Moser V C, Chanda S M, Mortensen S R, Padilla S
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 1998 Dec;46(2):211-22. doi: 10.1006/toxs.1998.2526.
Young rats are more sensitive than adults to a single oral dose of chlorpyrifos, an organophosphorus pesticide. A direct comparison of chlorpyrifos effects in young (postnatal day 17; PND17), adolescent (PND27), and adult (70 days) Long-Evans rats was conducted to determine quantitative and possibly qualitative differences in sensitivity in terms of behavioral changes and cholinesterase (ChE; total cholinesterase activity) inhibition at these three ages. Male and female rats were administered chlorpyrifos orally at one of two doses (PND17, 5 or 20 mg/kg; PND27, 20 or 50 mg/kg; adult, 20 or 80 mg/kg) and tested at either 3.5 or 6.5 h after dosing. Behavioral testing included observational evaluations and measurements of motor activity and was followed immediately by tissue collection for ChE determination in brain and blood. For both behavioral changes and ChE inhibition, peak effects occurred at 3.5 h in adult male and PND27 rats (both sexes) and at 6.5 h in adult female and PND17 rats (both sexes). Comparisons of the 20 mg/kg dose across ages showed generally less ChE inhibition and fewer behavioral effects with increasing age, except that the adult females were similar to the PND27 rats. The high dose used for each age group produced similar brain ChE inhibition (80-90%) and generally similar behavioral effects. Interestingly, a few end-points in the young rats were less affected than in adults at this level of ChE inhibition. The degree of ChE inhibition in the brain more closely paralleled the blood inhibition in the younger rats, compared to the adults. Carboxylesterase (CaE) and A-esterase are known to play an important role in the detoxification of organophosphates and may be partially responsible for these sensitivity differences. Liver and plasma CaE and A-esterase activities were measured in untreated male rats on PND1, 4, 7, 12, 17, and 21 and in adults of both sexes (82-92 days old). Preweanling rats had considerably less activity of both enzymes, and adult females had less liver CaE activity than males. These differences in detoxifying enzymes correlate with the age-related differences in behavioral and biochemical effects, as well as the gender differences seen in adult rats, and thus may be a major influence on the differential sensitivity to chlorpyrifos.
幼鼠对单剂量口服毒死蜱（一种有机磷农药）比成年鼠更敏感。对幼龄（出生后第17天；PND17）、青春期（PND27）和成年（70天）的Long-Evans大鼠进行了毒死蜱效应的直接比较，以确定这三个年龄段在行为变化和胆碱酯酶（ChE；总胆碱酯酶活性）抑制方面敏感性的定量差异以及可能的定性差异。雄性和雌性大鼠分别以两种剂量之一口服毒死蜱（PND17，5或20mg/kg；PND27，20或50mg/kg；成年鼠，20或80mg/kg），并在给药后3.5或6.5小时进行测试。行为测试包括观察评估和运动活动测量，随后立即采集组织以测定脑和血中的ChE。对于行为变化和ChE抑制，成年雄性和PND27大鼠（两性）在3.5小时出现峰值效应，成年雌性和PND17大鼠（两性）在6.5小时出现峰值效应。对各年龄段20mg/kg剂量的比较表明，随着年龄增长，ChE抑制作用总体上较小，行为效应也较少，但成年雌性与PND27大鼠相似。每个年龄组使用的高剂量产生相似的脑ChE抑制（80 - 90%）和总体相似的行为效应。有趣的是，在这种ChE抑制水平下，幼鼠的一些终点指标受影响程度比成年鼠小。与成年鼠相比，幼鼠脑中ChE抑制程度与血中抑制程度更密切相关。已知羧酸酯酶（CaE）和A酯酶在有机磷解毒中起重要作用，可能部分导致了这些敏感性差异。在PND1、4、7、12、17和21日龄的未处理雄性大鼠以及成年两性大鼠（82 - 92日龄）中测量了肝脏和血浆CaE及A酯酶活性。断奶前大鼠这两种酶的活性都相当低，成年雌性大鼠肝脏CaE活性低于雄性大鼠。这些解毒酶的差异与行为和生化效应的年龄相关差异以及成年大鼠中观察到的性别差异相关，因此可能是对毒死蜱敏感性差异的主要影响因素。
