Aop:11

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AOP Title

Percellome Toxicogenomics Approach for AOP Building: Case study on Pentachlorophenol
Short name: Pentachlorophenol Acute Response by Percellome

Authors

Jun Kanno Division of Cellular & Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences

1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan +81-3-3700-9619 kanno@nihs.go.jp

Status

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Under development: Do not distribute or cite.

This AOP was last modified on 12/5/2016.

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Abstract

This case study aims at making AOPs triggered by oral exposure to Pentachlorophenol (PCP) of liver and possible new aspect of systemic toxicity. In this case study, Pentachlorophenol (PCP) was monitored for adult mouse liver transcriptome responses 2, 4, 8 and 24 hours after single oral administration with four dose levels, 0, 10, 30 and 100mg/kg, using Affymetrix GeneChip MOE430 2.0. The expression data were absolutized by the Percellome method and expressed as three dimensional (3D) surface graphs with axises of time, dose and copy numbers of mRNA per cell. Homemade software RSort was used for comprehensive screening of the 3D surface data followed by visual inspection to confirm the significant responses, and PercellomeExploror for cross-referencing. In the first 8 hours, approximately 100 probe sets (PSs) related to PXR/SXR and Cyp2a4 and other metabolic enzymes were induced, and Fos and Junb were suppressed. At 24 hours, about 1,200 PSs were strongly induced. Cross-referencing the Percellome database consisting of 111 chemicals on liver transcriptome revealed that about half of the PSs belonged to the metabolic pathways including Nrf2-mediated oxidative stress response networks, sharing with some of the 111 chemicals. The other half was interferon signalling network genes (ISG), and was unique to PCP. Toll like receptors and other pattern recognition receptors, interferon regulatory factors and interferon alpha itself were included. On the other hand, inflammatory cytokines were not induced. In summary, functional symptoms of PCP, such as hyperthermia and profuse sweating might be mediated by the ISG rather than the hitherto documented mitochondrial uncoupling mechanism. Reports of imiquimod and RO8191 as agonists of toll-like receptor and interferon receptor might associate PCP with a seed for interferon mimetic drugs (cf. Figure below).

This case study will also serve as an example of how the Percellome Project Database and Percellome Analytical Tools can be effectively applied to the AOP development. Further studies including in silico data mining will expand the AOP to cover the chronic liver toxicity induced by PCP.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
PXR/SXR, Activation

Key Events

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Adverse Outcome

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Overall Assessment of the AOP

Weight of Evidence Summary

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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Quantitative Considerations

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Applicability of the AOP

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