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1.
Chem Res Toxicol ; 33(7): 1709-1718, 2020 07 20.
Article in English | MEDLINE | ID: mdl-32338872

ABSTRACT

A valuable approach to chemical safety assessment is the use of read-across chemicals to provide safety data to support the assessment of structurally similar chemicals. An inventory of over 6000 discrete organic chemicals used as fragrance materials in consumer products has been clustered into chemical class-based groups for efficient search of read-across sources. We developed a robust, tiered system for chemical classification based on (1) organic functional group, (2) structural similarity and reactivity features of the hydrocarbon skeletons, (3) predicted or experimentally verified Phase I and Phase II metabolism, and (4) expert pruning to consider these variables in the context of specific toxicity end points. The systematic combination of these data yielded clusters, which may be visualized as a top-down hierarchical clustering tree. In this tree, chemical classes are formed at the highest level according to organic functional groups. Each subsequent subcluster stemming from classes in this hierarchy of the cluster is a chemical cluster defined by common organic functional groups and close similarity in the hydrocarbon skeleton. By examining the available experimental data for a toxicological endpoint within each cluster, users can better identify potential read-across chemicals to support safety assessments.


Subject(s)
Consumer Product Safety , Cosmetics/chemistry , Cosmetics/classification , Odorants/analysis , Organic Chemicals/chemistry , Organic Chemicals/toxicity , Cluster Analysis , Cosmetics/adverse effects , Cosmetics/metabolism , Databases, Chemical , Molecular Structure , Organic Chemicals/classification , Organic Chemicals/metabolism , Risk Assessment
2.
Nanotoxicology ; 10(1): 118-27, 2016.
Article in English | MEDLINE | ID: mdl-26152688

ABSTRACT

Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 µg/g body weight) 20 and 110 nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110 nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.


Subject(s)
Immunity, Innate/drug effects , Metal Nanoparticles/toxicity , Respiratory Mechanics/drug effects , Silver/toxicity , Animals , Lung/drug effects , Lung/pathology , Male , Mice , Mice, Inbred C57BL , Particle Size , Positive-Pressure Respiration , Povidone/pharmacology
3.
J Proteome Res ; 9(10): 5358-69, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20734996

ABSTRACT

Fe-S cluster biogenesis is of interest to many fields, including bioenergetics and gene regulation. The CSD system is one of three Fe-S cluster biogenesis systems in E. coli and is comprised of the cysteine desulfurase CsdA, the sulfur acceptor protein CsdE, and the E1-like protein CsdL. The biological role, biochemical mechanism, and protein targets of the system remain uncharacterized. Here we present that the active site CsdE C61 has a lowered pK(a) value of 6.5, which is nearly identical to that of C51 in the homologous SufE protein and which is likely critical for its function. We observed that CsdE forms disulfide bonds with multiple proteins and identified the proteins that copurify with CsdE. The identification of Fe-S proteins and both putative and established Fe-S cluster assembly (ErpA, glutaredoxin-3, glutaredoxin-4) and sulfur trafficking (CsdL, YchN) proteins supports the two-pathway model, in which the CSD system is hypothesized to synthesize both Fe-S clusters and other sulfur-containing cofactors. We suggest that the identified Fe-S cluster assembly proteins may be the scaffold and/or shuttle proteins for the CSD system. By comparison with previous analysis of SufE, we demonstrate that there is some overlap in the CsdE and SufE interactomes.


Subject(s)
Carbon-Sulfur Lyases/metabolism , Escherichia coli Proteins/metabolism , Iron-Sulfur Proteins/metabolism , Proteomics/methods , Amino Acid Sequence , Binding Sites , Carbon-Sulfur Lyases/chemistry , Carbon-Sulfur Lyases/genetics , Catalytic Domain , Chromatography, Liquid , Disulfides/chemistry , Disulfides/metabolism , Escherichia coli Proteins/chemistry , Escherichia coli Proteins/genetics , Iron-Sulfur Proteins/chemistry , Iron-Sulfur Proteins/genetics , Mass Spectrometry , Models, Molecular , Molecular Sequence Data , Protein Binding , Protein Structure, Secondary , Protein Structure, Tertiary , Sequence Homology, Amino Acid
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