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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.

Neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, are major global health concerns and are linked to xenobiotic exposure. The rampant use of pesticides and increased number of radiological examinations can lead to neuronal alterations in the brain through oxidative stress and DNA damage. Understanding the impact of co-exposure to these agents can help identify interaction effects, enhance risk assessment, address vulnerable populations, and uncover long-term cumulative impacts that remain largely unknown. Therefore, in the current study, we aimed to explore the isolated and combined effects of low-dose radiation and malathion in the mouse brain. Mice were administered malathion (50 mg/kg) orally for 14 days, and a single whole-body low-dose radiation (0.5 Gy) on the 8th day. Five months post-exposure, behavioural, histological, enzymatic, and metabolomic analyses were carried out. Increased neuroinflammation and impaired neuronal maturation were observed in all treated groups, with neuronal death observed exclusively in the radiation group and persistent oxidative damage and acetylcholinesterase inhibition were identified in the malathion group. Additionally, the co-exposure group exhibited synergistic reductions in alpha-linoleic acid and linoleic acid metabolism, phosphatidylcholine biosynthesis, phospholipid biosynthesis, and sphingolipid metabolism within the hippocampus. Increased anxiety and reduced exploration were most pronounced in the co-exposure group, followed by the radiation group. This study provides insights into the effects of co-exposure to neurotoxicants such as low-dose radiation and malathion, revealing synergetic neuronal damage and dysregulated amino acid and lipid metabolism in the mouse hippocampus, and identifies metabolomic signatures enabling biomarker discovery and carries potential implications for the progression of neurodegeneration due to delayed systemic effects.

Pelvic irradiation effectively treats pelvic malignancies, but its side effects can be challenging, causing intestinal damage. Alterations in the gut environment can disrupt the microbiota balance, affecting key microbial communities essential for maintaining gut health. Because the gut microbiota helps maintain gut health, bacterial supplementation may reduce radiation-induced gut toxicity. This study explores the mechanism by which a multi-strain bacterial combination comprising Lactobacillus, Bifidobacterium , and Streptococcus mitigates pelvic irradiation-induced gut toxicity. Male Sprague–Dawley rats were orally administered a multi-strain bacterial combination throughout the study period or after radiation exposure. Changes in intestinal morphology, integrity, fibrosis, inflammation, and apoptosis were assessed. The prophylactic-therapeutic administration of the bacterial combination effectively preserved villus height, crypt depth, goblet cell count, and overall gut barrier integrity. Furthermore, prophylactic treatment significantly reduced radiation-induced fibrosis, inflammation, and the expression of apoptotic markers in both the jejunum and colon. In contrast, therapeutic bacterial combination treatment was less effective, suggesting that preventive administration is more beneficial in mitigating radiation-induced gastrointestinal damage. Thus, this study underscores the efficacy of pre-radiation bacterial supplementation in protecting the gut from radiation injury, with potential implications for improved patient quality of life.

Radiation-induced skin reactions (RISRs) adversely affect cancer patients by limiting treatment adherence and quality of life (QoL). The current study aimed to establish a murine model for early and late RISR by fractionated radiation, with 30 Gy (10 Gy X 3 sessions) and 50 Gy (10 Gy X 5 sessions) irradiation of the right hind limb of male Swiss albino mice. Early RISRs were monitored for 30 days via blinded RTOG grading, and tissue samples from days 15 and 30 were harvested for histological and morphometric analysis (H&E staining). For late RISR, mice exposed to 50 Gy were examined for 120 days by phenotypical, histological, and morphometric evaluations (H&E and Masson’s trichrome staining). The 30 Gy group presented a median RTOG grade of 2, resolving by day 30, whereas the 50 Gy group presented a median grade of 3, resolving by day 35. Early RISR in the 50 Gy group revealed dermal inflammation, ulceration, cellular infiltration, and reduced hair follicle density, with late effects of dermal indentations, excessive collagen, cellular inflammation, and persistent hair follicle loss ( p  < 0.05). The present murine model effectively replicated early and late RISR clinical and histological features for mechanistic investigations and developing therapeutic strategies in future studies.

