Liu J, Olivier K, Pope C N
College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe, Louisiana, 71209, USA.
Toxicol Appl Pharmacol. 1999 Jul 15;158(2):186-96. doi: 10.1006/taap.1999.8693.
Several studies have reported higher sensitivity based on lethality in young animals compared to adults following acute exposure to organophosphorus insecticides (OPs). We propose that age-related differences in sensitivity to OPs may differ qualitatively and quantitatively with different OPs and varying exposure conditions (e. g., high vs. low dose, acute vs. repeated). To test this hypothesis, we treated neonatal (7 days of age) and adult (90 days of age) rats with either methyl parathion (MPS) or chlorpyrifos (CPF) daily for 14 days and measured neurochemical endpoints {cholinesterase (ChE) inhibition, total muscarinic receptor ([(3)H]quinuclidinyl benzilate, QNB) and muscarinic M2 subtype-preferential ([(3)H]AF-DX 384) binding} in frontal cortex and striatum at timepoints both during (1 day after the 7(th) and 14(th) dose) and after (8 days after the 14(th) dose) exposures. Repeated CPF exposures were associated with relatively similar degrees of ChE inhibition between the age groups during dosing but more extensive inhibition was noted in adults after termination of exposures. Relatively similar changes in muscarinic receptor binding were also noted between age groups following CPF exposures. Moreover, the degree of muscarinic receptor binding reduction relative to ChE inhibition appeared similar in both age groups following CPF exposures. In contrast, ChE activity and muscarinic receptor binding were generally more reduced in neonatal relative to adult brain regions following repeated MPS exposures. Furthermore, the relationship between the degree of ChE inhibition and the reduction in cortical muscarinic receptor binding appeared different between the age groups, i.e., more extensive reduction was noted in neonates compared to adults with a given level of ChE inhibition. We conclude that OP-selective differences in in vivo ChE sensitivity, differential rates of enzyme recovery following inhibition, and age-dependent differences in muscarinic receptor adaptations can all influence the nature of age-related susceptibility to OPs.
多项研究报告称，与成年动物相比，幼龄动物急性接触有机磷杀虫剂（OPs）后基于致死率的敏感性更高。我们提出，对OPs敏感性的年龄相关差异可能在质量和数量上因不同的OPs和不同的暴露条件（例如，高剂量与低剂量、急性与重复暴露）而有所不同。为了验证这一假设，我们对新生（7日龄）和成年（90日龄）大鼠每日给予甲基对硫磷（MPS）或毒死蜱（CPF），持续14天，并在暴露期间（第7次和第14次给药后1天）和暴露后（第14次给药后8天）的时间点测量额叶皮质和纹状体中的神经化学终点指标{胆碱酯酶（ChE）抑制、总毒蕈碱受体（[³H]喹核醇基苯甲酸酯，QNB）和毒蕈碱M2亚型优先结合（[³H]AF-DX 384）}。重复给予CPF暴露期间，各年龄组之间的ChE抑制程度相对相似，但在暴露终止后，成年大鼠的ChE抑制更为广泛。CPF暴露后，各年龄组之间毒蕈碱受体结合的变化也相对相似。此外，CPF暴露后，两个年龄组中毒蕈碱受体结合减少程度相对于ChE抑制的程度似乎相似。相比之下，重复给予MPS暴露后，新生大鼠脑区的ChE活性和毒蕈碱受体结合通常比成年大鼠减少得更多。此外，ChE抑制程度与皮质毒蕈碱受体结合减少之间的关系在各年龄组之间似乎有所不同，即在给定的ChE抑制水平下，新生大鼠的减少程度比成年大鼠更广泛。我们得出结论，体内ChE敏感性的OP选择性差异、抑制后酶恢复的不同速率以及毒蕈碱受体适应性的年龄依赖性差异，都可能影响与年龄相关的对OPs易感性的性质。
