Sex-specific acute and chronic neurotoxicity of acute diisopropylfluorophosphate (DFP)-intoxication in juvenile Sprague-Dawley rats.
Sex-specific acute and chronic neurotoxicity of acute diisopropylfluorophosphate (DFP)-intoxication in juvenile Sprague-Dawley rats.
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DOI：
10.1016/j.crtox.2021.09.002
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发表时间：
2021
影响因子：
3.3
通讯作者：
Lein PJ
中科院分区：
文献类型：
--
作者：
González EA;Calsbeek JJ;Tsai YH;Tang MY;Andrew P;Vu J;Berg EL;Saito NH;Harvey DJ;Supasai S;Gurkoff GG;Silverman JL;Lein PJ
DFP 引起的癫痫发作和神经炎症在男性中比女性更严重。急性 DFP 中毒导致幼年大鼠持续性性别特异性脑损伤。在 DFP 中毒后 1 个月，男女都出现了认知缺陷。急性 DFP 中毒会增加男性海马神经发生，但不会增加女性海马神经发生。小胶质细胞激活可能是 OP 引起的认知缺陷的关键驱动因素。改善针对有机磷（OP）化学威胁剂的医疗对策的临床前工作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重复低水平有机磷暴露的神经毒性。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 天的 Sprague-Dawley 雄性和雌性大鼠暴露于 OP 二异丙基氟磷酸盐（DFP；3.4 mg/kg，s.c.）或等体积的载体（∼80 µL 盐水，s.c.），然后暴露于硫酸阿托品（0.1 mg/kg，i.m.）和解磷定（2-PAM；25 毫克/千克，肌内）。使用行为标准和脑电图 (EEG) 记录评估暴露后前 4 小时内的癫痫发作活动。在暴露后 1 天，测量皮质组织中的乙酰胆碱酯酶 (AChE) 活性，并在暴露后 1、7 和 28 天，收集大脑进行神经病理学分析。 DFP 后 1 个月，对动物的运动能力、学习和记忆以及海马神经发生进行分析。急性 DFP 中毒引发的男性癫痫发作行为比女性更严重，脑电图记录也证实了这一点。 DFP 在男女的许多大脑区域引起显着的神经变性和持续的小胶质细胞激活，但与女性相比，男性星形胶质细胞增生发生得更早，而且更严重。相对于性别匹配的对照组，DFP 男性和女性表现出明显的记忆缺陷。相比之下，急性 DFP 中毒会改变男性海马神经发生，但不会改变女性。这些发现表明，急性 DFP 中毒会引发雌雄幼年大鼠的癫痫发作，但癫痫发作的严重程度因性别而异。一些（但不是全部）慢性神经毒性结果也因性别而异。神经损伤的时空模式表明，在急性有机磷中毒幼年大鼠认知缺陷的发病机制中，小胶质细胞活化可能是比星形胶质细胞增生或神经发生改变更重要的因素。
DFP-induced seizures and neuroinflammation were more severe in males than females. Acute DFP intoxication caused persistent sex-specific brain damage in juvenile rats. Both sexes experienced cognitive deficits at 1 month post-DFP intoxication. Acute DFP intoxication increased hippocampal neurogenesis in males but not females. Microglial activation may be a critical driver of OP-induced cognitive deficits. 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.
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影响因子：
5.8
作者：
ELLMAN, GL;COURTNEY, KD;FEATHERSTONE, RM
通讯作者：
FEATHERSTONE, RM
DOI：
10.1124/jpet.115.230839
发表时间：
2016-03-01
影响因子：
3.5
作者：
Gao, Jie;Naughton, Sean X.;Terry, Alvin V., Jr.
通讯作者：
Terry, Alvin V., Jr.
影响因子：
3.3
作者：
Chudomel, O.;Herman, H.;Galanopoulou, A. S.
通讯作者：
Galanopoulou, A. S.
影响因子：
3.4
作者：
Couillard-Despres, S;Winner, B;Aigner, L
通讯作者：
Aigner, L
影响因子：
7.9
作者：
Comfort N;Re DB
通讯作者：
Re DB