Comparative developmental neurotoxicity of organophosphate insecticides: effects on brain development are separable from systemic toxicity.
Comparative developmental neurotoxicity of organophosphate insecticides: effects on brain development are separable from systemic toxicity.
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有机磷酸盐杀虫剂的比较发育神经毒性：对脑发育的影响与全身毒性分离。
DOI：
10.1289/ehp.8828
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发表时间：
2006-05
影响因子：
10.4
通讯作者：
Seidler, Frederic J
中科院分区：
文献类型：
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作者：
Slotkin, Theodore A;Levin, Edward D;Seidler, Frederic J
对有机磷酸酯的全身毒性和发育神经毒性之间的差异进行比较的方法对于确定多种毒性机制在此类杀虫剂的不同成员之间的程度至关重要。我们对比了给予不同有机磷酸盐（毒死蜱、二嗪农、对硫磷）的新生大鼠的神经炎生长和胆碱能突触发育，剂量跨越了生长和活力受损的阈值。动物在出生后第1-4天每天通过皮下注射进行治疗，以避免oxon的首过激活或分解代谢为非活性产物的差异。评估在第 5 天进行。对硫磷（最大耐受剂量，0.1 mg/kg）的全身毒性远高于毒死蜱或二嗪磷（最大耐受剂量，1-5 mg/kg）。低于最大耐受剂量，二嗪农会损害前脑和脑干的神经炎生长，表现为膜蛋白与总蛋白比率的缺陷。二嗪农还降低了胆碱乙酰转移酶（一种胆碱能神经元标记物）的活性，而它不影响 hemicholinium-3 与突触前胆碱转运蛋白（胆碱能神经元活性的指标）的结合。没有出现 m2-毒蕈碱乙酰胆碱受体下调，而慢性胆碱能过度刺激会发生这种情况。此前毒死蜱也发现了相同的模式。相比之下，对硫磷在其最大耐受剂量下不会引起任何这些变化。这些结果表明有机磷酸酯的全身毒性与其引发发育神经毒性的倾向之间存在完全的二分法。对硫磷的致死阈值低于对大脑发育产生不利影响所需的阈值，而毒死蜱和二嗪农则相反。
A comparative approach to the differences between systemic toxicity and developmental neurotoxicity of organophosphates is critical to determine the degree to which multiple mechanisms of toxicity carry across different members of this class of insecticides. We contrasted neuritic outgrowth and cholinergic synaptic development in neonatal rats given different organophosphates (chlorpyrifos, diazinon, parathion) at doses spanning the threshold for impaired growth and viability. Animals were treated daily on postnatal days 1–4 by subcutaneous injection so as to bypass differences in first-pass activation to the oxon or catabolism to inactive products. Evaluations occurred on day 5. Parathion (maximum tolerated dose, 0.1 mg/kg) was far more systemically toxic than was chlorpyrifos or diazinon (maximum tolerated dose, 1–5 mg/kg). Below the maximum tolerated dose, diazinon impaired neuritic outgrowth in the forebrain and brainstem, evidenced by a deficit in the ratio of membrane protein to total protein. Diazinon also decreased choline acetyltransferase activity, a cholinergic neuronal marker, whereas it did not affect hemicholinium-3 binding to the presynaptic choline transporter, an index of cholinergic neuronal activity. There was no m2-muscarinic acetylcholine receptor down-regulation, as would have occurred with chronic cholinergic hyper-stimulation. The same pattern was found previously for chlorpyrifos. In contrast, parathion did not elicit any of these changes at its maximum tolerated dose. These results indicate a complete dichotomy between the systemic toxicity of organophosphates and their propensity to elicit developmental neurotoxicity. For parathion, the threshold for lethality lies below that necessary for adverse effects on brain development, whereas the opposite is true for chlorpyrifos and diazinon.