Low-dose exposure to malathion and radiation results in the dysregulation of multiple neuronal processes, inducing neurotoxicity and neurodegeneration in mouse.

Neurodegenerative disorders are a debilitating and persistent threat to the global elderly population, carrying grim outcomes. Their genesis is often multifactorial, with a history of prior exposure to xenobiotics such as pesticides, heavy metals, enviornmental pollutants, ionizing radiation etc,. A holistic molecular insight into their mechanistic induction upon single or combinatorial exposure to different toxicants is still unclear. In the present study, one-month-old C57BL/6 male mice were administered orally with malathion (50 mg/kg body wt. for 14 days) and single whole-body radiation (0.5 Gy) on the 8th day. Post-treatment, behavioural assays for exploratory behaviour, memory, and learning were performed. After sacrifice, brains were collected for histology, biochemical assays, and transcriptomic analysis. Transcriptomic analysis revealed several altered processes like synaptic transmission and plasticity, neuronal survival, proliferation, and death. Signalling pathways like MAPK, PI3K-Akt, Apelin, NF-κB, cAMP, Notch etc., and pathways related to neurodegenerative diseases were altered. Increased astrogliosis was observed in the radiation and coexposure groups, with significant neuronal cell death and a reduction in the expression of NeuN. Sholl analysis, dendritic arborization and spine density studies revealed decreased total apical neuronal path length and dendritic spine density. Reduced levels of the antioxidants GST and GSH and acetylcholinesterase enzyme activity were also detected. However, no changes were seen in exploratory behaviour or learning and memory post-treatment. Thus, explicating the molecular mechanisms behind malathion and radiation can provide novel insights into external factor-driven neurotoxicity and neurodegenerative pathogenesis.

Radioprotective potential of probiotics against gastrointestinal and neuronal toxicity: a preclinical study.

PURPOSE: Radiotherapy is a critical component of cancer treatment, along with surgery and chemotherapy. Approximately, 90% of cancer patients undergoing pelvic radiotherapy show gastrointestinal (GI) toxicity, including bloody diarrhea, and gastritis, most of which are associated with gut dysbiosis. In addition to the direct effect of radiation on the brain, pelvic irradiation can alter the gut microbiome, leading to inflammation and breakdown of the gut-blood barrier. This allows toxins and bacteria to enter the bloodstream and reach the brain. Probiotics have been proven to prevent GI toxicity by producing short-chain fatty acids and exopolysaccharides beneficial for protecting mucosal integrity and oxidative stress reduction in the intestine and also shown to be beneficial in brain health. Microbiota plays a significant role in maintaining gut and brain health, so it is important to study whether bacterial supplementation will help in maintaining the gut and brain structure after radiation exposure. METHODS: In the present study, male C57BL/6 mice were divided into control, radiation, probiotics, and probiotics + radiation groups. On the 7th day, animals in the radiation and probiotics + radiation groups received a single dose of 4 Gy to  whole-body. Posttreatment, mice were sacrificed, and the intestine and brain tissues were excised for histological analysis to assess GI and neuronal damage. RESULTS: Radiation-induced damage to the villi height and mucosal thickness was mitigated by the probiotic treatment significantly (p < 0.01). Further, radiation-induced pyknotic cell numbers in the DG, CA2, and CA3 areas were substantially reduced with bacterial supplementation (p < 0.001). Similarly, probiotics reduced neuronal inflammation induced by radiation in the cortex, CA2, and DG region (p < 0.01). Altogether, the probiotics treatment helps mitigate radiation-induced intestinal and neuronal damage. CONCLUSION: In conclusion, the probiotic formulation could attenuate the number of pyknotic cells in the hippocampal brain region and decrease neuroinflammation by reducing the number of microglial cells.

Modulation of CREB and its associated upstream signaling pathways in pesticide-induced neurotoxicity.

Human beings are exposed to various environmental xenobiotics throughout their life consisting of a broad range of physical and chemical agents that impart bodily harm. Among these, pesticide exposure that destroys insects mainly by damaging their central nervous system also exerts neurotoxic effects on humans and is implicated in the etiology of several degenerative disorders. The connectivity between CREB (cAMP Response Element Binding Protein) signaling activation and neuronal activity is of broad interest and has been thoroughly studied in various diseased states. Several genes, as well as protein kinases, are involved in the phosphorylation of CREB, including BDNF (Brain-derived neurotrophic factor), Pi3K (phosphoinositide 3-kinase), AKT (Protein kinase B), RAS (Rat Sarcoma), MEK (Mitogen-activated protein kinase), PLC (Phospholipase C), and PKC (Protein kinase C) that play an essential role in neuronal plasticity, long-term potentiation, neuronal survival, learning, and memory formation, cognitive function, synaptic transmission, and suppressing apoptosis. These elements, either singularly or in a cascade, can result in the modulation of CREB, making it a vulnerable target for various neurotoxic agents, including pesticides. This review provides insight into how these various intracellular signaling pathways converge to bring about CREB activation and how the activated or deactivated CREB levels can affect the gene expression of the upstream molecules. We also discuss the various target genes within the cascade vulnerable to different types of pesticides. Thus, this review will facilitate future investigations associated with pesticide neurotoxicity and identify valuable therapeutic targets.