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Co-exposure to non-toxic levels of cadmium and fluoride induces hepatotoxicity in rats via triggering mitochondrial oxidative damage, apoptosis, and NF-kB pathways

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Abstract

Fluoride (F) and cadmium (Cd) are two common water pollutants. There is low information about their co-exposure in low doses. So, in this study, we evaluated the combination effects of non-toxic doses of F and Cd and the possible mechanism of their combined interaction. Male rats were exposed to non-toxic doses of sodium fluoride (30 mg/l) and/or cadmium chloride (40 mg/l) in drinking water for 6 weeks. Then, liver tissues were separated and several factors including oxidative stress, mitochondrial toxicity, inflammation, apoptosis, and biochemical and histopathological changes were evaluated. Cd and F alone did not induce any significant changes in evaluated factors compared to control group, while significant elevation in liver enzymes as well as histopathological changes were observed in rats treated with F+Cd. Also, a remarkable increase in oxidative stress markers including reactive oxygen species, lipid peroxidation, and protein carbonyl and also decreasing glutathione and superoxide dismutase levels were detected following co-exposure to F and Cd. Furthermore, a combination of F and Cd resulted in mitochondrial dysfunction, swelling, as well as a reduction in mitochondrial membrane potential in isolated liver mitochondria. On the other hand, TNF-α, IL-1β, and NF-kB inflammatory genes were upregulated in the liver after combined exposure to F and Cd compared to individual treatments. Also, F+Cd treatment increased the Bax expression but decreased the expression of Bcl-2 significantly. These findings suggest that Cd and F can potentiate their individual toxic effects on the liver tissue through disruption of the cellular redox status, inflammation, and apoptosis pathway.

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Acknowledgments

This study was extracted from the PhD thesis of Milad Arab-Nozari.

Funding

This study was supported by a grant from the Research Council of Mazandaran University of Medical Sciences, Sari, Iran (Grant Number: 1484).

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Authors and Affiliations

  1. Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran

    Milad Arab-Nozari

  2. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

    Milad Arab-Nozari, Mohammad Shokrzadeh & Fatemeh Shaki

  3. Environmental Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Ebrahim Mohammadi

  4. Pharmaceutical Science Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran

    Mohammad Shokrzadeh & Fatemeh Shaki

  5. Department of Pharmacology, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran

    Nematollah Ahangar

  6. Department of Anatomy, Faculty of Medicine, Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran

    Fereshteh Talebpour Amiri

Authors
  1. Milad Arab-Nozari
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  2. Ebrahim Mohammadi
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  3. Mohammad Shokrzadeh
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  4. Nematollah Ahangar
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  5. Fereshteh Talebpour Amiri
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  6. Fatemeh Shaki
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Contributions

Fatemeh Shaki designed the research. Milad Arab-Nozari, Ebrahim Mohammadi, Mohammad Shokrzadeh, and Fereshteh Talebpour Amiri collected the data. Fatemeh Shaki and Nematollah Ahangar analyzed and interpreted the data. Milad Arab-Nozari and Fatemeh Shaki prepared the manuscript. All authors read and approved the final manuscript.

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Correspondence to Fatemeh Shaki.

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Responsible editor: Mohamed M. Abdel-Daim

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Arab-Nozari, M., Mohammadi, E., Shokrzadeh, M. et al. Co-exposure to non-toxic levels of cadmium and fluoride induces hepatotoxicity in rats via triggering mitochondrial oxidative damage, apoptosis, and NF-kB pathways. Environ Sci Pollut Res 27, 24048–24058 (2020). https://doi.org/10.1007/s11356-020-08791-4

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