Integrative multi-omics reveals analogous developmental neurotoxicity mechanisms between perfluorobutanesulfonic acid and perfluorooctanesulfonic acid in zebrafish

Min, Eun Ki; Lee, Hyojin; Sung, Eun Ji; Seo, Seong Woo; Song, Miao; Wang, Seung-Jun; Kim, Seong Soon; Bae, Myung Ae; Kim, Tae-Young; Lee, Sangkyu; Kim, Ki-Tae

doi:10.1016/j.jhazmat.2023.131714

Cited by 12 publications

(6 citation statements)

References 66 publications

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“…For this reason, zebrafish models have the potential for hazard assessment of endocrine disruptors and other developmentally neurotoxic chemicals (Takesono et al 2022 ). Integrated multi-omics analysis using zebrafish has revealed the underlying molecular mechanism in response to polyfluoroalkyl substances (PFAS) used in the textile industry (Lee et al 2021 ; Min et al 2023 ). In conclusion, many qualitative endpoints for predicting DNT and ANT in mammals can be assessed in zebrafish, but direct comparison of zebrafish results to mammalian results still requires further validation.…”

Section: Nams and Neurotoxicity Assessmentmentioning

confidence: 99%

Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing

Serafini,

Sepehri,

Midali

et al. 2024

Arch Toxicol

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Adult neurotoxicity (ANT) and developmental neurotoxicity (DNT) assessments aim to understand the adverse effects and underlying mechanisms of toxicants on the human nervous system. In recent years, there has been an increasing focus on the so-called new approach methodologies (NAMs). The Organization for Economic Co-operation and Development (OECD), together with European and American regulatory agencies, promote the use of validated alternative test systems, but to date, guidelines for regulatory DNT and ANT assessment rely primarily on classical animal testing. Alternative methods include both non-animal approaches and test systems on non-vertebrates (e.g., nematodes) or non-mammals (e.g., fish). Therefore, this review summarizes the recent advances of NAMs focusing on ANT and DNT and highlights the potential and current critical issues for the full implementation of these methods in the future. The status of the DNT in vitro battery (DNT IVB) is also reviewed as a first step of NAMs for the assessment of neurotoxicity in the regulatory context. Critical issues such as (i) the need for test batteries and method integration (from in silico and in vitro to in vivo alternatives, e.g., zebrafish, C. elegans) requiring interdisciplinarity to manage complexity, (ii) interlaboratory transferability, and (iii) the urgent need for method validation are discussed.

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Section: Nams and Neurotoxicity Assessmentmentioning

confidence: 99%

Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing

Serafini,

Sepehri,

Midali

et al. 2024

Arch Toxicol

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“…25 Although single-omics analysis is limited regarding interactions between biomolecules, integrating lipidomic and transcriptomic analysis has shown more promise for comprehensively investigating the regulatory networks underlying metabolic disorders. 26,27 The correlation of gene transcription and small-molecule lipid metabolism alterations when combined with metabolic pathway enrichment and molecular interactions facilitates a more rapid identification of key genes and metabolic pathways. 28 Based on the aforementioned backgrounds, the main objectives of this study were to (1) observe how TBPH affects liver development and lipid metabolism by measuring fluorescence area and intensity in transgenic zebrafish larvae, (2) explore underlying mechanisms using an integration of lipidomic and transcriptomic analyses, and (3) validate the screened potential molecular mechanisms and the mediation factor.…”

Section: Introductionmentioning

confidence: 99%

“…Omics analysis techniques, such as transcriptomics and metabolomics, are useful for identifying biomolecular perturbations and screening pathways of adverse effects induced by chemical exposures, as shown by numerous toxicological evaluations of chemical substances in the zebrafish model . Although single-omics analysis is limited regarding interactions between biomolecules, integrating lipidomic and transcriptomic analysis has shown more promise for comprehensively investigating the regulatory networks underlying metabolic disorders. , The correlation of gene transcription and small-molecule lipid metabolism alterations when combined with metabolic pathway enrichment and molecular interactions facilitates a more rapid identification of key genes and metabolic pathways …”

Section: Introductionmentioning

confidence: 99%

Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate Enhances foxo1-Mediated Lipophagy to Remodel Lipid Metabolism in Zebrafish Liver

Zhou,

Li,

et al. 2024

Environ. Sci. Technol.

