Dose‐Dependent Autophagic Dysfunction and CCR5‐Mediated Neuroinflammation Drive Arsenic Trioxide‐Induced Cortical Neurodegeneration in Mice
- 1Department of Life Sciences, GITAM School of Science GITAM (Deemed to be University) Visakhapatnam AP India
- 2College of Animal Science and Veterinary Medicine Shanxi Agricultural University Taigu Shanxi China
Abstract
Neurotoxic environmental contaminant arsenic is widely present in global groundwater used for consumption and dietary sources, and has been significantly implicated in cognitive and neurodegenerative diseases. Although of increasing concern, the dose‐dependent molecular pathways mediating arsenic‐induced corticocerebral neurons dysfunction remain poorly understood, especially regarding the cross‐talk between regulation of autophagy and neuroinflammation. This research explored the molecular mechanisms underlying the neurotoxic effects of arsenic trioxide (As2O3) in the mice cerebral cortex, particularly PI3K‐AKT‐mTOR‐regulated autophagic activity and CCR5‐induced microglia‐driven neuroinflammation, at physiologically and experimentally relevant dosage. Thirty‐two adult male Kunming mice were randomly assigned to four groups (n = 8) and orally administered 0, 0.15, 1.5, or 15 ppm As2O3 for 90 days. Quantitative real‐time PCR, Western blot, hematoxylin and eosin histomorphometry and transmission electron microscopy were performed on cerebral cortex region. The PI3K/AKT/mTOR pathway and autophagy‐related genes ATG5, ATG7 and LC3 were significantly increased at low‐level exposure reflecting adaptive response, but strongly down‐regulated at lethal levels, with concurrent activation of mTOR, revealing defective autophagy. High level treatment led to significant up‐regulation of GLS1, CCR5, CCL2, CCL3, CCL5 and Iba1, reflecting glutaminolytic switch and threshold‐dependent microglial neuroinflammation. Histological morphometry supported dose‐dependent neurodegeneration, with healthy neurons decreasing and the pyknotic index increasing at high doses. Electron microscopy confirmed cytoplasmic vacuole accumulation, mitochondrial cristae distortion, and autophagosomes (AP)‐lysosomes (LY) co‐accumulation, indicating compromised autophagic flux. These findings reveal that high arsenic exposure may be associated with neurodegeneration involving convergent mTOR‐driven autophagic dysfunction, an excitotoxic metabolic shift and CCR5‐associated neuroinflammation, pointing to potential mechanistically interlinked therapeutic targets that warrant further functional validation.
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BibTeX
@article{koyya2026dosedependent,
title = {{Dose‐Dependent Autophagic Dysfunction and CCR5‐Mediated Neuroinflammation Drive Arsenic Trioxide‐Induced Cortical Neurodegeneration in Mice}},
author = {Prathyusha Koyya and Zilong Sun and Ram Kumar Manthari},
journal = {Journal of Biochemical and Molecular Toxicology},
year = {2026},
month = oct,
doi = {10.1002/jbt.71150},
url = {https://doi.org/10.1002/jbt.71150},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Dose‐Dependent Autophagic Dysfunction and CCR5‐Mediated Neuroinflammation Drive Arsenic Trioxide‐Induced Cortical Neurodegeneration in Mice
AU - Prathyusha Koyya
AU - Zilong Sun
AU - Ram Kumar Manthari
PY - 2026
DA - 2026/10/27
JO - Journal of Biochemical and Molecular Toxicology
DO - 10.1002/jbt.71150
UR - https://doi.org/10.1002/jbt.71150
AB - Neurotoxic environmental contaminant arsenic is widely present in global groundwater used for consumption and dietary sources, and has been significantly implicated in cognitive and neurodegenerative diseases. Although of increasing concern, the dose‐dependent molecular pathways mediating arsenic‐induced corticocerebral neurons dysfunction remain poorly understood, especially regarding the cross‐talk between regulation of autophagy and neuroinflammation. This research explored the molecular mechanisms underlying the neurotoxic effects of arsenic trioxide (As2O3) in the mice cerebral cortex, particularly PI3K‐AKT‐mTOR‐regulated autophagic activity and CCR5‐induced microglia‐driven neuroinflammation, at physiologically and experimentally relevant dosage. Thirty‐two adult male Kunming mice were randomly assigned to four groups (n = 8) and orally administered 0, 0.15, 1.5, or 15 ppm As2O3 for 90 days. Quantitative real‐time PCR, Western blot, hematoxylin and eosin histomorphometry and transmission electron microscopy were performed on cerebral cortex region. The PI3K/AKT/mTOR pathway and autophagy‐related genes ATG5, ATG7 and LC3 were significantly increased at low‐level exposure reflecting adaptive response, but strongly down‐regulated at lethal levels, with concurrent activation of mTOR, revealing defective autophagy. High level treatment led to significant up‐regulation of GLS1, CCR5, CCL2, CCL3, CCL5 and Iba1, reflecting glutaminolytic switch and threshold‐dependent microglial neuroinflammation. Histological morphometry supported dose‐dependent neurodegeneration, with healthy neurons decreasing and the pyknotic index increasing at high doses. Electron microscopy confirmed cytoplasmic vacuole accumulation, mitochondrial cristae distortion, and autophagosomes (AP)‐lysosomes (LY) co‐accumulation, indicating compromised autophagic flux. These findings reveal that high arsenic exposure may be associated with neurodegeneration involving convergent mTOR‐driven autophagic dysfunction, an excitotoxic metabolic shift and CCR5‐associated neuroinflammation, pointing to potential mechanistically interlinked therapeutic targets that warrant further functional validation.
SN - 1095-6670
SN - 1099-0461
ER -