Ramadoss Jayanth, Lunde Emilie R, Piña Kevin B, Chen Wei-Jung A, Cudd Timothy A
Department of Veterinary Physiology and Pharmacology and Michael E DeBakey Institute, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4466, USA.
Alcohol Clin Exp Res. 2007 Jul;31(7):1252-8. doi: 10.1111/j.1530-0277.2007.00422.x. Epub 2007 May 20.
The third trimester equivalent has been identified, both in rat and sheep models, as a period of cerebellar vulnerability to alcohol-mediated injury. We wished to determine whether alcohol exposure throughout gestation results in greater injury compared with exposure limited to the third trimester equivalent. While this question has previously been addressed in the rat model, where the third trimester equivalent occurs postnatally, it has not yet been addressed in an animal model where all 3 trimester equivalents occur prenatally, as in the ovine. We also wished to correlate cerebellar Purkinje cell loss to alcohol-mediated alterations in maternal arterial pH and blood gases as these responses might be important mechanistically in mediating the damage.
Three groups of pregnant sheep were used: an untreated normal control group, a saline control group, and an alcohol group (1.75 g/kg of the body weight). The alcohol exposure regimen was designed to mimic a human binge pattern; alcohol was administered intravenously on 3 consecutive days, followed by 4 days without alcohol, beginning day 4 of gestation, continuing to the end of the third trimester equivalent of human brain growth, day 132 of gestation.
All 3 trimester alcohol-exposed fetal brains exhibited significant deficits in cerebellar volume and Purkinje cell number compared with those of control subjects. We did not detect a difference in the reduction of Purkinje cell number when comparing between all 3 trimester and third trimester alcohol exposure studies. The neuronal loss was accompanied by maternal hypercapnea, acidemia, and normoxemia.
These findings demonstrate in an ovine model where all 3 trimester equivalent of brain growth occur in utero that the fetal cerebellar Purkinje cells are more sensitive to the timing of alcohol exposure and less so to the duration of exposure. Decreases in maternal P(a)O(2) were not detected, suggesting that maternal hypoxia does not play a role in fetal Purkinje cell loss. And finally, we conclude that alcohol-induced changes in maternal arterial pH may play a role in alcohol-mediated developmental brain injury.
在大鼠和绵羊模型中，已确定相当于人类孕晚期的时期是小脑易受酒精介导损伤的阶段。我们想确定与仅限于相当于孕晚期的时期接触酒精相比，整个孕期接触酒精是否会导致更严重的损伤。虽然这个问题之前在大鼠模型中已得到解决，在大鼠模型中相当于孕晚期的阶段发生在出生后，但在像绵羊这样所有相当于三个孕期阶段都发生在产前的动物模型中尚未得到解决。我们还希望将小脑浦肯野细胞的损失与酒精介导的母体动脉pH值和血气变化相关联，因为这些反应在介导损伤的机制中可能很重要。
使用三组怀孕的绵羊：一个未处理的正常对照组、一个生理盐水对照组和一个酒精组（1.75克/千克体重）。酒精暴露方案旨在模拟人类暴饮模式；从妊娠第4天开始，连续3天静脉注射酒精，随后4天不注射酒精，持续到相当于人类脑生长孕晚期结束，即妊娠第132天。
与对照组相比，所有三个孕期阶段暴露于酒精的胎儿大脑在小脑体积和浦肯野细胞数量上均表现出明显缺陷。在比较所有三个孕期阶段和孕晚期酒精暴露研究时，我们未检测到浦肯野细胞数量减少存在差异。神经元损失伴随着母体高碳酸血症、酸血症和正常氧血症。
这些发现在一个所有相当于三个孕期阶段的脑生长都发生在子宫内的绵羊模型中表明，胎儿小脑浦肯野细胞对酒精暴露的时间更敏感，而对暴露持续时间的敏感性较低。未检测到母体P(a)O(2)降低，表明母体缺氧在胎儿浦肯野细胞损失中不起作用。最后，我们得出结论，酒精引起的母体动脉pH值变化可能在酒精介导的发育性脑损伤中起作用。
