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Fluoride-Induced Cortical Toxicity in Rats: the Role of Excessive Endoplasmic Reticulum Stress and Its Mediated Defective Autophagy

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Abstract

The cerebral cortex is closely associated with learning and memory, and fluoride is capable of inducing cortical toxicity, but its mechanism is unclear. This study aimed to investigate the role of endoplasmic reticulum stress and autophagy in fluoride-induced cortical toxicity. Rats exposed to sodium fluoride (NaF) were used as an in vivo model. The results showed that NaF exposure impaired the learning and memory capacities and increased urinary fluoride levels in rats. In addition, NaF exposure induced excessive endoplasmic reticulum stress and associated apoptosis, as evidenced by elevated IRE1α, GRP78, cleaved caspase-12, and cleaved caspase-3, as well as defective autophagy, as evidenced by increased expression of Beclin1, LC3-II, and p62 in cortical areas. Importantly, the endoplasmic reticulum stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated endoplasmic reticulum stress as well as defective autophagy, thus confirming the critical role of endoplasmic reticulum stress and autophagy in fluoride-induced cortical toxicity. Taken together, these results suggest that excessive endoplasmic reticulum stress and its mediated defective autophagy lead to fluoride-induced cortical toxicity. This provides new insights into the mechanisms of fluoride-induced neurotoxicity and a new theoretical basis for the prevention and treatment of fluoride-induced neurotoxicity.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81860559 and Grant No. 82060580), the Program of Science and Technology Innovation in Bingtuan (Grant No. 2021CB046), and the High-Level Talent Research Project of Shihezi University (Grant No. RCZK2018C02).

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Authors and Affiliations

  1. Department of Preventive Medicine, School of Medicine, Shihezi University, North 2th Road, Shihezi, Xinjiang, 832000, People’s Republic of China

    Jingjing Zhang, Yanling Tang, Wanjing Xu, Zeyu Hu, Shangzhi Xu & Qiang Niu

  2. Key Laboratory of Preventive Medicine, Shihezi University, Shihezi, Xinjiang, People’s Republic of China

    Jingjing Zhang, Yanling Tang, Wanjing Xu, Zeyu Hu, Shangzhi Xu & Qiang Niu

  3. Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi, Xinjiang, People’s Republic of China

    Jingjing Zhang, Yanling Tang, Wanjing Xu, Zeyu Hu, Shangzhi Xu & Qiang Niu

  4. NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, People’s Republic of China

    Jingjing Zhang, Yanling Tang, Wanjing Xu, Zeyu Hu, Shangzhi Xu & Qiang Niu

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  1. Jingjing Zhang
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  2. Yanling Tang
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Contributions

Jingjing Zhang: methodology, formal analysis, writing — original draft. Yanling Tang: methodology, writing — review and editing. Wanjing Xu: writing — review and editing. Zeyu Hu: visualization, investigation. Shangzhi Xu: writing — review and editing. Qiang Niu: conceptualization, resources, writing — review and editing, funding acquisition.

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Correspondence to Qiang Niu.

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Highlights

1. NaF causes cortical toxicity in rats, leading to learning and memory impairment.

2. NaF induces excessive ERS and ERS-mediated apoptosis in the rat cortex.

3. NaF induces defective autophagy in the rat cortex.

4. 4-PBA alleviates NaF-induced cortical excessive ERS and its mediated defective autophagy.

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Zhang, J., Tang, Y., Xu, W. et al. Fluoride-Induced Cortical Toxicity in Rats: the Role of Excessive Endoplasmic Reticulum Stress and Its Mediated Defective Autophagy. Biol Trace Elem Res 201, 3850–3860 (2023). https://doi.org/10.1007/s12011-022-03463-5

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