An integrative data-centric approach to derivation and characterization of an adverse outcome pathway network for cadmium-induced toxicity

The Science of The Total Environment, Год журнала: 2024, Номер 920, С. 170968 - 170968

Опубликована: Фев. 16, 2024

Язык: Английский

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A combination of high-throughput in vitro and in silico new approach methods (NAMs) for ecotoxicology hazard assessment for fish

Environmental Toxicology and Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 6, 2025

Fish acute toxicity testing is used to inform environmental hazard assessment of chemicals. In silico and in vitro approaches have the potential reduce number fish increase efficiency generating data for assessing ecological hazards. Here, two bioactivity assays were adapted use high-throughput chemical screening. First, a miniaturized version Organisation Economic Co-operation Development (OECD) test guideline 249 plate reader-based assay RTgill-W1 cells was developed. Second, Cell Painting (CP) along with an imaging-based cell viability assay. Then, 225 chemicals tested each Potencies calls from reader comparable. The CP more sensitive than either that it detected larger as bioactive, phenotype altering concentrations (PACs) lower decreased viability. An disposition (IVD) model accounted sorption plastic over time applied predict freely dissolved PACs compared vivo data. Adjustment using IVD modeling improved concordance For 65 where comparison values possible, 59% adjusted within one order magnitude lethal 50% organisms. protective 73% This combination has or replace testing.

Язык: Английский

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Machine Learning‐Enabled Drug‐Induced Toxicity Prediction

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Фев. 3, 2025

Abstract Unexpected toxicity has become a significant obstacle to drug candidate development, accounting for 30% of discovery failures. Traditional assessment through animal testing is costly and time‐consuming. Big data artificial intelligence (AI), especially machine learning (ML), are robustly contributing innovation progress in toxicology research. However, the optimal AI model different types usually varies, making it essential conduct comparative analyses methods across domains. The diverse sources also pose challenges researchers focusing on specific studies. In this review, 10 categories drug‐induced examined, summarizing characteristics applicable ML models, including both predictive interpretable algorithms, striking balance between breadth depth. Key databases tools used prediction highlighted, toxicology, chemical, multi‐omics, benchmark databases, organized by their focus function clarify roles prediction. Finally, strategies turn into opportunities analyzed discussed. This review may provide with valuable reference understanding utilizing available resources bridge mechanistic insights, further advance application drugs‐induced

Язык: Английский

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Leveraging integrative toxicogenomic approach towards development of stressor-centric adverse outcome pathway networks for plastic additives

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 29, 2024

Abstract Plastics are widespread pollutants found in atmospheric, terrestrial and aquatic ecosystems due to their extensive usage environmental persistence. Plastic additives, that utilized achieve specific functionality plastics, leach into the environment upon plastic degradation pose considerable risk ecological human health. Limited knowledge concerning presence of additives throughout life cycle has hindered effective regulation, thereby posing risks product safety. In this study, we leveraged adverse outcome pathway (AOP) framework understand mechanisms underlying additives-induced toxicities. We first identified an exhaustive list 6470 from chemicals documented be plastics. Next, heterogenous toxicogenomics biological endpoints data five exposome-relevant resources, associations between 1287 322 complete high quality AOPs within AOP-Wiki. Based on these additive-AOP associations, constructed a stressor-centric AOP network, wherein stressors categorized 10 priority use sectors linked 27 disease categories. visualized additives-AOP network for each made them available dedicated website: https://cb.imsc.res.in/saopadditives/ . Finally, showed utility by identifying 28 highly relevant associated with benzo[a]pyrene, thereafter, explored toxicity pathways leading respiratory gastrointestinal system diseases humans developmental disorders species. Overall, will enable regulatory assessment contributing towards toxic-free circular economy

Язык: Английский

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Using Zebrafish to Screen Developmental Toxicity of Per- and Polyfluoroalkyl Substances (PFAS)

Toxics, Год журнала: 2024, Номер 12(7), С. 501 - 501

Опубликована: Июль 10, 2024

Per- and polyfluoroalkyl substances (PFAS) are found in many consumer industrial products. While some PFAS, notably perfluorooctanoic acid (PFOA) perfluorooctanesulfonic (PFOS), developmentally toxic mammals, the vast majority of PFAS have not been evaluated for developmental toxicity potential. A concentration-response study 182 unique chemicals using zebrafish medium-throughput, vertebrate assay was conducted to investigate chemical structural identifiers toxicity. Embryos were exposed each compound (≤100 μM) beginning on day fertilization. At 6 days post-fertilization (dpf), two independent observers graded landmarks larva (e.g., mortality, hatching, swim bladder inflation, edema, abnormal spine/tail, or craniofacial structure). Thirty percent toxic, but there no enrichment any OECD category. PFOS (benchmark concentration [BMC] = 7.48 μM); however, other more potent: perfluorooctanesulfonamide (PFOSA), N-methylperfluorooctane sulfonamide (N-MeFOSA), ((perfluorooctyl)ethyl)phosphonic acid, perfluoro-3,6,9-trioxatridecanoic perfluorohexane sulfonamide. The profile these potent is largely unexplored mammals species. Based results, additional screening may be warranted understand