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An emerging environmental contaminant, bis(2-ethylhexyl)-2,3,4,5tetrabromophthalate (TBPH), can bioaccumulate in the liver and affect hepatic lipid metabolism. However, the in-depth mechanism has yet to be comprehensively explored. In this study, we utilized transgenic zebrafish Tg (Apo14: GFP) to image the interference of TBPH on zebrafish liver development and lipid metabolism at the early development stage. Using integrated lipidomic and transcriptomic analyses to profile the lipid remodeling effect, we uncovered the potential effects of TBPH on lipophagy-related signaling pathways in zebrafish larvae. Decreased lipid contents accompanied by enhanced lipophagy were confirmed by the measurements of Oil Red O staining and transmission electron microscopy in liver tissues. Particularly, the regulatory role of the foxo1 factor was validated via its transcriptional inhibitor. Double immunofluorescence staining integrated with biochemical analysis indicated that the enhanced lipophagy and mitochondrial fatty acid oxidation induced by TBPH were reversed by the foxo1 inhibitor. To summarize, our study reveals, for the first time, the essential role of foxo1-mediated lipophagy in TBPH-induced lipid metabolic disorders and hepatoxicity, providing new insights for metabolic disease studies and ecological health risk assessment of TBPH.

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“…Alternative test methods that seek to minimise animal testing, known as New Approach Methodologies (NAMs), include in silico methods and their integration with in vitro bioassays that use human cells for determining a molecular point of departure (PoD). In the context of New Generation Risk Assessment (NGRA) ( Johnson et al, 2022 ; Barutcu et al, 2023 ), the application of “omics” technologies to derive PoDs has been growing rapidly ( Farmahin et al, 2017 ; Shah et al, 2021 ; Alcaraz et al, 2022 ; Beal et al, 2022 ; Jin et al, 2022 ; Kuo et al, 2022 ; Gou et al, 2023 ; Malinowska et al, 2023 ; Min et al, 2023 ; Ramirez-Hincapie et al, 2023 ; Reardon et al, 2023 ; Song et al, 2023 ). PoDs are used as the basis for the derivation of safe levels of human exposure known as Health Based Guidance Values (HBGV) ( Ingenbleek L et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A novel method to derive a human safety limit for PFOA by gene expression profiling and modelling

Silva,

Loizou,

McNally

et al. 2024

Front. Toxicol.

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Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant that can accumulate in the human body due to its long half-life. This substance has been associated with liver, pancreatic, testicular and breast cancers, liver steatosis and endocrine disruption. PFOA is a member of a large group of substances also known as “forever chemicals” and the vast majority of substances of this group lack toxicological data that would enable their effective risk assessment in terms of human health hazards. This study aimed to derive a health-based guidance value for PFOA intake (ng/kg BW/day) from in vitro transcriptomics data. To this end, we developed an in silico workflow comprising five components: (i) sourcing in vitro hepatic transcriptomics concentration-response data; (ii) deriving molecular points of departure using BMDExpress3 and performing pathway analysis using gene set enrichment analysis (GSEA) to identify the most sensitive molecular pathways to PFOA exposure; (iii) estimating freely-dissolved PFOA concentrations in vitro using a mass balance model; (iv) estimating in vivo doses by reverse dosimetry using a PBK model for PFOA as part of a quantitative in vitro to in vivo extrapolation (QIVIVE) algorithm; and (v) calculating a tolerable daily intake (TDI) for PFOA. Fourteen percent of interrogated genes exhibited in vitro concentration-response relationships. GSEA pathway enrichment analysis revealed that “fatty acid metabolism” was the most sensitive pathway to PFOA exposure. In vitro free PFOA concentrations were calculated to be 2.9% of the nominal applied concentrations, and these free concentrations were input into the QIVIVE workflow. Exposure doses for a virtual population of 3,000 individuals were estimated, from which a TDI of 0.15 ng/kg BW/day for PFOA was calculated using the benchmark dose modelling software, PROAST. This TDI is comparable to previously published values of 1.16, 0.69, and 0.86 ng/kg BW/day by the European Food Safety Authority. In conclusion, this study demonstrates the combined utility of an “omics”-derived molecular point of departure and in silico QIVIVE workflow for setting health-based guidance values in anticipation of the acceptance of in vitro concentration-response molecular measurements in chemical risk assessment.

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Integrative multi-omics reveals analogous developmental neurotoxicity mechanisms between perfluorobutanesulfonic acid and perfluorooctanesulfonic acid in zebrafish

Cited by 12 publications

References 66 publications

Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing

Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing

Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate Enhances foxo1-Mediated Lipophagy to Remodel Lipid Metabolism in Zebrafish Liver

A novel method to derive a human safety limit for PFOA by gene expression profiling and modelling

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