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WIREs Nanomed Nanobiotechnol
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The effects of gene × environment interactions on silver nanoparticle toxicity in the respiratory system: An adverse outcome pathway

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Abstract The Adverse Outcome Pathway (AOP) framework is serving as a basis to integrate new data streams in order to enhance the power of predictive toxicology. AOP development for engineered nanomaterials (ENM), including silver nanoparticles (AgNP), is currently lagging behind other chemicals of regulatory interest due to our limited understanding of the mechanism by which underlying genetics or diseases directly modify host response to AgNP exposures. This also highlights the importance of considering the Aggregate Exposure Pathway (AEP) framework, which precedes the AOP framework and outlines source to target site exposure. The AEP and AOP frameworks interface at the target site, where a molecular initiating event (MIE) occurs and is followed by key events (KE) for adverse cellular and organ responses along a biological pathway and ends with the adverse organism response. The primary goal of this study is to use AgNP to interrogate the AEP‐AOP framework by organizing and integrating in vitro dose–response data and in vivo exposure‐response data from previous studies to evaluate the effects of interactions between host genetic and acquired factors, or gene × environment interactions (G × E), on AgNP toxicity in the respiratory system. Using this framework will help us to identify plausible key event relationships (KER) between MIE and adverse organism responses when KE are not measured using the same assay in order to derive future predictive models, guide research, and support development of tools for making risk‐based, regulatory decisions on ENM. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine
AEP‐AOP framework. The AEP framework outlines source to target site exposure (only target site exposure shown); the AEP and AOP frameworks interface at the target site, where a molecular initiating event (MIE) occurs and is followed by key events (KE) for adverse cellular and organ responses along a biological pathway and ends with the adverse organism response
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AEP‐AOP framework for adverse organ responses at subchronic exposures. Subchronic exposures (21 to 90 days): Ag mass (μg Ag/mg tissue). Molecular initiating event: ROS (reactive oxygen species). Oxidative stress: BALF (bronchoalveolar lavage fluid); MDA (malondialdehyde). Lung inflammation: BALF (bronchoalveolar lavage fluid); T2 (type 2); T17 (type 17)
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AEP‐AOP framework for adverse organ responses at subacute exposures. Subacute exposures (4 to 21 days): Ag mass (μg Ag/mg tissue). Molecular initiating event: ROS (reactive oxygen species). Oxidative stress: 8‐OHdG (8‐hydroxy‐2′‐deoxyguanosine); NF‐κB (nuclear factor kappa‐light‐chain‐enhancer of activated B cells); ROS (reactive oxygen species); GSH (glutathione). Lung inflammation: BALF (bronchoalveolar lavage fluid); T2 (type 2)
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AEP‐AOP framework for adverse organ responses at acute exposures. Acute exposures (24 h): Ag mass (μg Ag/mg tissue). Molecular initiating event: ROS (reactive oxygen species). Lung inflammation: BALF (bronchoalveolar lavage fluid); Ano6 (anoctamin 6); Nedd4l (E3 ubiquitin‐protein ligase NEDD4‐like); Rnf220 (E3 ubiquitin‐protein ligase RNF220)
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AEP‐AOP framework for adverse cellular responses at acute exposures. Acute exposures (24 h): Ag mass (μg Ag/mg protein). Molecular initiating event: ROS (reactive oxygen species). Oxidative stress: GSH (glutathione); ROS (reactive oxygen species). Mitochondrial function: WNT (wingless‐related integration site). Inflammation: T1 (type 1); T2 (type 2); T17 (type 17). Cytotoxicity: LDH (lactate dehydrogenase)
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Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine
Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

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