Язык: Английский

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Leveraging integrative toxicogenomic approach towards development of stressor-centric adverse outcome pathway networks for plastic additives

Archives of Toxicology, Год журнала: 2024, Номер 98(10), С. 3299 - 3321

Опубликована: Авг. 3, 2024

Abstract Plastics are widespread pollutants found in atmospheric, terrestrial and aquatic ecosystems due to their extensive usage environmental persistence. Plastic additives, that intentionally added achieve specific functionality plastics, leach into the environment upon plastic degradation pose considerable risk ecological human health. Limited knowledge concerning presence of additives throughout life cycle has hindered effective regulation, thereby posing risks product safety. In this study, we leveraged adverse outcome pathway (AOP) framework understand mechanisms underlying additives-induced toxicities. We first identified an exhaustive list 6470 from chemicals documented plastics. Next, heterogenous toxicogenomics biological endpoints data five exposome-relevant resources, associations between 1287 322 complete high quality AOPs within AOP–Wiki. Based on these additive–AOP associations, constructed a stressor-centric AOP network, wherein stressors categorized ten priority use sectors linked 27 disease categories. visualized additives–AOP network for each made them available dedicated website: https://cb.imsc.res.in/saopadditives/ . Finally, showed utility by identifying highly relevant associated with benzo[a]pyrene (B[a]P), bisphenol A (BPA), bis(2-ethylhexyl) phthalate (DEHP) thereafter, explored toxicity pathways humans species. Overall, will assist regulatory assessment contributing towards toxic-free circular economy

Язык: Английский

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Effect driven prioritization of contaminants in wastewater treatment plants across China: A data mining-based toxicity screening approach

Water Research, Год журнала: 2024, Номер 264, С. 122223 - 122223

Опубликована: Авг. 5, 2024

Язык: Английский

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Application of new approach methodology-derived points of departure with predicted or regulatory exposures to estimate bioactivity to exposure ratios (BER) for risk assessment

Human and Ecological Risk Assessment An International Journal, Год журнала: 2025, Номер unknown, С. 1 - 39

Опубликована: Янв. 26, 2025

Язык: Английский

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Profiling assay performance in the DevTox germ layer reporter platform

Current Research in Toxicology, Год журнала: 2025, Номер 8, С. 100223 - 100223

Опубликована: Янв. 1, 2025

The U.S. Environmental Protection Agency (U.S. EPA) is mandated to develop new approach methods (NAMs) detect chemicals risks susceptible populations, including effects on pregnant women and their offspring. With limited hazard information available for current chemicals, NAMs can provide greater relevance human biology, mechanistic insight, higher testing capacity than traditional animal models. DevTox Germ Layer Reporter (GLR) model platform was recently established high-throughput screening prioritization of potential developmental hazards. utilizes the RUES2-GLR pluripotent stem cell reporter line that expresses fluorescent fusion protein biomarkers SOX17 (endoderm), Brachyury (mesoderm), SOX2 (ectoderm pluripotency); enabling a multi-lineage readout gastrulation lineages. GLR-Endo assay used evaluate chemical differentiating endoderm, yielding balanced accuracy (BA) 72% against training set 43 toxicants 23 non-developmental toxicants. To assess predictivity additional early embryonic lineages, assays pluripotency (DevTox GLR-Pluri), ectoderm GLR-Ecto), mesoderm GLR-Meso) were developed. Chemical reference (12 4 toxicants) activity each revealed BAs 92% GLR-Pluri, 71% GLR-Ecto, 58% GLR-Meso. Expanded GLR-Pluri with 63 yielded 75% 68%, respectively. Amongst four GLR assays, maintained highest degree efficacy overall predictive compound evaluated in this study.

Язык: Английский

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A Simple Physiologically Based Toxicokinetic Model for Multi-Route In Vitro–In Vivo Extrapolation

Environmental Science & Technology Letters, Год журнала: 2025, Номер unknown

Опубликована: Фев. 12, 2025

Many chemicals found in the environment and commerce have been characterized for potential hazards by using vitro screens. Translating concentrations that cause bioactivity into real-world exposures, other words, vitro–in vivo extrapolation (IVIVE), requires chemical-specific parameters mathematical models. An administered (for example, oral) equivalent dose rate (milligrams per kilogram day) causes steady-state human plasma (micromolar) to bioactive can be derived a simple IVIVE equation. Herein, we explain how this equation approximates physiologically based toxicokinetic (PBTK) model. Through derivation of solution PBTK model, show relevant flows tissues. We then extend modifying oral exposure model include gas inhalation exhalation. Gas exhalation increases clearance, potentially allowing more accurate prediction semivolatile organic chemicals. The revised equations also allow doses, parts million concentration would concentrations. comparison an new developed, describing exhaled doses.

Язык: Английский

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