Abstract
Exposure to fluoride (F) or arsenite (As) through contaminated drinking water has been associated with chronic nephrotoxicity in humans. Autophagy is a regulated mechanism ubiquitous for the body in a toxic environment with F and As, but the underlying mechanisms of autophagy in the single or combined nephrotoxicity of F and As are unclear. In the present study, we established a rat model of prenatal and postnatal exposure to F and As with the aim of investigating the mechanism underlying nephrotoxicity of these pollutants in offspring. Rats were randomly divided into four groups that received NaF (100 mg/L), NaAsO2 (50 mg/L), or NaF (100 mg/L) with NaAsO2 (50 mg/L) in drinking water or clean water during pregnancy and lactation; after weaning, pups were exposed to the same treatment as their mothers until puberty. The results revealed that F and As exposure (alone or combined) led to significant increases of arsenic and fluoride levels in blood and bone, respectively. In this context, F and/or As disrupted histopathology and ultrastructure in the kidney, and also altered creatinine (CRE), urea nitrogen (BUN) and uric acid (UA) levels. Intriguingly, F and/or As uptake induced the formation of autophagosomes in kidney tissue and resulted in the upregulation of genes encoding autophagy-related proteins. Collectively, these results suggest that nephrotoxicity of F and As for offspring exposed to the pollutants from in utero to puberty is associated with deregulation of autophagy and there is an antagonism between F and As in the toxicity autophagy process.
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Acknowledgements
This research was sponsored by the National Natural Science Foundation of China (81773405), the Postdoctoral Science Foundation of China (2016M600199), the Program for the Outstanding Innovative Teams of Higher Learning Institutions of Shanxi, the Outstanding Youth Science Foundation of Shanxi Province (201701D211008), the Shanxi Scholarship Council of China (2017-058), and the PhD Start-up Fund of Shanxi Medical University (BS03201647). X.R. is supported by the National Institutes of Health (NIH) grants (ES022629).
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Tian, X., Xie, J., Chen, X. et al. Deregulation of autophagy is involved in nephrotoxicity of arsenite and fluoride exposure during gestation to puberty in rat offspring. Arch Toxicol 94, 749–760 (2020). https://doi.org/10.1007/s00204-019-02651-y
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DOI: https://doi.org/10.1007/s00204-019-02651-y