Cellular and molecular approaches are being explored to find a biomarker which can predict the development of radiation induced acute toxicity prior to radiation therapy. SNPs in radiation responsive genes may be considered as an approach to develop tools for finding the inherited basis of clinical radiosensitivity. The current study attempts to screen single nucleotide polymorphisms/deletions in DNA damage response, DNA repair, profibrotic cytokine as well as antioxidant response genes and its predictive potential with the normal tissue adverse reactions from 183 head and neck cancer patients undergoing platinum based chemoradiotherapy or radiotherapy alone. We analysed 22 polymorphisms in 17 genes having functional relevance to radiation response. Radiation therapy induced oral mucositis and skin erythema was considered as end point for clinical radiosensitivity. Direct correlation of heterozygous and mutant alleles with acute reactions as well as haplotype correlation revealed NBN variants to be of predictive significance in analysing oral mucositis prior to radiotherapy. In addition, genetic linkage disequilibrium existed in XRCC1 polymorphisms for >grade 2 oral mucositis and skin reaction indicating the complex inheritance pattern. The current study indicates an association for polymorphism in NBN with normal tissue radiosensitivity and further warrants the replication of such studies in a large set of samples.

Microbial-derived metabolites are the intermediate or end products of bacterial digestion. They are one of the most important molecules for the gut to connect with the brain. Depending on the levels of specific metabolites produced in the host, it can exert beneficial or detrimental effects on the brain and have been linked to several neurodegenerative and neuropsychiatric disorders. However, the underlying mechanisms remain largely unexplored. Insight into these mechanisms could reveal new pathways or targets, resulting in novel treatment approaches targeting neurodegenerative diseases. We have reviewed selected metabolites, including short-chain fatty acids, aromatic amino acids, trimethylamine-N-oxide,  urolithin A, anthocyanins, equols, imidazole, and propionate to highlight their mechanism of action, underlying role in maintaining intestinal homeostasis and regulating neuro-immunoendocrine function. Further discussed on  how altered metabolite levels can influence the gut–brain axis could lead to new prevention strategies or novel treatment approaches to neural disorders.

Lead (Pb) is a hazardous heavy metal frequently used because it is readily available and inexpensive. Due to contaminated soil, dust, and items like paints and batteries, lead exposure is still an issue of concern in many nations. There is no known safe threshold of exposure, and it can have serious adverse effects on human health. Exposure to lead has been linked to detrimental effects on the developing nervous system of both children and adults. Alzheimer's disease (AD) is the most prevalent type of dementia affecting adults over the age of 65, resulting in a decrease in memory and thinking skills. In this review, we describe the role of lead in exacerbating the build-up of hyperphosphorylated tau proteins and formation of amyloid-β (Aβ) plaques, major neurotoxicants which can impair neuronal function leading to AD. We highlight the effect of developmental and lifelong lead exposure on various gene expression changes resulting in the formation of the neurotoxicants responsible to AD. Understanding the mechanisms related to Aβ plaques and neurofibrillary tangles (NFTs) formation serves as a novel approach to identify biomarkers for lead-induced AD and developing therapeutic interventions. Lead exposure has been related to adverse effects on the developing neurological systems of both adults and children.

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 7 th 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.

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 8 th 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.

Cellular and molecular approaches are being explored to find a biomarker which can predict the development of radiation induced acute toxicity prior to radiation therapy. SNPs in radiation responsive genes may be considered as an approach to develop tools for finding the inherited basis of clinical radiosensitivity. The current study attempts to screen single nucleotide polymorphisms/deletions in DNA damage response, DNA repair, profibrotic cytokine as well as antioxidant response genes and its predictive potential with the normal tissue adverse reactions from 183 head and neck cancer patients undergoing platinum based chemoradiotherapy or radiotherapy alone. We analysed 22 polymorphisms in 17 genes having functional relevance to radiation response. Radiation therapy induced oral mucositis and skin erythema was considered as end point for clinical radiosensitivity. Direct correlation of heterozygous and mutant alleles with acute reactions as well as haplotype correlation revealed NBN variants to be of predictive significance in analysing oral mucositis prior to radiotherapy. In addition, genetic linkage disequilibrium existed in XRCC1 polymorphisms for >grade 2 oral mucositis and skin reaction indicating the complex inheritance pattern. The current study indicates an association for polymorphism in NBN with normal tissue radiosensitivity and further warrants the replication of such studies in a large set of samples.