Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA; David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA; Friends Research Institute, Cerritos, CA, USA.
J Neurosci Methods. 2019 Oct 1;326:108376. doi: 10.1016/j.jneumeth.2019.108376. Epub 2019 Jul 27.
Electronic cigarettes (E-cig) use is increasing rapidly, particularly among youths. Animal models for E-cig exposure with pharmacokinetics resembling human E-cig users are lacking. We developed an E-cig aerosol exposure system for rodents and a chronic intermittent delivery method that simulates E-cig users who vape episodically during wakefulness and abstain during sleep. Mice were exposed to E-cig in a programmed schedule at very low, low, medium, or high doses defined by duration of each puff, number of puffs per delivery episode and frequency of episodes in the dark phase of a 12/12-h circadian cycle for 9 consecutive days. The plasma nicotine/cotinine levels and their time courses were determined using LC/MS-MS. We assessed the body weight, food intake and locomotor activity of Apolipoprotein E null (ApoE-/-) mice exposed to chronic intermittent E-cig aerosol. Plasma nicotine and cotinine levels were positively correlated with exposure doses. Nicotine and cotinine levels showed a circadian variation as they increased with time up to the maximum nicotine level of 21.8 ± 7.1 ng/mL during the daily intermittent E-cig exposure in the 12-h dark phase and then declined during the light phase when there was no E-cig delivery. Chronic E-cig exposure to ApoE-/- mice decreased body weight, food intake and increased locomotion. Our rodent E-cig exposure system and chronic intermittent exposure method yield clinically relevant nicotine pharmacokinetics associated with behavioral and metabolic changes. The methodologies are essential tools for in vivo studies of the health impacts of E-cig exposure on CNS, cardiovascular, pulmonary, hepatic systems, metabolism and carcinogenesis.
电子烟（E-cig）的使用正在迅速增加，尤其是在年轻人中。缺乏与人类 E-cig 用户相似的药代动力学的 E-cig 暴露动物模型。我们开发了一种用于啮齿动物的 E-cig 气溶胶暴露系统和一种慢性间歇性给药方法，该方法模拟了在清醒期间间歇性吸烟且在睡眠期间不吸烟的 E-cig 用户。通过在 12/12 小时昼夜节律的黑暗阶段中以编程方式按非常低、低、中或高剂量（通过每次抽吸的持续时间、每个输送段的抽吸次数和段的频率来定义）连续 9 天对小鼠进行 E-cig 暴露。使用 LC/MS-MS 确定血浆尼古丁/可替宁水平及其时间过程。我们评估了在慢性间歇性 E-cig 气溶胶暴露下的载脂蛋白 E 缺失（ApoE-/-）小鼠的体重、食物摄入量和运动活动。血浆尼古丁和可替宁水平与暴露剂量呈正相关。尼古丁和可替宁水平呈昼夜节律变化，随着时间的增加而增加，在 12 小时黑暗期内每天间歇性 E-cig 暴露的最大尼古丁水平达到 21.8±7.1ng/mL，然后在没有 E-cig 输送的光期下降。慢性 E-cig 暴露会降低 ApoE-/-小鼠的体重、食物摄入量并增加运动。我们的啮齿动物 E-cig 暴露系统和慢性间歇性暴露方法产生了与 CNS、心血管、肺部、肝脏系统、代谢和致癌作用的健康影响相关的临床相关尼古丁药代动力学。这些方法是研究 E-cig 暴露对 CNS、心血管、肺部、肝脏系统、代谢和致癌作用的健康影响的体内研究的重要工具。
