Dose-dependent teratogenicity of the synthetic cannabinoid CP-55,940 in mice
Dose-dependent teratogenicity of the synthetic cannabinoid CP-55,940 in mice
复制标题
DOI：
10.1016/j.ntt.2015.12.004
复制
发表时间：
2016-11-01
影响因子：
2.9
通讯作者：
Parnell, Scott E.
中科院分区：
文献类型：
--
作者：
Gilbert, Marcoita T.;Sulik, Kathleen K.;Parnell, Scott E.
强效合成大麻素（SCB）是非法销售的滥用药物，尽管有不良后果，但仍经常被消费。本研究旨在通过在哺乳动物模型中检查这些SCB之一CP-55，940的发育毒性/致畸性，确定在成人中观察到的毒性是否也延伸至产前。首先，免疫组织化学用于大麻素受体1（CB 1）定位在妊娠第8天（GD）的小鼠胚胎，这种受体被确定在颅神经板，表明内源性大麻素系统可能参与正常发育。根据这些信息和以前的鸟类致畸性研究，目前的调查集中在神经形成期间的大麻素暴露。给药模式包括在妊娠第8天对同期交配的C57 Bl/6 J小鼠急性腹膜内给予溶剂、0.0625、0.125、0.25、0.5、1.0或2.0 mg/kg CP-55，940（每个给药组n > 10窝）。在GD 17，收获窝仔并检查活胎、死胎或吸收胎仔数量以及胎仔体重、身长和大体形态异常。在任何试验的CP-55，940剂量下均未观察到对窝仔数、胎仔体重或头臀长度的影响。在所有药物治疗组中均观察到涉及颅面和/或眼睛的严重畸形。对选定的颅面畸形胎仔进行组织学切片和染色，以研究脑异常。在给药胎仔中观察到的颅面、眼和脑异常包括侧面和正中面裂、腭裂、小眼畸形、虹膜缺损、无眼畸形、露脑畸形、前脑无裂畸形和皮质发育不良。由于最常观察到的缺陷涉及眼睛，因此将容易识别的眼部畸形的发生率和严重程度用作剂量反应分析的基础。眼部畸形评级显示，在测试的全部剂量范围内，CP-55，940具有剂量依赖性致畸性。虽然需要检查额外的关键期和深入的机制研究，但本研究的结果明确显示了该SCB的剂量依赖性致畸性。(C)© 2015 Elsevier Inc版权所有。
Potent synthetic cannabinoids (SCBs) are illegally distributed drugs of abuse that are frequently consumed in spite of their adverse consequences. This study was designed to determine if the toxicity observed in adults also extends to the prenatal period by examining the developmental toxicity/teratogenicity of one of these SCBs, CP-55,940, in a mammalian model. First, immunohistochemistry was employed for cannabinoid receptor 1 (CB1) localization within gestational day (GD) 8 mouse embryos; this receptor was identified in the cranial neural plate, suggesting that the endogenous cannabinoid system may be involved in normal development. Based on this information and on previous avian teratogenicity studies, the current investigation focused on cannabinoid exposure during neurulation. The treatment paradigm involved acute i.p. administration of vehicle, 0.0625, 0.125, 0.25, 0.5,1.0, or 2.0 mg/kg CP-55,940 to time-mated C57Bl/6J mice on their 8th day of pregnancy (n > 10 litters per treatment group). On GD 17, litters were harvested and examined for numbers of live, dead, or resorbed fetuses, as well as for fetal weight, length, and gross morphological abnormalities. No effect on litter size, fetal weight, or crown rump length was seen at any of the CP-55,940 dosages tested. Major malformations involving the craniofacies and/or eyes were noted in all drug-treated groups. Selected fetuses with craniofacial malformations were histologically sectioned and stained, allowing investigation of brain anomalies. Observed craniofacial, ocular, and brain abnormalities in drug-treated fetuses included lateral and median facial clefts, cleft palate, microphthalmia, iridial coloboma, anophthalmia, exencephaly, holoprosencephaly, and cortical dysplasia. With the most commonly observed defects involving the eyes, the incidence and severity of readily identifiable ocular malformations were utilized as a basis for dose response analyses. Ocular malformation ratings revealed dose-dependent CP-55,940 teratogenicity within the full range of dosages tested. While examination of additional critical periods and in depth mechanistic studies is warranted, the results of this investigation dearly show the dose-dependent teratogenicity of this SCB. (C) 2015 Elsevier Inc All rights reserved.