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Arsenic induces autophagy in developmental mouse cerebral cortex and hippocampus by inhibiting PI3K/Akt/mTOR signaling pathway: involvement of blood–brain barrier’s tight junction proteins

  • Inorganic Compounds
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Abstract

For the past decade, there has been an increased concern about the health risks from arsenic (As) exposure, because of its neurotoxic effects on the developing brain. The exact mechanism underlying As-induced neurotoxicity during sensitive periods of brain development remains unclear, especially the role of blood–brain barrier’s (BBB) tight junction (TJ) proteins during As-induced neurotoxicity. Here, we highlight the involvement of TJ proteins in As-induced autophagy in cerebral cortex and hippocampus during developmental periods [postnatal day (PND) 21, 28, 35 and 42]. Here, the administration of arsenic trioxide (As2O3) at doses of 0.15 mg or 1.5 mg or 15 mg As2O3/L in drinking water from gestational to lactational and continued to the pups till PND42 resulted in a significant decrease in the mRNA expression levels of TJ proteins (Occludin, Claudin, ZO-1 and ZO-2) and Occludin protein expression level. In addition, As exposure significantly decreased PI3K, Akt, mTOR, and p62 with a concomitant increase in Beclin1, LC3I, LC3II, Atg5 and Atg12. Moreover, As exposure also significantly downregulated the protein expression levels of mTOR with a concomitant upregulation of Beclin 1, LC3 and Atg12 in all the developmental age points. However, no significant alterations were observed in low and medium dose-exposed groups of PND42. Histopathological analysis in As-exposed mice revealed decreased number of pyramidal neurons in hippocampus; and neurons with degenerating axons, shrinkage of cells, remarkable vacuolar degeneration in cytoplasm, karyolysis and pyknosis in cerebral cortex. Ultrastructural analysis by transmission electron microscopy revealed the occurrence of autophagosomes and vacuolated axons in the cerebral cortex and hippocampus of the mice exposed to high dose As at PND21 and 42. The severities of changes were found to more persist in the cerebral cortex than in the hippocampus of As-exposed mice. Finally, we conclude that the leaky BBB in cerebral cortex and hippocampus may facilitate the transfer of As and induces autophagy by inhibiting PI3K/Akt/mTOR signaling pathway in an age-dependent manner, i.e., among the four different developmental age points, PND21 animals were found to be more vulnerable to the As-induced neurotoxicity than the other three age points.

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Acknowledgements

This work is supported by China National Natural Science Foundation (Grant No. 31672623 and 31372497).

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  1. Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China

    Ram Kumar Manthari, Chiranjeevi Tikka, Mohammad Mehdi Ommati, Ruiyan Niu, Zilong Sun, Jinming Wang, Jianhai Zhang & Jundong Wang

  2. Department of Animal Science, College of Agriculture, Shiraz University, Shiraz, 71441-65186, Iran

    Mohammad Mehdi Ommati

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Manthari, R.K., Tikka, C., Ommati, M.M. et al. Arsenic induces autophagy in developmental mouse cerebral cortex and hippocampus by inhibiting PI3K/Akt/mTOR signaling pathway: involvement of blood–brain barrier’s tight junction proteins. Arch Toxicol 92, 3255–3275 (2018). https://doi.org/10.1007/s00204-018-2304-y

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