a range of toxicological response to xenobiotics was analyzed in the gills and liver using real-time PCR. Uptake of silver particles from the water into the tissues of exposed fish was low but nevertheless occurred for current estimated environmental exposures. Of the silver particles tested, N(10) were found to be the most highly concentrated within gill tissues and N(10) and N(Bulk) were the most highly concentrated in liver. There were no effects on lipid peroxidation in any of the tissues analyzed for any of the silver particles tested, and this is likely due to the low uptake rates. However, exposure to N(10) particles was found to induce expression of cyp1a2 in the gills, suggesting a possible increase in oxidative metabolism in this tissue.

An approach to controlling blood glucose levels in individuals with type 2 diabetes is to target alpha-amylases and intestinal glucosidases using alpha-glucosidase inhibitors acarbose and miglitol. One of the intestinal glucosidases targeted is the N-terminal catalytic domain of maltase-glucoamylase (ntMGAM), one of the four intestinal glycoside hydrolase 31 enzyme activities responsible for the hydrolysis of terminal starch products into glucose. Here we present the X-ray crystallographic studies of ntMGAM in complex with a new class of alpha-glucosidase inhibitors derived from natural extracts of Salacia reticulata, a plant used traditionally in Ayuverdic medicine for the treatment of type 2 diabetes. Included in these extracts are the active compounds salacinol, kotalanol, and de-O-sulfonated kotalanol. This study reveals that de-O-sulfonated kotalanol is the most potent ntMGAM inhibitor reported to date (K(i) = 0.03 microM), some 2000-fold better than the compounds currently used in the clinic, and highlights the potential of the salacinol class of inhibitors as future drug candidates.

Nanoparticles (NPs) are reported to be a potential environmental health hazard. For organisms living in the aquatic environment there is much uncertainty on exposure because of a fundamental lack of understanding and data regarding the fate, behavior and bioavailability of the nanomaterials in the water column. This paper reports on a series of integrative biological and physicochemical studies on the uptake of unmodified commercial nanoscale metal oxides, zinc oxide (ZnO), cerium dioxide (CeO 2 ), and titanium dioxide (TiO 2 ) from the water and diet to determine their potential ecotoxicological impacts on fish as a function of concentration. Particle characterizations were performed and tissue concentrations measured using a wide range of analytical methods. Definitive uptake from the water column and localization of TiO 2 NPs in gills was demonstrated for the first time using coherent anti-Stokes Raman Scattering (CARS) microscopy. Zinc concentrations in zebrafish, and titanium in trout did not differ in exposed fish, compared with controls. Significant uptake of cerium occurred in the liver of zebrafish exposed via the water and ionic titanium in the gut of trout exposed via the diet. For the aqueous exposures undertaken, formation of large NP aggregates (up to 3µm) occurred and it is likely that this resulted in limited bioavailability of the unmodified metal oxide NPs in fish.3

An increasing number and quantity of manufactured nanoparticles are entering the environment as the diversity of their applications increases, and this will lead to the exposure of both humans and wildlife. However, little is known regarding their potential health effects. We compared the potential biological effects of silver (Ag; nominally 35 and 600-1,600 nm) and cerium dioxide (CeO(2;) nominally <25 nm and 1-5 µm) particles in a range of cell (human hepatocyte and intestinal and fish hepatocyte) and animal (Daphnia magna, Cyprinus carpio) models to assess possible commonalities in toxicity across taxa. A variety of analytical techniques were employed to characterize the particles and investigate their biological uptake. Silver particles were more toxic than CeO(2) in all test systems, and an equivalent mass dose of Ag nanoparticles was more toxic than larger micro-sized material. Cellular uptake of all materials tested was shown in C3A hepatocytes and Caco-2 intestinal cells, and for Ag, into the intestine, liver, gallbladder, and gills of carp exposed via the water. The commonalities in toxicity of these particle types across diverse biological systems suggest that cross-species extrapolations may be possible for metal nanoparticle test development in the future. Our findings also suggest transport of particles through the gastrointestinal barrier, which is likely to be an important uptake route when assessing particle risk.

Silver nanoparticles cause toxicity in exposed organisms and are an environmental health concern. The mechanisms of silver nanoparticle toxicity, however, remain unclear. We examined the effects of exposure to silver in nano-, bulk-, and ionic forms on zebrafish embryos (Danio rerio) using a Next Generation Sequencing approach in an Illumina platform (High-Throughput SuperSAGE). Significant alterations in gene expression were found for all treatments and many of the gene pathways affected, most notably those associated with oxidative phosphorylation and protein synthesis, overlapped strongly between the three treatments indicating similar mechanisms of toxicity for the three forms of silver studied. Changes in oxidative phosphorylation indicated a down-regulation of this pathway at 24 h of exposure, but with a recovery at 48 h. This finding was consistent with a dose-dependent decrease in oxygen consumption at 24 h, but not at 48 h, following exposure to silver ions. Overall, our data provide support for the hypothesis that the toxicity caused by silver nanoparticles is principally associated with bioavailable silver ions in exposed zebrafish embryos. These findings are important in the evaluation of the risk that silver particles may pose to exposed vertebrate organisms.