Department of Molecular Biosciences.
Department of Anatomy, Physiology, and Cell Biology, University of California, Davis, California 95616.
Toxicol Sci. 2018 Sep 1;165(1):244-253. doi: 10.1093/toxsci/kfy158.
Occupational and environmental exposures to organophosphorus pesticides (OPs) are associated with increased incidence of asthma and other pulmonary diseases. Although the canonical mechanism of OP neurotoxicity is inhibition of acetylcholinesterase (AChE), it was previously reported that the OP chlorpyrifos (CPF) causes airway hyperreactivity (AHR) in guinea pigs at levels that do not inhibit lung or brain AChE. The guinea pig is considered to have inherently hyperresponsive airways, thus, cross-species validation is needed to confirm relevance to humans. Additionally, sex differences in asthma incidence have been demonstrated in the human population, but whether OP-induced AHR is sex-dependent has not been systematically studied in a preclinical model. In this study, 8-week old male and female Sprague Dawley rats were administered CPF at doses causing comparable AChE inhibition in whole lung homogenate (30 mg/kg in males, 7 mg/kg in females, sc) prior to assessing pulmonary mechanics in response to electrical stimulation of the vagus nerves at 24 h, 48 h, 72 h, 7 d or 14 d post-exposure in males, and 24 h or 7 d post-exposure in females. CPF significantly potentiated vagally induced airway resistance and tissue elastance at 7 d post-exposure in males, and at 24 h and 7 d post-exposure in females. These effects occurred independent of significant AChE inhibition in cerebellum, blood, trachealis, or isolated airway, suggesting that AChE independent OP-induced airway hyperreactivity is a cross-species phenomenon. These findings have significant implications for assessing the risk posed by CPF, and potentially other OPs, to human health and safety.
职业和环境暴露于有机磷农药（OPs）与哮喘和其他肺部疾病发病率的增加有关。尽管 OP 神经毒性的典型机制是抑制乙酰胆碱酯酶（AChE），但先前有报道称，OP 毒死蜱（CPF）在不抑制肺或脑 AChE 的水平下会引起豚鼠气道高反应性（AHR）。豚鼠被认为具有固有高反应性的气道，因此需要进行跨物种验证以确认与人类的相关性。此外，在人类人群中已经证明了哮喘发病率的性别差异，但 OP 诱导的 AHR 是否具有性别依赖性尚未在临床前模型中进行系统研究。在这项研究中，8 周龄雄性和雌性 Sprague Dawley 大鼠在暴露前给予 CPF，剂量导致全肺匀浆中 AChE 抑制相当（雄性 30mg/kg，雌性 7mg/kg，sc），然后在暴露后 24、48、72、7 或 14 小时，以及雄性暴露后 7 天，评估对迷走神经电刺激的肺力学反应，并在雌性暴露后 24 或 7 小时进行评估。CPF 在暴露后 7 天显著增强了雄性的迷走神经诱导气道阻力和组织弹性，在暴露后 24 小时和 7 天也增强了雌性的迷走神经诱导气道阻力和组织弹性。这些作用发生在小脑、血液、气管和离体气道中的 AChE 抑制不显著的情况下，表明 AChE 非依赖性 OP 诱导的气道高反应性是一种跨物种现象。这些发现对评估 CPF 以及可能其他 OPs 对人类健康和安全构成的风险具有重要意义。
