Adverse Outcome Pathway for the Neurotoxicity of Per- and Polyfluoroalkyl Substances: A Systematic Review
Open accessAbstract
Per-and polyfluoroalkyl substances (PFAS) are endocrine disruptors with unambiguous neurotoxic effects.However, due to variability in experimental models, population characteristics, and molecular endpoints, the elucidation of mechanisms underlying PFAS-induced neurotoxicity remains incomplete.In this review, we utilized the adverse outcome pathway (AOP) framework, a comprehensive tool for evaluating toxicity across multiple biological levels (molecular, cellular, tissue and organ, individual, and population), to elucidate the mechanisms of neurotoxicity induced by PFAS.Based on 271 studies, the reactive oxygen species (ROS) generation emerged as the molecular initiating event 1 (MIE1).Subsequent key events (KEs) at the cellular level include oxidative stress, neuroinflammation, apoptosis, altered Ca 2þ signal transduction, glutamate and dopamine signaling dyshomeostasis, and reduction of cholinergic and serotonin.These KEs culminate in synaptic dysfunction at organ and tissue levels.Further insights were offered into MIE2 and upstream KEs associated with altered thyroid hormone levels, contributing to synaptic dysfunction and hypomyelination at the organ and tissue levels.The inhibition of Na þ /I À symporter (NIS) was identified as the MIE2, initiating a cascade of KEs at the cellular level, including altered thyroid hormone synthesis, thyroid hormone transporters, thyroid hormone metabolism, and binding with thyroid hormone receptors.All KEs ultimately result in adverse outcomes (AOs), including cognition and memory impairment, autism spectrum disorders, attention deficit hyperactivity disorders, and neuromotor development impairment.To our knowledge, this review represents the first comprehensive and systematic AOP analysis delineating the intricate mechanisms responsible for PFAS-induced neurotoxic effects, providing valuable insights for risk assessments and mitigation strategies against PFAS-related health hazards.
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A review of 271 studies using an adverse outcome pathway (AOP) framework identified reactive oxygen species (ROS) generation as the primary molecular initiating event, triggering oxidative stress, neuroinflammation, apoptosis, dysregulation of Ca2+ signaling, neurotransmitters, synaptic dysfunction, and ultimately cognitive and neurodevelopmental impairments including ASD and ADHD.
“Utilizing an adverse outcome pathway (AOP) framework, a review of 271 studies identified reactive oxygen species (ROS) generation as the primary molecular initiating event, triggering oxidative stress, neuroinflammation, apoptosis, dysregulation of Ca2+ signaling, neurotransmitters (glutamate, dopamine, and serotonin), synaptic dysfunction, and ultimately cognitive and neurodevelopmental ImpairMEn”
From Exposure to Per- and Polyfluoroalkyl Substances (PFASs) in Healthcare: Environmental and Clinical Insights (2025) · cites this paper as [115]
Na+/I- symporter (NIS) inhibition is a secondary initiating event that leads to downstream effects on hormone synthesis, transport, and receptor binding, culminating in myelination deficits and neurological dysfunction.
“Additionally, PFAS exposure has been linked to thyroid hormone disruption [116], with Na+/I- symporter (NIS) inhibition identified as a secondary initiating event that leads to downstream effects on hormone synthesis, transport, and receptor binding, mechanisms culminating in myelination deficits and neurological dysfunction [115].”
From Exposure to Per- and Polyfluoroalkyl Substances (PFASs) in Healthcare: Environmental and Clinical Insights (2025) · cites this paper as [115]
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References 276 · Cited by 54
- Authors
- Li, S., Qin, S., Zeng, H., Chou, W., Oudin, A., Kanninen, K. M., Jalava, P., Dong, G., & Zeng, X.
- Affiliations
- Sun Yat-sen University (CN)
- Umeå University (SE)
- University of Eastern Finland (FI)
- Venue
- Eco-Environment & Health
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 3
- Issue
- 4
- Pages
- 476-493
- ISSN
- 2772-9850 (ISSN-L)
- PMC
- PMC11599988
- OpenAlex
- W4402068919
- Cited by
- 54
- References
- 276
- Citations by year
- 2026: 32 · 2025: 22
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Eco-Environment & Health (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Guangzhou Municipal Science and Technology Project (2024A04J6476)
- Natural Science Foundation of Guangdong Province (2021B1515020015)
- Sun Yat-Sen University
- National Natural Science Foundation of China (82073503)
- Topics
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Keywords
- per- and polyfluoroalkyl substances, adverse outcome pathways, reactive oxygen species, oxidative stress, neuroinflammation, apoptosis, calcium signaling, glutamate signaling, dopamine signaling, cholinergic dysfunction, serotonin, synaptic dysfunction, thyroid hormones, hypomyelination, autism spectrum disorder, attention deficit hyperactivity disorder, neuromotor development, cognitive impairment, endocrine disruptors
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