Nanomaterials are highly dynamic in biological and environmental media. A critical need for advancing environmental health and safety research for nanomaterials is to identify commonly occurring physical and chemical transformations affecting nanomaterial properties and toxicity. Silver nanoparticles, one of the most ecotoxic and well-studied nanomaterials, readily sulfidize in the environment. Here, we show that very low degrees of sulfidation (0.019 S/Ag mass ratio) universally and significantly decreases the toxicity of silver nanoparticles to four diverse types of aquatic and terrestrial eukaryotic organisms. Toxicity reduction is primarily associated with a decrease in Ag+ availability after sulfidation due to the lower solubility of Ag2S relative to elemental Ag (Ag(0)). We also show that chloride in exposure media determines silver nanoparticle toxicity by controlling the speciation of Ag. These results highlight the need to consider environmental transformation of NPs in assessing their toxicity to accurately portray their potential environmental risks.

There are tens of thousands of man-made chemicals in the environment; the inherent safety of most of these chemicals is not known. Relevant biological platforms and new computational tools are needed to prioritize testing of chemicals with limited human health hazard information. We describe an experimental design for high-throughput characterization of multidimensional in vivo effects with the power to evaluate trends relating to commonly cited chemical predictors. We evaluated all 1060 unique U.S. EPA ToxCast phase 1 and 2 compounds using the embryonic zebrafish and found that 487 induced significant adverse biological responses. The utilization of 18 simultaneously measured endpoints means that the entire system serves as a robust biological sensor for chemical hazard. The experimental design enabled us to describe global patterns of variation across tested compounds, evaluate the concordance of the available in vitro and in vivo phase 1 data with this study, highlight specific mechanisms/value-added/novel biology related to notochord development, and demonstrate that the developmental zebrafish detects adverse responses that would be missed by less comprehensive testing strategies.

The 5-cap and the poly(A) tail act synergistically to increase the translational efficiency of eukaryotic mRNAs, which suggests that these two mRNA elements communicate during translation. We report here that the cap-associated eukaryotic initiation factors (eIFs), i.e. the two isoforms of the cap-binding complex (eIF-4F and eIF-iso4F) and eIF-4B, bind to the poly(A)-binding protein (PABP) both in the presence and absence of poly(A) RNA. The interactions between PABP and eIF-4F, eIF-iso4F, and eIF-4B were measured in the absence of poly(A) RNA using far Western analysis and confirmed by direct fluorescence titration studies. The functional consequence of the interaction between these initiation factors and PABP was examined using RNA binding assays and RNA mobility shift analysis. eIF-4F, eIF-iso4F, and eIF-4B promoted PABP activity through a shift in its equilibrium affinity for poly(A). eIF-iso4G, the large subunit of eIF-iso4F, was the subunit responsible for the interaction between eIF-iso4F and PABP and was the subunit that promoted PABP RNA binding activity. Truncation analysis of eIF-iso4G indicated that a domain close to its N-terminal end appeared to be involved in binding PABP. These results suggest that the interaction between PABP and eIF-4B and eIF-iso4G may be involved in mediating the functional co-dependence observed between the cap and the poly(A) tail during translation.Most eukaryotic mRNAs contain a cap (m 7

The promoter region of the X-linked human phosphoglycerate kinase-I [PGK-I) gene is a CpG island, similar to those often found near autosomal genes. We used ligation-mediated polymerase chain reaction (PCR) for a genomie sequencing study in which 450 bp of the human PGK-1 promoter region was analyzed for the presence of in vivo protein footprints and cytosine methylation at all CpG sites. A technique was devised to selectively visualize the DNA of the inactive X chromosome (Xi), even in the presence of the active X chromosome (Xa). We found that the human Xa in both normal male lymphoeytes and hamster-human hybrids is completely unmethylated at all 120 CpG sites. In contrast, 118 of the CpG sites are methylated on the human Xi in hamster-human hybrids. The Xi in normal female lymphoeytes is also highly methylated, but some GCG or CGC trinueleotides partially escape methylation; all other CpGs are fully methylated. In vivo footprinting studies with dimethylsulfate (DMS) revealed eight regions of apparent protein-DNA contacts on the Xa. Four of the footprints contained the consensus sequence of the binding site for transcription factor Spl. The other regions include potential binding sites for transcription factors ATF, NF1, and a CCAAT-binding protein. The Xi did not show any specifically protected sequences, and with the exception of four hyperreaetive sites, the in vivo DMS reactivity profile of Xi DNA was very similar to that of purified, linear Xi DNA. The implications of these findings with regard to the maintenance of methylation-free islands, X chromosome inactivation, and the ehromatin structure of faeultative heteroehromatin are discussed.

The increased use of flammable plastics and electronic devices along with stricter fire safety standards has led to the heavy use of flame retardant chemicals in many consumer, commercial, and industrial products. Although flame retardant use has increased, a great deal of uncertainty surrounds their safety with some evidence showing toxicity and risk to human and environmental health. Recent efforts have focused on designing high-throughput biological platforms with nonmammalian models to evaluate and prioritize chemicals with limited hazard information. To complement these efforts, this study used a new morphological and behavioral testing platform with embryonic zebrafish to characterize the developmental toxicity of 44 halogenated and organophosphate flame retardants, including several of their known metabolites. Zebrafish were exposed to flame retardants from 6 to 120 h post fertilization (hpf) across concentrations spanning 4 orders of magnitude (eg, 6.4 nM to 64 µM). Flame retardant effects on survival and development were evaluated at 24 and 120 hpf, and neurobehavioral changes were measured using 2 photomotor response (PMR) assays. Compared to controls, 93% (41/44) of flame retardants studied elicited adverse effects among one or more of the bioassays and concentrations tested with the aryl phosphate ester (APE)-based mono-isopropylated triaryl phosphate and the brominated-bisphenol-A analog tetrabromobisphenol-A producing the greatest array of malformations. Hierarchical clustering showed that APE flame retardants with isopropyl, butyl, and cresyl substituents on phenyl rings clustered tightly and were particularly potent. Both PMR assays were highly predictive of morphological defects supporting their use as nonlethal means of evaluating teratogenicity that could allow for additional evaluations of long-term or delayed effects in older animals. Taken together, evidence presented here indicates that zebrafish neurodevelopment is highly sensitive to many flame retardants currently in use and can be used to understand potential vulnerabilities to human health.