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Clofibrate, a Peroxisome Proliferator–Activated Receptor-Alpha (PPARα) Agonist, and Its Molecular Mechanisms of Action against Sodium Fluoride–Induced Toxicity

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Abstract

Sodium fluoride (NaF) is one of the neglected environmental pollutants. It is ubiquitously found in the soil, water, and environment. Interestingly, fluoride has been extensively utilized for prevention of dental caries and tartar formation, and may be added to mouthwash, mouth rinse, and toothpastes. This study is aimed at mitigating fluoride-induced hypertension and nephrotoxicity with clofibrate, a peroxisome proliferator–activated receptor-alpha (PPARα) agonist. For this study, forty male Wistar rats were used and randomly grouped into ten rats per group, control, sodium fluoride (NaF; 300 ppm) only, NaF plus clofibrate (250 mg/kg) and NaF plus lisinopril (10 mg/kg), respectively, for 7 days. The administration of NaF was by drinking water ad libitum, while clofibrate and lisinopril were administered by oral gavage. Administration of NaF induced hypertension, and was accompanied with exaggerated oxidative stress; depletion of antioxidant defence system; reduced nitric oxide production; increased systolic, diastolic and mean arterial pressure; activation of angiotensin-converting enzyme activity and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB); and testicular apoptosis. Treatment of rats with clofibrate reduced oxidative stress, improved antioxidant status, lowered high blood pressure through the inhibition of angiotensin-converting enzyme activity, mineralocorticoid receptor over-activation, and abrogated testicular apoptosis. Taken together, clofibrate could offer exceptional therapeutic benefit in mitigating toxicity associated with sodium fluoride.

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Acknowledgements

The authors are grateful to Cape Peninsula University of Technology and National Research Foundation (South Africa) for financial support granted to Prof. OO Oguntibeju.

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Authors and Affiliations

  1. Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

    Ademola Adetokunbo Oyagbemi, Fasilat Oluwakemi Hassan & Olufunke Eunice Ola-Davies

  2. Department of Veterinary Medicine, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

    Olumuyiwa Abiola Adejumobi, Blessing Seun Ogunpolu & Temidayo Olutayo Omobowale

  3. Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

    Theophilus Aghogho Jarikre & Benjamin Obukowho Emikpe

  4. Department of Theriogenology, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

    Olumide Samuel Ajani & Matthew Olugbenga Oyeyemi

  5. Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Benin, Benin, Nigeria

    Ebunoluwa Racheal Asenuga

  6. Department of Botany, Faculty of Science, University of Ibadan, Ibadan, Nigeria

    Idayat Titilayo Gbadamosi

  7. Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria

    Aduragbenro Deborah A. Adedapo

  8. Department of Agriculture and Animal Health, College of Agriculture and Environmental Sciences, University of South Africa, Florida, South Africa

    Abimbola Obemisola Aro & Prudence Ngalula Kayoka-Kabongo

  9. Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

    Olufunke Olubunmi Falayi, Iyanuoluwa Omolola Ogunmiluyi, Adebowale Benard Saba & Adeolu Alex Adedapo

  10. Department of Biochemistry, Faculty of Sciences, Lead City University, Ibadan, Nigeria

    Oluwatosin Adetola Arojojoye

  11. Phytomedicine Programme, Department of Paraclinical Science, Faculty of Veterinary Science, University of Pretoria, Old Soutpan Road, Onderstepoort, Pretoria, 0110, South Africa

    Sanah Malomile Nkadimeng & Lyndy Joy McGaw

  12. Phytomedicine and Phytochemistry Group, Oxidative Stress Research Centre, Department of Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Bellville, Cape Town, 7535, South Africa

    Oluwafemi Omoniyi Oguntibeju

  13. Department of Environmental & Interdisciplinary Sciences, College of Science, Engineering & Technology, Vascular Biology Unit, Center for Cardiovascular Diseases, Texas Southern University, Houston, TX, USA

    Momoh Audu Yakubu

Authors
  1. Ademola Adetokunbo Oyagbemi
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  2. Olumuyiwa Abiola Adejumobi
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Contributions

Conceptualization: Ademola Adetokunbo Oyagbemi

Methodology: Blessing Seun Ogunpolu, Fasilat Oluwakemi Hassan, Olufunke Olubunmi Falayi, and Iyanuoluwa Omolola Ogunmiluyi

Formal analysis and investigation: Olumuyiwa Abiola Adejumobi, Theophilus Aghogho Jarikre, Olumide Samuel Ajani, Ebunoluwa Racheal Asenuga, Idayat Titilayo Gbadamosi, Aduragbenro Deborah A. Adedapo, Abimbola Obemisola Aro

Writing—original draft preparation: Ademola Adetokunbo Oyagbemi

Writing—review and editing: Ademola Adetokunbo Oyagbemi, Sanah Malomile Nkadimeng, Lyndy Joy McGaw, and Prudence Ngalula Kayoka-Kabongo

Funding acquisition: Temidayo Olutayo Omobowale, Oluwatosin Adetola Arojojoye, Oluwafemi Omoniyi Oguntibeju and Momoh Audu Yakubu

Resources: Oluwafemi Omoniyi Oguntibeju and Momoh Audu Yakubu

Supervision: Olufunke Eunice Ola-Davies, Adebowale Benard Saba, Adeolu Alex Adedapo, Benjamin Obukowho Emikpe, Matthew Olugbenga Oyeyemi

Corresponding author

Correspondence to Ademola Adetokunbo Oyagbemi.

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Ethics Approval

All animals were treated in accordance with Guide for the Care and Use of Laboratory Animals (8th edition, National Academies Press). The Animal Care and Use Research Ethical Committee of the Faculty of Veterinary Medicine of Ibadan approved the study with ethical approval number UI-ACUREC/19/124.

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Oyagbemi, A.A., Adejumobi, O.A., Jarikre, T.A. et al. Clofibrate, a Peroxisome Proliferator–Activated Receptor-Alpha (PPARα) Agonist, and Its Molecular Mechanisms of Action against Sodium Fluoride–Induced Toxicity. Biol Trace Elem Res 200, 1220–1236 (2022). https://doi.org/10.1007/s12011-021-02722-1

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