The brainstem represents a major tissue area affected by
sarin organophosphate poisoning due to its function in respiratory and cardiovascular control. While the acute toxic effects of
sarin on brainstem-related responses are relatively unknown, other brain areas e.g., cortex or cerebellum, have been studied more extensively. The study objective was to analyze the guinea pig brainstem toxicology response following
sarin (2×LD50) exposure by
proteome pathway analysis to gain insight into the complex regulatory mechanisms that lead to impairment of respiratory and cardiovascular control. Guinea pig exposure to
sarin resulted in the typical acute behavior/physiology outcomes with death between 15 and 25min. In addition, brain and blood
acetylcholinesterase activity was significantly reduced in the presence of
sarin to 95%, and 89%, respectively, of control values. Isobaric-tagged (iTRAQ) liquid chromatography tandem mass spectrometry (LC-MS/MS) identified 198 total
proteins of which 23% were upregulated, and 18% were downregulated following
sarin exposure. Direct gene ontology (GO) analysis revealed a
sarin-specific broad-spectrum proteomic profile including
glutamate-mediated excitotoxicity,
calcium overload, energy depletion responses, and compensatory carbohydrate metabolism, increases in ROS defense, DNA damage and chromatin remodeling, HSP response, targeted protein degradation (ubiquitination) and cell death response. With regards to the
sarin-dependent effect on respiration, our study supports the potential interference of
sarin with CO2/H(+) sensitive chemoreceptor neurons of the brainstem retrotrapezoid nucleus (RTN) that send excitatory glutamergic projections to the respiratory centers. In conclusion, this study gives insight into the brainstem broad-spectrum
proteome following acute
sarin exposure and the gained information will assist in the development of novel countermeasures.