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Application of the hard and soft, acids and bases (HSAB) theory as a method to predict cumulative neurotoxicity.

ABSTRACT: Xenobiotic electrophiles can form covalent adducts that may impair protein function, damage DNA, and may lead a range of adverse effects. Cumulative neurotoxicity is one adverse effect that has been linked to covalent protein binding as a Molecular Initiating Event (MIE). This paper describes a mechanistic in silico chemical screening approach for neurotoxicity based on Hard and Soft Acids and Bases (HSAB) theory. We evaluated the applicability of HSAB-based electrophilicity screening protocol for neurotoxicity on 19 positive and 19 negative reference chemicals. These reference chemicals were identified from the literature, using available information on mechanisms of neurotoxicity whenever possible. In silico screening was based on structural alerts for protein binding motifs and electrophilicity index in the range of known neurotoxicants. The approach demonstrated both a high positive prediction rate (82-90 %) and specificity (90 %). The overall sensitivity was relatively lower (47 %). However, when predicting the toxicity of chemicals known or suspected of acting via non-specific adduct formation mechanism, the HSAB approach identified 7/8 (sensitivity 88 %) of positive control chemicals correctly. Consequently, the HSAB-based screening is a promising approach of identifying possible neurotoxins with adduct formation molecular initiating events. While the approach must be expanded over time to capture a wider range of MIEs involved in neurotoxicity, the mechanistic nature of the screen allows users to flag chemicals for possible adduct formation MIEs. Thus, the HSAB based toxicity screening is a promising strategy for toxicity assessment and chemical prioritization in neurotoxicology and other health endpoints that involve adduct formation.

SUBMITTER: Melnikov F

PROVIDER: S-EPMC7369154 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To understand the proximate and ultimate causes that shape acoustic communication in animals, objective characterizations of the vocal repertoire of a given species are critical, as they provide the foundation for comparative analyses among individuals, populations and taxa. Progress in this field has been hampered by a lack of standard in methodology, however. One problem is that researchers may settle on different variables to characterize the calls, which may impact on the classification of calls. More important, there is no agreement how to best characterize the overall structure of the repertoire in terms of the amount of gradation within and between call types. Here, we address these challenges by examining 912 calls recorded from wild chacma baboons (Papio ursinus). We extracted 118 acoustic variables from spectrograms, from which we constructed different sets of acoustic features, containing 9, 38, and 118 variables; as well 19 factors derived from principal component analysis. We compared and validated the resulting classifications of k-means and hierarchical clustering. Datasets with a higher number of acoustic features lead to better clustering results than datasets with only a few features. The use of factors in the cluster analysis resulted in an extremely poor resolution of emerging call types. Another important finding is that none of the applied clustering methods gave strong support to a specific cluster solution. Instead, the cluster analysis revealed that within distinct call types, subtypes may exist. Because hard clustering methods are not well suited to capture such gradation within call types, we applied a fuzzy clustering algorithm. We found that this algorithm provides a detailed and quantitative description of the gradation within and between chacma baboon call types. In conclusion, we suggest that fuzzy clustering should be used in future studies to analyze the graded structure of vocal repertoires. Moreover, the use of factor analyses to reduce the number of acoustic variables should be discouraged.

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Application of the hard and soft, acids and bases (HSAB) theory as a method to predict cumulative neurotoxicity.

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