Levin Edward D, Addy Nii, Baruah Avanti, Elias Alana, Christopher N Channelle, Seidler Frederic J, Slotkin Theodore A
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Neurotoxicol Teratol. 2002 Nov-Dec;24(6):733-41. doi: 10.1016/s0892-0362(02)00272-6.
Use of chlorpyrifos (CPF) has been curtailed due to its developmental neurotoxicity. In rats, postnatal CPF administration produces lasting changes in cognitive performance, but less information is available about the effects of prenatal exposure. We administered CPF to pregnant rats on gestational days (GD) 17-20, a peak period of neurogenesis, using doses (1 or 5 mg/kg/day) below the threshold for fetal growth impairment. We then evaluated performance in the T-maze, Figure-8 apparatus and 16-arm radial maze, beginning in adolescence and continuing into adulthood. CPF elicited initial locomotor hyperactivity in the T-maze. Females showed slower habituation in the Fig. 8 maze; no effects were seen in males. In the radial-arm maze, females showed impaired choice accuracy for both working and reference memory and again, males were unaffected. Despite the deficits, all animals eventually learned the maze with continued training. At that point, we challenged them with the muscarinic antagonist, scopolamine, to determine the dependence of behavioral performance on cholinergic function. Whereas control females showed impairment with scopolamine, CPF-exposed females did not, implying that the delayed acquisition of the task had been accomplished through alternative mechanisms. The differences were specific to muscarinic circuits, as control and CPF groups responded similarly to the nicotinic antagonist, mecamylamine. Surprisingly, adverse effects of CPF were greater in the group receiving 1 mg/kg as compared to 5 mg/kg. Promotional effects of acetylcholine (ACh) on cell differentiation may thus help to offset CPF-induced developmental damage that occurs through other noncholinergic mechanisms. Our results indicate that late prenatal exposure to CPF induces long-term changes in cognitive performance that are distinctly gender-selective. Additional defects may be revealed by similar strategies that subject the animals to acute challenges, thus, uncovering the adaptive mechanisms that maintain basal performance.
由于毒死蜱（CPF）具有发育神经毒性，其使用已受到限制。在大鼠中，出生后给予CPF会导致认知能力产生持久变化，但关于产前接触CPF影响的信息较少。我们在神经发生的高峰期，即妊娠第17 - 20天，给怀孕大鼠施用CPF，使用的剂量（1或5毫克/千克/天）低于胎儿生长受损阈值。然后，我们从青春期开始并持续到成年期，评估大鼠在T型迷宫、8字形装置和16臂放射状迷宫中的表现。CPF在T型迷宫中引发了最初的运动性多动。雌性在8字形迷宫中表现出较慢的习惯化；雄性未见影响。在放射状臂迷宫中，雌性在工作记忆和参考记忆方面的选择准确性受损，同样，雄性未受影响。尽管存在缺陷，但所有动物最终通过持续训练学会了迷宫。此时，我们用毒蕈碱拮抗剂东莨菪碱对它们进行挑战，以确定行为表现对胆碱能功能的依赖性。对照雌性大鼠在给予东莨菪碱后表现出功能受损，而接触CPF的雌性大鼠则没有，这意味着任务的延迟习得是通过其他机制完成的。这些差异特定于毒蕈碱回路，因为对照和CPF组对烟碱拮抗剂美加明的反应相似。令人惊讶的是，与5毫克/千克组相比，接受1毫克/千克组的CPF不良反应更大。因此，乙酰胆碱（ACh）对细胞分化的促进作用可能有助于抵消通过其他非胆碱能机制发生的CPF诱导的发育损伤。我们的结果表明，产前晚期接触CPF会诱导认知能力产生长期变化，且这种变化具有明显的性别选择性。通过使动物接受急性挑战的类似策略可能会揭示其他缺陷，从而揭示维持基础表现的适应性机制。
