Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany.
Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilian-University Munich, Goethestraße 33, 80336, Munich, Germany.
Arch Toxicol. 2018 Jan;92(1):337-346. doi: 10.1007/s00204-017-2064-0. Epub 2017 Sep 20.
The chemical agent sulfur mustard (SM) causes erythema, skin blisters, ulcerations, and delayed wound healing. It is accepted that the underlying molecular toxicology is based on DNA alkylation. With an expected delay, DNA damage causes impairment of protein biosynthesis and disturbance of cell division. However, using the cockroach model Blaptica dubia, the presented results show that alkylating compounds provoke immediate behavior responses along with fast changes in the electrical field potential (EFP) of neurons, suggesting that lesions of DNA are probably not the only effect of alkylating compounds. Blaptica dubia was challenged with SM or 2-chloroethyl-ethyl sulfide (CEES). Acute toxicity was objectified by a disability score. Physiological behavior responses (antennae pullback reflex, escape attempts, and grooming) were monitored after exposure. To estimate the impact of alkylating agents on neuronal activity, EFP recordings of the antennae and the thoracic ganglion were performed. After contact to neat SM, a pullback reflex of the antennae was the first observation. Subsequently, a striking escape behavior occured which was characterized by persistent movement of the legs. In addition, an instantaneous processing of the electrical firing pattern from the antennae to the descending ganglia was detectable. Remarkably, comparing the toxicity of the applied alkylating agents, effects induced by CEES were much more pronounced compared to SM. In summary, our findings document immediate effects of B. dubia after exposure to alkylating substances. These fast responses cannot be interpreted as a consequence of DNA alkylation. Therefore, the dogma that DNA alkylation is the exclusive cause for SM toxicity has to be questioned.
化学战剂芥子气（SM）会引起红斑、水疱、溃疡和延迟愈合。人们普遍认为，其潜在的分子毒理学基础是基于 DNA 烷化。预计会有延迟，DNA 损伤会导致蛋白质生物合成受损和细胞分裂紊乱。然而，使用蟑螂模型 Blaptica dubia，呈现的结果表明，烷化化合物会立即引起行为反应，同时神经元的电场电位（EFP）发生快速变化，这表明 DNA 损伤可能不是烷化化合物的唯一作用。用 SM 或 2-氯乙基-乙基硫醚（CEES）对 Blaptica dubia 进行了挑战。通过残疾评分来客观地评价急性毒性。暴露后监测生理行为反应（触角回缩反射、逃避尝试和梳理）。为了评估烷化剂对神经元活性的影响，对触角和胸神经节进行了 EFP 记录。接触纯 SM 后，首先观察到触角回缩反射。随后，出现了明显的逃避行为，其特征是腿部持续运动。此外，还可以检测到触角到下行神经节的电活动模式的瞬时处理。值得注意的是，与应用的烷化剂的毒性相比，CEES 引起的作用要明显得多。总之，我们的研究结果记录了 B. dubia 在接触烷化物质后立即产生的影响。这些快速反应不能解释为 DNA 烷化的后果。因此，DNA 烷化是 SM 毒性的唯一原因的观点必须受到质疑。
