Locomotor and sensorimotor performance deficit in rats following exposure to pyridostigmine bromide, DEET, and permethrin, alone and in combination
Locomotor and sensorimotor performance deficit in rats following exposure to pyridostigmine bromide, DEET, and permethrin, alone and in combination
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DOI：
10.1093/toxsci/60.2.305
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发表时间：
2001-04-01
影响因子：
3.8
通讯作者：
Khan, WA
中科院分区：
文献类型：
--
作者：
Abou-Donia, MB;Goldstein, LB;Khan, WA
自从他们从波斯湾战争（PGW）返回以来，许多退伍军人抱怨症状包括肌肉和关节疼痛，共济失调，慢性疲劳，头痛和注意力难以集中。症状的原因仍然未知。由于这些退伍军人接触了溴化吡斯的明（PB）、避蚊胺和氯菊酯等化学物质的组合，我们研究了这些药物单独和组合对大鼠感觉运动行为和中枢胆碱能系统的影响。雄性Sprague-Dawley大鼠（200-250 gm）接受避蚊胺（40 mg/kg，经皮）或氯菊酯（0.13 mg/kg，经皮）单独治疗，以及与PB（1.3 mg/kg，口服，仅持续15天）联合治疗，持续45天。在治疗后第30天和第45天，通过一系列行为测试评估感觉运动能力，这些测试包括横梁行走评分、横梁行走时间、斜面性能和前爪抓握。在第45天处死动物，评价血浆和CNS胆碱酯酶、脑胆碱乙酰转移酶、毒蕈碱和烟碱乙酰胆碱受体。与对照组相比，PB单独或与避蚊胺和氯菊酯联合治疗的动物在梁行走评分和梁行走时间方面表现出显着不足。无论是避蚊胺或氯菊酯，单独或相互结合，治疗没有显着影响梁步行评分。所有化学品，单独或组合，导致在治疗后第30天和第45天的斜面测试中的显著损害。PB，避蚊胺，或氯菊酯单独治疗没有任何抑制作用，血浆或脑胆碱酯酶的活动，除了PB单独引起中度抑制中脑乙酰胆碱酯酶（AChE）的活性。氯菊酯单独治疗引起皮质和小脑AChE活性显着增加。避蚊胺和氯菊酯或PB和避蚊胺的组合导致脑干和中脑和脑干AChE活性显着下降。脑干AChE活性显着下降，观察到PB和氯菊酯联合暴露后。PB、DEET和氯菊酯共暴露导致脑干和中脑AChE显著抑制。没有观察到对脑干或皮层胆碱乙酰转移酶活性的影响，除了联合暴露于PB，避蚊胺，和氯菊酯引起皮质胆碱乙酰转移酶活性轻微但显着增加。PB，避蚊胺，和氯菊酯单独治疗引起的M2毒蕈碱乙酰胆碱受体（mAChR）在皮质中的配体结合显着增加。共暴露PB，避蚊胺，氯菊酯没有任何影响超过PB诱导的配体结合增加。有没有显着的变化，烟碱乙酰胆碱受体（nAChR）的配体结合与单独的化学治疗;结合PB和避蚊胺或与PB，避蚊胺，氯菊酯共暴露引起了显着增加nAChR配体结合在皮质。因此，这些结果表明，暴露于生理相关剂量的PB，避蚊胺，和氯菊酯，单独或组合，导致神经行为缺陷和区域特异性改变乙酰胆碱酯酶和乙酰胆碱受体。
Since their return from Persian Gulf War (PGW), many veterans have complained of symptoms including muscle and joint pain, ataxia, chronic fatigue, headache, and difficulty with concentration. The causes of the symptoms remain unknown. Because these veterans were exposed to a combination of chemicals including pyridostigmine bromide (PB), DEET, and permethrin, we investigated the effects of these agents, alone and in combination, on the sensorimotor behavior and central cholinergic system of rats. Male Sprague-Dawley rats (200-250 gm) were treated with DEET (40 mg/kg, dermal) or permethrin (0.13 mg/kg, dermal), alone and in combination with PB (1.3 mg/kg, oral, last 15 days only), for 45 days. Sensorimotor ability was assessed by a battery of behavioral tests that included beam-walk score, beam-walk time, incline plane performance, and forepaw grip on days 30 and 45 following the treatment. On day 45 the animals were sacrificed, and plasma and CNS cholinesterase, and brain choline acetyl transferase, muscarinic and nicotinic acetylcholine receptors were evaluated. Animals treated with PB, alone or in combination with DEET and permethrin, showed a significant deficit in beam-walk score as well as beam-walk time as compared with controls. Treatment with either DEET or permethrin, alone or in combination with each other, did not have a significant effect on beam-walk score. All chemicals, alone or in combination, resulted in a significant impairment in incline plane testing on days 30 and 45 following treatment. Treatment with PB, DEET, or permethrin alone did not have any inhibitory effect on plasma or brain cholinesterase activities, except that PB alone caused moderate inhibition in midbrain acetylcholinesterase (AChE) activity. Treatment with permethrin alone caused significant increase in cortical and cerebellar AChE activity. A combination of DEET and permethrin or PB and DEET led to significant decrease in AChE activity in brainstem and midbrain and brainstem, respectively. A significant decrease in brainstem AChE activity was observed following combined exposure to PB and permethrin. Coexposure with PB, DEET, and permethrin resulted in significant inhibition in AChE in brainstem and midbrain. No effect was observed on choline acetyl transferase activity in brainstem or cortex, except combined exposure to PB, DEET, and permethrin caused a slight but significant increase in cortical choline acetyltransferase activity. Treatment with PB, DEET, and permethrin alone caused a significant increase in ligand binding for m2 muscarinic acetylcholine receptor (mAChR) in the cortex. Coexposure to PB, DEET, and permethrin did not have any effect over that of PB-induced increase in ligand binding. There was no significant change in ligand binding for nicotinic acetylcholine receptor (nAChR) associated with treatment with the chemical alone; a combination of PB and DEET or coexposure with PB, DEET, and permethrin caused a significant increase in nAChR ligand binding in the cortex. Thus, these results suggest that exposure to physiologically relevant doses of PB, DEET, and permethrin, alone or in combination, leads to neurobehavioral deficits and region-specific alterations in AChE and acetylcholine receptors.