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Dose-Dependent Impacts of Fluoride Exposure on Behavior, Oxidative Stress, Liver Metabolism, and Molecular responses in Cyprinus carpio.
| Ecotoxicology | Habib SS, Amouri RE, Latif F, Masud S, Naz S, Kesbiç OS, Mohany M, Al-Rejaie SS, Fazio F. | 35(5):101.
Apoptosis mitochondrial dysfunction Neurotoxicity Apoptosis Behavior Liver Oxidative Stress Animal Study

Abstract

Original abstract online at
https://link.springer.com/article/10.1007/s10646-026-03086-9

 

This study investigates the effects of fluoride exposure on tissue accumulation, behavior, oxidative stress, neurotoxicity, metabolomic, and molecular alterations in Cyprinus carpio. The effects were evaluated at four different concentrations (Control: 0.8 mg/L, Group 1: 1.52 mg/L, Group 2: 3.0 mg/L, Group 3: 4.2 mg/L) over a 30-day period. Behavioral analysis revealed progressive neurobehavioral impairments including erratic swimming, lethargy, and respiratory distress. Fluoride accumulation followed the order: bone > gill > skin > muscle, indicating both systemic absorption and organ-specific retention. Enzymatic assays showed significant elevation of antioxidant enzymes (SOD, CAT, GPx) coupled with acetylcholinesterase inhibition, signifying oxidative stress and neurotoxicity. Metabolomic profiling demonstrated marked depletion of glutathione and ATP, with elevated lactate, AMP, and succinate levels, reflecting mitochondrial dysfunction and energy crisis. Concurrently, upregulation of IL-17, TNF-a, RORy, and FoxO3a, alongside downregulation of IL-10 and Foxp3, indicated transcriptional signatures consistent with Th17-associated pro-inflammatory signaling and reduced Treg-related gene expression. Apoptotic gene activation (JNK, Bax, PUMA, Apaf-1, Caspase-9/3) and Bcl-2 suppression confirmed intrinsic mitochondrial apoptosis. Collectively, fluoride toxicity appears to progress through an integrated oxidative stress–mitochondrial dysfunction–immune imbalance–apoptotic cascade, which suggests that oxidative stress may function as an upstream trigger. These findings demonstrate that fluoride induces behavioral impairments, tissue accumulation, oxidative stress, metabolic disruption, immune imbalance, and apoptosis in C. carpio, with effects showing a strong dose-dependent (graded) response pattern, and identify key metabolites and molecular markers as early indicators of fluoride toxicity in aquatic environments.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors acknowledge and appreciate the Ongoing Research Funding Program (ORF-2026-758), King Saud University, Riyadh, Saudi Arabia.

Funding

This research was supported by the Ongoing Research Funding Program (ORF-2026-758) at King Saud University in Riyadh, Saudi Arabia.

Author information

Authors and Affiliations

  1. Department of Zoology, University of Sargodha, Sargodha Punjab, 40100, Pakistan

    Syed Sikandar Habib

  2. Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Shantou University, Shantou, 515063, China

    Rim EL Amouri

  3. Institute of Zoology, Bahauddin Zakariya University, Multan, 60800, Punjab, Pakistan

    Fariha Latif & Samrah Masud

  4. Department of Cell Biology, Physiology and Immunology, Universitat Autonoma de Barcelona, Barcelona, 08193, Spain

    Saira Naz

  5. Department of Animal Nutrition and Nutritional Diseases, Kastamonu University Veterinary Faculty, Kastamonu, 37150, Turkey

    Osman Sabri Kesbiç

  6. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 55760, Riyadh, 11451, Saudi Arabia

    Mohamed Mohany & Salim S. Al-Rejaie

  7. Department of Veterinary Science, Polo Universitario dell’Annunziata, University of Messina, Messina, 98168, Italy

    Francesco Fazio

Contributions

S.S. Habib and R.A. Amouri conceived the idea and designed the experiment. The first draft of the manuscript was written by S.S. Habib, R.A. Amouri and F. Latif Samples collection and analysis were performed by S.S. Habib, S. Masud and S.Naz. Manuscript was reviewed and edited by F. Fazio, O.S. Kesbic, S.S. Al-Rejaie and M. Mohany All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Francesco Fazio.

Ethics declarations

Ethics approval

The study was conducted after ethical committee approval of Department of Zoology, University of Sargodha Punjab Pakistan.

Conflict of interests

The authors declare no competing interests.