OECD Series on Adverse Outcome Pathways

doi:10.1787/2415170x

DOI: 10.1787/2415170x

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OECD Series on Adverse Outcome Pathways

Abstract: Events Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO) Sequence Type Event ID Title Short name 1 MIE 18 Activation, AhR Activation, AhR 2 KE 944 dimerization, AHR/ARNT dimerization, AHR/ARNT 3 KE 945 reduced dimerization, ARNT/HIF1-alpha reduced dimerization, ARNT/HIF1-alpha 4 KE 948 reduced production, VEGF reduced production, VEGF 5 KE 110 Impairment, Endothelial network Impairment, Endothelial network 6 KE 317 Altered, Cardiovascular development/function Altered, Cardiovascular dev… Show more

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Cited by 9 publications

(1 citation statement)

References 74 publications

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“…Status (extracted from the Users' handbook[48]): SAAOP status (Society for the Advancement of AOPs): "Under development"-content still under development, not ready for formal review; "Included in OECD work plan"-an AOP development project has been reviewed, accepted into the OECD workplan, and the project number assigned. OECD status-reflects the progress after the AOP has been included in the OECD AOP Development Workplan.…”

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confidence: 99%

Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways

2019

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Background: Flame retardants (FRs) are used in most consumer products and textiles to comply with current flammability standards. After the restriction of polybrominated diphenyl ethers, a large number of chemically diverse replacement FRs are increasingly used, but the risk they represent is not yet properly evaluated and their toxicity pathways are still poorly understood. Approach:We collected in vivo toxicological information on 62 (including 52 non-regulated) FRs and established five prioritization categories (Cat I to V) based on data availability and toxicological concern. We then considered available in vitro toxicological data from ToxCast, as a complement to in vivo information. By combining these information sources, we then explored relevant toxicity mechanisms for nine selected FRs (Cat I) using the AOP (Adverse Outcome Pathway) framework. Results:For 20 FRs (Cat V), toxicological data on mammals were absent. Data available were scarce for another 22 FRs, of which 14 FRs (Cat II) may be of toxicological concern. We found substantial information for only ten replacement FRs, of which nine (Cat I) present some toxicological concern: tris-2-chloroethyl phosphate (TCEP), tris(1,3dichloropropyl)phosphate (TDCIPP), triphenyl phosphate (TPhP), tricresyl phosphate (TMPP), tetrabromobisphenol A (TBBPA), tri-n-butyl phosphate (TNBP), tri(2-butoxyethyl) phosphate (TBOEP), tris(1-chloro-2-propyl) phosphate (TCIPP), 2-ethylhexyl diphenyl phosphate (EHDPP). ToxCast results confirmed in vivo based categorization for several FRs and identified potential molecular targets. For the nine Cat I FRs, we identified several molecular targets, health outcomes and some potential AOPs. However, the complete toxicity pathways leading from molecular targets to adverse health outcomes are still unknown, with the exception of TBBPA-induced neurotoxicity. Conclusions:The approach presented in this study was particularly useful for the categorization of a large group of replacement FRs with relatively low data availability. We highlight priority compounds that critically need more toxicological studies or FRs for which regulatory measures could be envisaged. Our research also suggests that high toxicity indicated by ToxCast is particularly relevant for predicting higher hazard in vivo. Finally, we indicate several gaps and directions for future research, such as molecular targets that could be tested in vitro and health outcomes for cohort studies. which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways

2019

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Ketamine induces insomnia‐like symptom of zebrafish at environmentally relevant concentrations by mediating GABAergic synapse

Guo,

He,

Mao

et al. 2024

Environmental Toxicology

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Although the stimulative effects on the normal behaviors of fish posed by ketamine (KET) were well‐studied, the adverse effects on the behavioral functions induced by KET at nighttime were unknown. Here, we used zebrafish larvae as a model exposed to KET (10, 50, 100, and 250 ng/L) at environmental levels for 21 days. The behavioral functions at nighttime, morphological changes during exposure stage, and alterations on the associated genes transcriptional levels of fish were determined. The difficultly initiating sleep was found in the fish exposed to KET, while the sleep duration of the animals was at the normal levels in exposure groups. The significant suppressions of the developmentally relevant genes, including bmp2, bmp4, and pth2ra were consistent with the developmental abnormalities of fish found in exposure groups. Moreover, the expression of γ‐aminobutyric acid (GABA) receptor increased and melatonin (MTN) receptor decreased while the levels of GABA and MTN remained unchanged after exposure, by gene expression analysis and molecular docking. In addition, the transcriptional expression of apoptotic genes, including tp53, aifm1, and casp6, was significantly upregulated by KET. After a 7‐day recovery, the insomnia‐like behaviors (shorter sleep duration) were observed in zebrafish from the 250 ng/L‐KET group. Accordingly, the adverse outcome pathway framework of KET was constructed by prognostic assessment of zebrafish larvae. This study suggested that the adverse outcomes of KET on the sleep health of organisms at environmentally relevant concentrations should be concerned.

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Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia

Itkonen,

Hakkola,

Rysä

2023

Arch Toxicol

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Pharmaceuticals and environmental contaminants contribute to hypercholesterolemia. Several chemicals known to cause hypercholesterolemia, activate pregnane X receptor (PXR). PXR is a nuclear receptor, classically identified as a sensor of chemical environment and regulator of detoxification processes. Later, PXR activation has been shown to disrupt metabolic functions such as lipid metabolism and recent findings have shown PXR activation to promote hypercholesterolemia through multiple mechanisms. Hypercholesterolemia is a major causative risk factor for atherosclerosis and greatly promotes global health burden. Metabolic disruption by PXR activating chemicals leading to hypercholesterolemia represents a novel toxicity pathway of concern and requires further attention. Therefore, we constructed an adverse outcome pathway (AOP) by collecting the available knowledge considering the molecular mechanisms for PXR-mediated hypercholesterolemia. AOPs are tools of modern toxicology for systematizing mechanistic knowledge to assist health risk assessment of chemicals. AOPs are formalized and structured linear concepts describing a link between molecular initiating event (MIE) and adverse outcome (AO). MIE and AO are connected via key events (KE) through key event relationships (KER). We present a plausible route of how PXR activation (MIE) leads to hypercholesterolemia (AO) through direct regulation of cholesterol synthesis and via activation of sterol regulatory element binding protein 2-pathway.

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OECD Series on Adverse Outcome Pathways

Cited by 9 publications

References 74 publications

Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways

Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways

Ketamine induces insomnia‐like symptom of zebrafish at environmentally relevant concentrations by mediating GABAergic synapse

Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia

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