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Roles of mitochondrial fission inhibition in developmental fluoride neurotoxicity: mechanisms of action in vitro and associations with cognition in rats and children

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Abstract

Fluoride neurotoxicity is associated with mitochondrial disruption. Mitochondrial fission/fusion dynamics is crucial to maintain functional mitochondria, yet little is known about how fluoride perturbs this dynamics and whether such perturbation contributes to impaired neurodevelopment. Here in human neuroblastoma SH-SY5Y cells treated with sodium fluoride (NaF, 20, 40 and 60 mg/L), mitochondrial fission suppression exerted a central role in NaF-induced mitochondrial abnormalities and the resulting autophagy deficiency, apoptosis augmentation, and compromised neuronal survival. Mechanically, pharmacological inhibition of mitochondrial fission exacerbated NaF-induced mitochondrial defects and cell death through promoting apoptosis despite partial autophagy restoration. Conversely, genetic enhancement of mitochondrial fission alleviated NaF-produced detrimental mitochondrial and cellular outcomes by elevating autophagy and inhibiting apoptosis. Further suppressing autophagy was harmful, while blocking apoptosis was beneficial for cellular survival in this context. Consistently, using Sprague–Dawley rats developmentally exposed to NaF (10, 50, and 100 mg/L) from pre-pregnancy until 2 months of delivery to mimic human exposure, we showed that perinatal exposure to environmentally relevant levels of fluoride caused learning and memory impairments, accompanied by hippocampal mitochondrial morphological alterations manifested as fission suppression and fusion acceleration, along with defective autophagy, excessive apoptosis and neuronal loss. Intriguingly, the disturbed circulating levels of identified mitochondrial fission/fusion molecules were closely associated with intellectual loss in children under long-term environmental drinking water fluoride exposure. Collectively, our results suggest that mitochondrial fission inhibition induces mitochondrial abnormalities, triggering abnormal autophagy and apoptosis, thus contributing to neuronal death, and that the mitochondrial dynamics molecules may act as promising indicators for developmental fluoride neurotoxicity.

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Acknowledgements

We would like to express our sincere thanks to all children donors who volunteered to participate in this study. We also sincerely thank the Tianjin Center for Disease Control and Prevention for its assistance for sample collection. This work was supported by grants from the State Key Program of National Natural Science of China (Grant No. 81430076), the National Natural Science Foundation of China (Grants No. 81502785 and No. 81773388) and the Fundamental Research Funds for the Central Universities (HUST 2016YXMS221 and HUST 2015ZDTD052).

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Authors and Affiliations

  1. Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China

    Qian Zhao, Qiang Niu, Jingwen Chen, Tao Xia, Guoyu Zhou, Pei Li, Lixin Dong, Chunyan Xu, Zhiyuan Tian, Chen Luo, Luming Liu, Shun Zhang & Aiguo Wang

  2. Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China

    Qian Zhao, Qiang Niu, Jingwen Chen, Tao Xia, Guoyu Zhou, Pei Li, Lixin Dong, Chunyan Xu, Zhiyuan Tian, Chen Luo, Luming Liu, Shun Zhang & Aiguo Wang

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  1. Qian Zhao
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  2. Qiang Niu
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Correspondence to Shun Zhang or Aiguo Wang.

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Zhao, Q., Niu, Q., Chen, J. et al. Roles of mitochondrial fission inhibition in developmental fluoride neurotoxicity: mechanisms of action in vitro and associations with cognition in rats and children. Arch Toxicol 93, 709–726 (2019). https://doi.org/10.1007/s00204-019-02390-0

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