改善针对有机磷酸酯(OP)化学威胁剂的医疗对策的临床前努力主要集中在成年男性模型上。然而,年龄和性别已被证明会影响反复低水平OP暴露的神经毒性.因此,为了确定性别和年龄对急性OP中毒相关结局的影响,出生后第28天Sprague-Dawley雄性和雌性大鼠暴露于OP二异丙基氟磷酸盐(DFP;3.4mg/kg,s.c.)或等体积的载体(~80微升盐水,s.c.),然后是硫酸阿托品(0.1mg/kg,i.m.)和普利肟(2-PAM;25mg/kg,i.m.).使用行为标准和脑电图(EEG)记录在暴露后的前4小时内评估癫痫发作活动。在暴露后1d,在皮质组织中测量乙酰胆碱酯酶(AChE)活性,在暴露后1、7和28天,收集大脑进行神经病理学分析.在DFP后1个月,分析动物的运动能力,学习和记忆,和海马神经发生。急性DFP中毒引发男性比女性更严重的癫痫发作行为,这得到了脑电图记录的支持。DFP在两性的许多脑区引起显著的神经变性和持续的小胶质细胞活化,但与女性相比,男性星形胶质增生发生得更早,更严重。相对于性别匹配的对照,DFP男性和女性表现出明显的记忆缺陷。相比之下,急性DFP中毒改变了男性海马神经发生,但不是女性。这些发现表明,急性DFP中毒会引发两性幼年大鼠的癫痫发作,但是癫痫发作的严重程度因性别而异。一些,但不是全部,慢性神经毒性结局也因性别而异。神经损伤的时空模式表明,在急性中毒的幼鼠认知缺陷的发病机理中,小胶质细胞活化可能比星形胶质细胞增生或神经发生改变更重要。
Preclinical efforts to improve medical countermeasures against organophosphate (OP) chemical threat agents have largely focused on adult male models. However, age and sex have been shown to influence the neurotoxicity of repeated low-level OP exposure. Therefore, to determine the influence of sex and age on outcomes associated with acute OP intoxication, postnatal day 28 Sprague-Dawley male and female rats were exposed to the OP diisopropylfluorophosphate (DFP; 3.4 mg/kg, s.c.) or an equal volume of vehicle (∼80 µL saline, s.c.) followed by atropine sulfate (0.1 mg/kg, i.m.) and pralidoxime (2-PAM; 25 mg/kg, i.m.). Seizure activity was assessed during the first 4 h post-exposure using behavioral criteria and electroencephalographic (EEG) recordings. At 1 d post-exposure, acetylcholinesterase (AChE) activity was measured in cortical tissue, and at 1, 7, and 28 d post-exposure, brains were collected for neuropathologic analyses. At 1 month post-DFP, animals were analyzed for motor ability, learning and memory, and hippocampal neurogenesis. Acute DFP intoxication triggered more severe seizure behavior in males than females, which was supported by EEG recordings. DFP caused significant neurodegeneration and persistent microglial activation in numerous brain regions of both sexes, but astrogliosis occurred earlier and was more severe in males compared to females. DFP males and females exhibited pronounced memory deficits relative to sex-matched controls. In contrast, acute DFP intoxication altered hippocampal neurogenesis in males, but not females. These findings demonstrate that acute DFP intoxication triggers seizures in juvenile rats of both sexes, but the seizure severity varies by sex. Some, but not all, chronic neurotoxic outcomes also varied by sex. The spatiotemporal patterns of neurological damage suggest that microglial activation may be a more important factor than astrogliosis or altered neurogenesis in the pathogenesis of cognitive deficits in juvenile rats acutely intoxicated with OPs.