Lipton J W, Robie H C, Ling Z, Weese-Mayer D E, Carvey P M
Department of Pediatrics, Rush Medical College of Rush University, Rush Children's Hospital, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL, USA.
Neurotoxicol Teratol. 1998 Jul-Aug;20(4):373-82. doi: 10.1016/s0892-0362(97)00143-8.
Cocaine's teratogenicity remains equivocal in the literature. The variance in cocaine-induced teratogenic data led us to consider that the intrauterine exposure to cocaine is not homogeneous and that sampling methods presently utilized in the literature lead to inconsistent results. Cocaine's vasoconstrictive actions, in concert with regional variance in the uterine milieu of the rodent, were postulated to differentially reduce the distribution of cocaine to fetal brains as a function of uterine position. Fetuses in positions with the highest levels of cocaine exposure were also hypothesized to have the most pronounced deficits in whole brain dopamine (DA). The results indicated that whole brain cocaine levels vary significantly in relation to a fetus' position in the uterine horn following a single SC injection of 30 mg/kg cocaine HCI as measured by GC/MS. Brains of fetuses from the most proximal uterine position (in relation to the cervix) received an average of 329% of the cocaine of fetuses from the most distal uterine position, whereas no such relationship existed for amniotic fluid cocaine levels. Following exposure to cocaine from embryonic days 7 to 21, brain DA levels were significantly reduced in distal fetuses relative to proximal fetuses and to distal controls. Contrary to the initial hypothesis, the results indicated that the magnitude of cocaine exposure was inversely related to the magnitude of DA reduction. Based upon findings in the literature related to the uterine gradient of placental progesterone distribution in the rat, cocaine's ability to lower brain DA levels was attributed primarily to its vasoconstrictive actions. Recommendations on how to statistically treat littermates, when foreknowledge of uterine position exists, are discussed.
可卡因的致畸性在文献中仍不明确。可卡因诱导的致畸数据存在差异，这使我们认为子宫内接触可卡因的情况并非均匀一致，且目前文献中使用的采样方法导致结果不一致。可卡因的血管收缩作用，与啮齿动物子宫环境的区域差异共同作用，被推测会根据子宫位置不同而使可卡因向胎儿大脑的分布有差异地减少。还假设处于可卡因暴露水平最高位置的胎儿，其全脑多巴胺（DA）的缺陷最为明显。结果表明，单次皮下注射30mg/kg盐酸可卡因后，通过气相色谱/质谱法测量发现，全脑可卡因水平与胎儿在子宫角中的位置显著相关。来自子宫最近端位置（相对于子宫颈）的胎儿大脑所接受的可卡因量平均是来自最远端位置胎儿的329%，而羊水可卡因水平不存在这种关系。在胚胎第7天至21天暴露于可卡因后，相对于近端胎儿和远端对照组，远端胎儿的脑DA水平显著降低。与最初的假设相反，结果表明可卡因暴露程度与DA降低程度呈负相关。基于与大鼠胎盘孕酮分布的子宫梯度相关的文献研究结果，可卡因降低脑DA水平的能力主要归因于其血管收缩作用。本文还讨论了在已知子宫位置的情况下，如何对同窝幼崽进行统计学处理的建议。
