How does organophosphorus chemical warfare agent exposure affect respiratory physiology in mice?

In the absence of appropriate medical care, exposure to organophosphorus nerve agents, such as VX, can lead to respiratory failure, and potentially death by asphyxiation. Despite the critical role of respiratory disturbances in organophosphorus-induced toxicity, the nature and underlying mechanisms of respiratory failure remain poorly understood. This study aimed to characterize respiratory alterations by determining their type and duration in mice exposed to a subcutaneous sublethal dose of VX. Respiratory ventilation in Swiss mice was monitored using dual-chamber plethysmography for up to 7 days post-exposure. Cholinesterase activity was assessed via spectrophotometry, and levels of inflammatory biomarkers were quantified using Luminex technology in blood and tissues involved in respiration (diaphragm, lung, and medulla oblongata). Additionally, a histological study was conducted on these tissues to ensure their structural integrity. Ventilatory alterations appeared 20-25 minutes after the injection of 0.9 LD50 VX and increased until the end of the recording, i.e., 40 minutes after intoxication. Concurrent with the occurrence of apnea, increased inspiratory and expiratory times resulted in a significant decrease in respiratory rate in exposed mice compared to controls. Ventilatory amplitude and, consequently, minute volume were reduced, while specific airway resistance significantly increased, indicating bronchoconstriction. These ventilatory effects persisted up to 24 or even 72 hours post-intoxication, resolving on the 7th day. They were correlated with a decrease in acetylcholinesterase activity in the diaphragm, which persisted for up to 72 hours, and with the triggering of an inflammatory reaction in the same tissue. No significant histologic lesions were observed in the examined tissues. The ventilatory alterations observed up to 72 hours post-VX exposure appear to result from a functional failure of the respiratory system rather than tissue damage. This comprehensive characterization contributes to a better understanding of the respiratory effects induced by VX exposure, which is crucial for developing specific medical countermeasures.

Steady electrocorticogram characteristics predict specific stress-induced behavioral phenotypes.

Introduction: Depending on the individual, exposure to an intense stressor may, or may not, lead to a stress-induced pathology. Predicting the physiopathological evolution in an individual is therefore an important challenge, at least for prevention. In this context, we developed an ethological model of simulated predator exposure in rats: we call this the multisensorial stress model (MSS). We hypothesized that: (i) MSS exposure can induce stress-induced phenotypes, and (ii) an electrocorticogram (ECoG) recorded before stress exposure can predict phenotypes observed after stress. Methods: Forty-five Sprague Dawley rats were equipped with ECoG telemetry and divided into two groups. The Stress group (n = 23) was exposed to an MSS that combined synthetic fox feces odor deposited on filter paper, synthetic blood odor, and 22 kHz rodent distress calls; the Sham group (n = 22) was not exposed to any sensorial stimulus. Fifteen days after initial exposure, the two groups were re-exposed to a context that included a filter paper soaked with water as a traumatic object (TO) reminder. During this re-exposure, freezing behavior and avoidance of the filter paper were measured. Results: Three behaviors were observed in the Stress group: 39% developed a fear memory phenotype (freezing, avoidance, and hyperreactivity); 26% developed avoidance and anhedonia; and 35% made a full recovery. We also identified pre-stress ECoG biomarkers that accurately predicted cluster membership. Decreased chronic 24 h frontal Low θ relative power was associated with resilience; increased frontal Low θ relative power was associated with fear memory; and decreased parietal ß2 frequency was associated with the avoidant-anhedonic phenotype. Discussion: These predictive biomarkers open the way to preventive medicine for stress-induced diseases.