Zabala Valerie, Silbermann Elizabeth, Re Edward, Andreani Tomas, Tong Ming, Ramirez Teresa, Gundogan Fusun, de la Monte Suzanne M
Molecular Pharmacology and Physiology Graduate Program, Brown University, Providence, RI, USA.
Department of Neurology, Washington University, St. Louis, MO, USA.
Gynecol Obstet Res. 2016 Apr;2(5):112-125. doi: 10.17140/GOROJ-2-125. Epub 2016 Mar 15.
Cerebellar developmental abnormalities in Fetal Alcohol Spectrum Disorder (FASD) are linked to impairments in insulin signaling. However, co-morbid alcohol and tobacco abuses during pregnancy are common. Since smoking leads to tobacco specific Nitrosamine (NNK) exposures which have been shown to cause brain insulin resistance, we hypothesized that neurodevelopmental abnormalities in FASD could be mediated by ethanol and/or NNK.
Long Evans rat pups were intraperitoneal (IP) administered ethanol (2 g/kg) on postnatal days (P) 2, 4, 6 and/or NNK (2 mg/kg) on P3, P5, and P7 to simulate third trimester human exposures. The Cerebellar function, histology, insulin and Insulin-like Growth Factor (IGF) signaling, and neuroglial protein expression were assessed.
Ethanol, NNK and ethanol+NNK groups had significant impairments in motor function (rotarod tests), abnormalities in cerebellar structure (Purkinje cell loss, simplification and irregularity of folia, and altered white matter), signaling through the insulin and IGF-1 receptors, IRS-1, Akt and GSK-3β, and reduced expression of several important neuroglial proteins. Despite similar functional effects, the mechanisms and severity of NNK and ethanol+NNK induced alterations in cerebellar protein expression differed from those of ethanol.
Ethanol and NNK exert independent but overlapping adverse effects on cerebellar development, function, insulin signaling through cell survival, plasticity, metabolic pathways, and neuroglial protein expression. The results support the hypothesis that tobacco smoke exposure can serve as a co-factor mediating long-term effects on brain structure and function in FASD.
胎儿酒精谱系障碍（FASD）中的小脑发育异常与胰岛素信号传导受损有关。然而，孕期同时滥用酒精和烟草的情况很常见。由于吸烟会导致接触烟草特有的亚硝胺（NNK），而NNK已被证明会导致脑胰岛素抵抗，我们推测FASD中的神经发育异常可能由乙醇和/或NNK介导。
对Long Evans大鼠幼崽在出生后第2、4、6天腹腔注射乙醇（2 g/kg），和/或在出生后第3、5、7天腹腔注射NNK（2 mg/kg），以模拟人类孕期第三个月的接触情况。评估小脑功能、组织学、胰岛素和胰岛素样生长因子（IGF）信号传导以及神经胶质蛋白表达。
乙醇组、NNK组和乙醇+NNK组在运动功能（转棒试验）方面有显著损伤，小脑结构存在异常（浦肯野细胞丢失、小叶简化和不规则以及白质改变），胰岛素和IGF-1受体、IRS-1、Akt和GSK-3β的信号传导异常，并且几种重要神经胶质蛋白的表达降低。尽管功能效应相似，但NNK和乙醇+NNK诱导的小脑蛋白表达改变的机制和严重程度与乙醇不同。
乙醇和NNK对小脑发育、功能、通过细胞存活、可塑性、代谢途径和神经胶质蛋白表达的胰岛素信号传导产生独立但重叠的不利影响。结果支持以下假设：接触烟草烟雾可作为一个辅助因素，介导对FASD脑结构和功能的长期影响。
