Subchronic neurotoxicity of diazinon in albino mice: Impact of oxidative stress, AChE activity, and gene expression disturbances in the cerebral cortex and hippocampus on mood, spatial learning, and memory function

Asieh Karimani; Nasrin Ramezani; Amir Afkhami Goli; Mohammad Hossein Nazem Shirazi; Hosein Nourani; Amir Moghaddam Jafari

doi:10.1016/j.toxrep.2021.06.017

Subchronic neurotoxicity of diazinon in albino mice: Impact of oxidative stress, AChE activity, and gene expression disturbances in the cerebral cortex and hippocampus on mood, spatial learning, and memory function

Toxicol Rep. 2021 Jun 19:8:1280-1288. doi: 10.1016/j.toxrep.2021.06.017. eCollection 2021.

Authors

Asieh Karimani¹, Nasrin Ramezani¹, Amir Afkhami Goli¹, Mohammad Hossein Nazem Shirazi², Hosein Nourani³, Amir Moghaddam Jafari¹

Affiliations

¹ Department of Toxicology, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran.
² Central Veterinary Laboratory, Veterinary Head Office of Khorasan Razavi, Mashhad, Iran.
³ Department of Pathology, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran.

Abstract

Diazinon (DZN) with prominent neurotoxic effects perturbs CNS function via multiple mechanisms. This investigation intends to explore mood, spatial learning, and memory dysfunction, acetylcholine esterase (AChE) activity, and neurodegeneration-related gene expression in the cortex and hippocampus regions of mice exposed to DZN for 63 consecutive days (subchronic exposure). Adult male albino mice were orally given sublethal DZN (DZN_L = 0.1 mg/kg, DZN_M = 1 mg/kg and DZN_H = 10 mg/kg). All mice in the DZN_H group died within 3 weeks postexposure. DZN_L and DZN_M caused body and brain weight loss (p < 0.05). Completing 9 weeks of DZN exposure, a marked decline in AChE activity and oxidative stress level was indicated in both brain regions (p < 0.05). Also, synaptophysin, vesicular acetylcholine transferase, and glutamate decarboxylase gene expressions were affected in both brain regions (p < 0.05). Furthermore, the present study revealed that DZN administration increased anxiety and depressive-like behaviors (p < 0.0001). Spatial learning and short- and long-memory were severely affected by DZN_L and DZN_M treatments (p < 0.0001). Taken together, subchronic exposure to low and medium doses of DZN can cause AChE inhibition, oxidative damage, and neurotransmitter disturbances in brain cells and induce neurodegeneration. These changes would impair mood, spatial learning, and memory function.

Keywords: AChE, acetylcholine esterase; AD, Alzheimer’s disease; Ach, acetylcholine; COX-2, cyclooxygenase-2; CX, cerebral cortex; Cerebral cortex; DZN, diazinon; DZO, diazoxon; Diazinon; FRAP, ferric reducing antioxidant power; FST, forced swim test; GABA, ϒ-aminobutyric acid; GAD65, glutamate decarboxylase 65; HP, hippocampus; Hippocampus; LD50, lethal dose 50; MB, marble burying test; MDA, malondialdehyde; MWM, Morris water maze test; Memory; NOAEL, no-observed-adverse-effect level; Neurodegenerative diseases; Ops, organophosphates; PD, Parkinson’s disease; RNS, reactive nitrogen species; ROS, reactive oxygen species; SEM, standard error of the mean; SYP, synaptophysin; Spatial learning; VAChT, vesicular acetylcholine transferase; qRT-PCR, quantitative reverse transcription-polymerase chain reaction.