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Long-term impairments associated with gut-brain axis dysregulation following sublethal VX exposure in mice
Assia Belkebir1, Julie Somkhit2, Rosalie Bel2
1Department of Toxicology and Chemical Risks, French Armed Forces Biomedical Research Institute, Bretigny sur Orge, France; Laboratoire d'Imagerie Biomédicale Multimodale (BioMaps), CEA, Service Hospitalier Frederic Joliot, Universite Paris-Saclay, Orsay, France.
Abstract:
Exposure to organophosphorus (OP) compounds can induce transient cognitive, neurological, and somatic symptoms that may persist over time. OP poisoning mostly occurs from pesticides used in developing countries; however, several OP nerve agent (NA) events have been reported in the last decade. OP toxicity is based on cholinesterase inhibition, which leads to varying degrees of neurotoxicity. According to clinical reports, asymptomatic victims of OP exposure may experience long-term neurological sequelae. Given the continuous communication between the nervous and enteric systems, evaluating the neurotoxic effects of OP exposure on the gut-brain axis is important. A male Swiss mouse model was employed to investigate the short- and long-term consequences of acute exposure to a sublethal dose of VX at 0.5 LD50. The investigation focused on alterations in the inflammatory system and the endocrine system, with particular attention to the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, the study encompassed an evaluation of the intestinal barrier structural and functional integrity and gut microbiota composition. A longitudinal behavioral study was also conducted to assess cognitive and emotional functions. Our results indicate that sublethal exposure to a VX disrupts the HPA axis and the intestinal homeostasis as evidenced by local inflammation, structural changes and gut microbiota shifts. Our data also indicate long-term neurological deficits as well as long-term neuroendocrine and metabolic effects suggesting a systemic homeostatic disorder. These findings highlight the necessity for comprehensive care for individuals exposed to NA and underscore the importance of identifying biomarkers for low-dose to sublethal exposure to facilitate early diagnosis and the development of effective treatments.
Insights
Sublethal exposure to VX nerve agent disrupts the gut-brain axis, causing long-term neurological and neuroendocrine effects. This highlights the need for comprehensive care and biomarkers for organophosphorus compound exposure.
Area of Science:
- Neuroscience
- Toxicology
- Gastroenterology
Background:
- Organophosphorus (OP) compounds, including nerve agents (NA), cause toxicity via cholinesterase inhibition, leading to neurotoxicity.
- Even asymptomatic victims of OP exposure may experience persistent neurological issues.
- The gut-brain axis plays a crucial role in maintaining homeostasis, making its evaluation critical following OP exposure.
Purpose of the Study:
- To investigate the short- and long-term consequences of acute sublethal VX exposure on the gut-brain axis in a mouse model.
- To assess alterations in the inflammatory, endocrine (specifically the hypothalamic-pituitary-adrenal [HPA] axis), and nervous systems.
- To evaluate the impact on intestinal barrier integrity, gut microbiota, and cognitive/emotional functions.
Main Methods:
- Acute sublethal exposure (0.5 LD50) of male Swiss mice to VX.
- Assessment of HPA axis function, inflammatory markers, and endocrine system alterations.
- Evaluation of intestinal barrier structure and function, gut microbiota composition, and longitudinal behavioral studies for cognitive and emotional assessment.
Main Results:
- Sublethal VX exposure disrupted the HPA axis and intestinal homeostasis, indicated by inflammation, structural changes, and gut microbiota shifts.
- Long-term neurological deficits, neuroendocrine, and metabolic effects were observed, suggesting a systemic homeostatic disorder.
- VX exposure led to significant alterations in gut-brain axis signaling and function.
Conclusions:
- Sublethal VX exposure induces lasting disruptions in the gut-brain axis, impacting multiple physiological systems.
- Findings underscore the necessity for comprehensive medical care and the development of biomarkers for early diagnosis of low-dose to sublethal OP exposure.
- This research emphasizes the systemic nature of OP neurotoxicity and its long-term health implications.
