Exploring the neurodegenerative potential of per- and polyfluoroalkyl substances through an adverse outcome pathway network

The Science of The Total Environment, Journal Year: 2025, Volume and Issue: 969, P. 178972 - 178972

Published: Feb. 28, 2025

While emerging evidence links per- and polyfluoroalkyl substances (PFAS) to neurotoxicity, their potential role in neurodegeneration remains poorly understood. Moreover, existing neurodegeneration-related adverse outcome pathways (AOPs) available on AOP-Wiki have not yet been integrated into a unified network. To address these gaps, this study aims develop the first AOP network utilize it explore possible contributions of long-chain legacy PFAS neurodegeneration, specifically concerning Alzheimer's Parkinson's diseases. A total 74 AOPs were screened from AOP-Wiki, which 13 met eligibility criteria incorporated We analyzed resulting using topological parameters such as in-degree, out-degree, eccentricity, betweenness centrality. elucidate mechanistic exposure neurodegenerative pathways, we linking key events (KEs) within The results highlighted increased intracellular calcium hub with highest connectivity followed by critical KEs neuronal apoptosis, oxidative stress, N-methyl-d-aspartate receptor (NMDA-R) overactivation, mitochondrial dysfunction. Consistent toxicological evidence, indicate that may adversely affect neurotransmitter systems, particularly through NMDA-R leading excitotoxicity. This result dyshomeostasis, dysfunction, inflammatory-oxidative cascades, neuroinflammation, cell death. By providing basis for understanding PFAS, offers crucial framework assessing risks associated chemicals inform future regulatory measures public health strategies. Further experimental validation is needed confirm animal models or human populations.

Language: Английский

---

Perfluoroalkyl and polyfluoroalkyl substances crossing the blood-joint barrier: Their occurrence and distribution in synovial fluid

Journal of Hazardous Materials, Journal Year: 2025, Volume and Issue: unknown, P. 138189 - 138189

Published: April 1, 2025

Language: Английский

---

Towards a Better Understanding of the Human Health Risk of Per- and Polyfluoroalkyl Substances Using Organoid Models

Bioengineering, Journal Year: 2025, Volume and Issue: 12(4), P. 393 - 393

Published: April 7, 2025

The ubiquitous presence of per- and polyfluoroalkyl substances (PFAS) in the environment has garnered global public concern. Epidemiological studies have proved that exposure to PFAS is associated with human health risks. Although evidence demonstrated toxic mechanisms based on animal models traditional cell cultures, their limitations inter-species differences lack human-relevant microenvironments hinder understanding risks from exposure. There an increasing necessity explore alternative methodologies can effectively evaluate Human organoids derived stem cells accurately mimic sophisticated multicellular structures native organs, providing promising for toxicology research. Advanced combined innovative technologies are expected improve breadth depth toxicity.

Language: Английский

---

Development of an Interpretable Machine Learning Model for Neurotoxicity Prediction of Environmentally Related Compounds

Environmental Science & Technology, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

The rising prevalence of nervous system disorders has become a significant global health challenge, with environmental pollutants identified as key contributors. However, the large number related compounds, combined low efficiency traditional methods, resulted in substantial gaps neurotoxicity data. In this study, we developed robust and interpretable prediction model using high-quality data set. To identify best predictive model, three molecular representation methods (molecular fingerprints, descriptors, graphs) six machine learning (ML) algorithms two deep (DL) approaches were evaluated. optimal combining fingerprints descriptors eXtreme Gradient Boosting (XGBoost), achieved training accuracy 0.93 an area under curve (AUC) 0.99, outperforming other ML DL models, while maintaining interpretability. was used to screen 1170 compounds detected human blood, predicting 1145 successfully. Among 89 known data, 0.74. It 821 potentially neurotoxic including 36 high detection concentrations, warranting further study. An online platform (http://www.envwind.site/tools.html) expand accessibility. This offers efficient tool for managing risks.

Language: Английский

---

Sea Squirt-Derived Peptide WLP Mitigates OKA-Induced Alzheimer’s Disease-like Phenotypes in Human Cerebral Organoid

Antioxidants, Journal Year: 2025, Volume and Issue: 14(5), P. 553 - 553

Published: May 7, 2025

Alzheimer’s disease (AD), a prevalent neurodegenerative disorder in the elderly, poses significant humanistic and economic burdens worldwide. Previously, we identified Trp-Leu-Pro (WLP), novel antioxidant peptide derived from sea squirt (Halocynthia roretzi); however, its effects on AD remained unexplored. In this study, developed rapid efficient method to generate cerebral organoids with consistent quality using okadaic acid (OKA) exposure. This study aimed evaluate protective of WLP OKA-induced pathology elucidate underlying mechanisms. Our results demonstrated that exposed 25 nM OKA successfully recapitulated hallmark pathologies, including amyloid-beta (Aβ) plaque deposits, neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau proteins, neuronal loss. treatment significantly enhanced cell viability, increased proportion progenitor cells, reduced Aβ plaques NFTs organoids. Furthermore, transcriptomic analysis revealed neuroprotective are primarily mediated through regulation synapse-related oxidative stress pathways. These findings highlight potential as promising nutraceutical candidate for prevention.

Language: Английский

---

Investigating the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells through Transcriptomics and Lipidomics Analysis

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(24), P. 4568 - 4579

Published: Nov. 27, 2024

Per- and polyfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that bioaccumulate in tissues pose risks to human health. Increasing evidence links PFAS neurodegenerative behavioral disorders, yet the underlying mechanisms of their effects on neuronal function remain largely unexplored. In this study, we utilized SH-SY5Y neuroblastoma cells, differentiated into neuronal-like investigate impact six compounds─perfluorooctanoic acid (PFOA), perfluorooctanesulfonic (PFOS), perfluorodecanoic (PFDA), perfluorodecanesulfonic (PFDS), 8:2 fluorotelomer sulfonate (8:2 FTS), alcohol FTOH)─on Following a 30 μM exposure for 24 h, accumulation ranged from 40–6500 ng/mg protein. Transcriptomic analysis revealed 721 differentially expressed genes (DEGs) across treatments (padj < 0.05), with 11 DEGs shared among all exposures, indicating potential biomarkers toxicity. PFOA-treated cells showed downregulation involved synaptic growth neural function, while PFOS, PFDS, FTS, FTOH exposures resulted upregulation related hypoxia response amino metabolism. Lipidomic profiling further demonstrated significant increases fatty levels PFDA, FTS depletion triacylglycerols treatments. These findings suggest neurotoxic structurally dependent, offering insights molecular processes may drive PFAS-induced dysfunction.

Language: Английский

---