Moser V C, Padilla S
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Toxicol Appl Pharmacol. 1998 Mar;149(1):107-19. doi: 10.1006/taap.1997.8354.
It is well known that young animals are generally more sensitive to lethal effects of cholinesterase-inhibiting pesticides, but there are sparse data comparing less-than-lethal effects. We compared the behavioral and biochemical toxicity of chlorpyrifos in young (postnatal Day 17; PND17) and adult (about 70 days old) rats. First, we established that the magnitude of the age-related differences decreased as the rat matures. Next, we evaluated the time course of a single oral dose of chlorpyrifos in adult and PND17 male and female rats. Behavioral changes were assessed using a functional observational battery (with age-appropriate modifications for pre-weanling rats) and an evaluation of motor activity. Cholinesterase (ChE) activity was measured in brain and peripheral tissues and muscarinic receptor binding assays were conducted on selected tissues. Rats received either vehicle (corn oil) or chlorpyrifos (adult dose: 80 mg/kg; PND17 dose: 15 mg/kg); these doses were equally effective in inhibiting ChE. The rats were tested, and tissues were then taken at 1, 2, 3.5, 6.5, 24, 72, 168, or 336 h after dosing. In adult rats, peak behavioral changes and ChE inhibition occurred in males at 3.5 h after dosing, while in females the onset of functional changes was sooner, the time course was more protracted and recovery was slower. In PND17 rats, maximal behavioral effects and ChE inhibition occurred at 6.5 h after dosing, and there were no gender-related differences. Behavioral changes showed partial to full recovery at 24 to 72 h, whereas ChE inhibition recovered markedly slower. Blood and brain ChE activity in young rats had nearly recovered by 1 week after dosing, whereas brain ChE in adults had not recovered at 2 weeks. Muscarinic-receptor binding assays revealed apparent down-regulation in some brain areas, mostly at 24 and 72 h. PND17 rats generally showed more receptor down-regulation than adults, whereas only adult female rats showed receptor changes in striatal tissue that persisted for 2 weeks. Thus, compared to adults (1) PND17 rats show similar behavioral changes and ChE inhibition although at a five-fold lower dose; (2) the onset of maximal effects is somewhat delayed in the young rats; (3) ChE activity tended to recover more quickly in the young rats; (4) young rats appear to have more extensive muscarinic receptor down-regulation, and (5) young rats show no gender-related differences.
众所周知，幼龄动物通常对胆碱酯酶抑制性农药的致死效应更为敏感，但比较非致死效应的数据却很稀少。我们比较了毒死蜱对幼龄（出生后第17天；PND17）和成年（约70日龄）大鼠的行为和生化毒性。首先，我们确定随着大鼠成熟，与年龄相关的差异幅度会减小。接下来，我们评估了成年和PND17雄性及雌性大鼠单次口服毒死蜱后的时间进程。使用功能观察组合（对断奶前大鼠进行适合其年龄的修改）和运动活动评估来评估行为变化。在脑和外周组织中测量胆碱酯酶（ChE）活性，并在选定组织上进行毒蕈碱受体结合测定。大鼠接受溶剂（玉米油）或毒死蜱（成年剂量：80 mg/kg；PND17剂量：15 mg/kg）；这些剂量在抑制ChE方面同样有效。对大鼠进行测试，然后在给药后1、2、3.5、6.5、24、72、168或336小时采集组织。在成年大鼠中，雄性大鼠在给药后3.5小时出现行为变化和ChE抑制的峰值，而雌性大鼠功能变化的开始时间更早，时间进程更长且恢复更慢。在PND17大鼠中，最大行为效应和ChE抑制在给药后6.5小时出现，且无性别相关差异。行为变化在24至72小时显示部分至完全恢复，而ChE抑制的恢复明显较慢。幼龄大鼠的血液和脑ChE活性在给药后1周时几乎已恢复，而成年大鼠的脑ChE在2周时仍未恢复。毒蕈碱受体结合测定显示在一些脑区有明显的下调，主要在24和72小时。PND17大鼠通常比成年大鼠表现出更多的受体下调，而只有成年雌性大鼠在纹状体组织中显示出持续2周的受体变化。因此，与成年大鼠相比，（1）PND17大鼠表现出相似的行为变化和ChE抑制，尽管剂量低五倍；（2）幼龄大鼠最大效应的出现稍有延迟；（3）幼龄大鼠的ChE活性倾向于恢复得更快；（4）幼龄大鼠似乎有更广泛的毒蕈碱受体下调，并且（5）幼龄大鼠未显示出性别相关差异。
