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In silico prediction of the developmental toxicity of diverse organic chemicals in rodents for regulatory purposes.

ABSTRACT: The experimental determination of the developmental toxicity potential (LEL) of chemicals is not only tedious, time and resource intensive, but it also involves unethical tests on animals. In this study, we have established quantitative structure activity relationship (QSAR) models for predicting the developmental toxicity potential of chemicals in rodents following the OECD guidelines. Accordingly, decision tree forest (DTF) and decision tree boost (DTB) based local (L-QSAR), global (G-QSAR) and interspecies quantitative structure activity-activity relationship (ISC QSAAR) models were developed for estimating the LEL (lowest effective level) dose of chemicals for developmental toxicity in rats and rabbits. The structural features of chemicals responsible for developmental toxicity in rodents were extracted and used in QSAR/QSAAR analysis. The external predictive power of the developed models was evaluated through the internal and external validation procedures. In test data, the L-QSAR models (DTF, DTB) yielded R² values of >0.846 (rat) and >0.906 (rabbit), whereas in G-QSAR, the correlation value was >0.870 between the measured and predicted endpoint values. In ISC QSAAR models, the R² values in test data were 0.830 (DTF) and 0.927 (DTB), respectively. Values of various statistical validation coefficients derived from the test data (except r_m² in DTF based rat L-QSAR and ISC QSAAR models) were above their respective threshold limits, thus putting a high confidence in this analysis. The prediction quality of the developed QSAR/QSAAR models was also assessed using the mean absolute error (MAE) criteria and found good. The applicability domains of the constructed models were defined using the descriptor range, leverage, and standardization approaches. The results suggest that the developed QSAR/QSAAR models can reliably predict the developmental toxicity potential of structurally diverse chemicals in rodents, generating useful toxicity data for risk assessment in humans.

SUBMITTER: Basant N

PROVIDER: S-EPMC6061034 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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<i>In silico</i> prediction of the developmental toxicity of diverse organic chemicals in rodents for regulatory purposes.

Basant Nikita N Gupta Shikha S Singh Kunwar P KP

Toxicology research 20160229 3

The experimental determination of the developmental toxicity potential (LEL) of chemicals is not only tedious, time and resource intensive, but it also involves unethical tests on animals. In this study, we have established quantitative structure activity relationship (QSAR) models for predicting the developmental toxicity potential of chemicals in rodents following the OECD guidelines. Accordingly, decision tree forest (DTF) and decision tree boost (DTB) based local (L-QSAR), global (G-QSAR) an ...[more]

PMID: 30090388

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Project description:Gene-regulatory enhancers have been identified using various approaches, including evolutionary conservation, regulatory protein binding, chromatin modifications, and DNA sequence motifs. To integrate these different approaches, we developed EnhancerFinder, a two-step method for distinguishing developmental enhancers from the genomic background and then predicting their tissue specificity. EnhancerFinder uses a multiple kernel learning approach to integrate DNA sequence motifs, evolutionary patterns, and diverse functional genomics datasets from a variety of cell types. In contrast with prediction approaches that define enhancers based on histone marks or p300 sites from a single cell line, we trained EnhancerFinder on hundreds of experimentally verified human developmental enhancers from the VISTA Enhancer Browser. We comprehensively evaluated EnhancerFinder using cross validation and found that our integrative method improves the identification of enhancers over approaches that consider a single type of data, such as sequence motifs, evolutionary conservation, or the binding of enhancer-associated proteins. We find that VISTA enhancers active in embryonic heart are easier to identify than enhancers active in several other embryonic tissues, likely due to their uniquely high GC content. We applied EnhancerFinder to the entire human genome and predicted 84,301 developmental enhancers and their tissue specificity. These predictions provide specific functional annotations for large amounts of human non-coding DNA, and are significantly enriched near genes with annotated roles in their predicted tissues and lead SNPs from genome-wide association studies. We demonstrate the utility of EnhancerFinder predictions through in vivo validation of novel embryonic gene regulatory enhancers from three developmental transcription factor loci. Our genome-wide developmental enhancer predictions are freely available as a UCSC Genome Browser track, which we hope will enable researchers to further investigate questions in developmental biology.

Dataset Information

In silico prediction of the developmental toxicity of diverse organic chemicals in rodents for regulatory purposes.

Publications

<i>In silico</i> prediction of the developmental toxicity of diverse organic chemicals in rodents for regulatory purposes.

Similar Datasets

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