Department of Molecular and Biochemical Pharmacology, University of Kentucky College of Medicine, 132 Health Sciences Research Building, 1095 Veterans Drive, Lexington, KY, 40536, USA.
Metab Brain Dis. 2013 Dec;28(4):667-76. doi: 10.1007/s11011-013-9430-2. Epub 2013 Aug 27.
Fetal alcohol spectrum disorders (FASD) results from ethanol exposure to the developing fetus and is the leading cause of mental retardation. FASD is associated with a broad range of neurobehavioral deficits which may be mediated by ethanol-induced neurodegeneration in the developing brain. An immature brain is more susceptible to ethanol neurotoxicity. We hypothesize that the enhanced sensitivity of the immature brain to ethanol is due to a limited capacity to alleviate cellular stress. Using a third trimester equivalent mouse model of ethanol exposure, we demonstrated that subcutaneous injection of ethanol induced a wide-spread neuroapoptosis in postnatal day 4 (PD4) C57BL/6 mice, but had little effect on the brain of PD12 mice. We analyzed the expression profile of genes regulating apoptosis, and the pathways of ER stress response (also known as unfolded protein response, UPR) and autophagy during these ethanol-sensitive and resistant periods (PD4 versus PD12) using PCR microarray. The expression of pro-apoptotic genes, such as caspase-3, was much higher on PD4 than PD12; in contrast, the expression of genes that regulate UPR and autophagy, such as atf6, atg4, atg9, atg10, beclin1, bnip3, cebpb, ctsb, ctsd, ctss, grp78, ire1α, lamp, lc3 perk, pik3c3, and sqstm1 was significantly higher on PD12 than PD4. These results suggest that the vulnerability of the immature brain to ethanol could result from high expression of pro-apoptotic proteins and a deficiency in the stress responsive system, such as UPR and autophagy.
胎儿酒精谱系障碍（FASD）是由乙醇对发育中的胎儿的暴露引起的，是智力迟钝的主要原因。FASD 与广泛的神经行为缺陷有关，这些缺陷可能是由发育中的大脑中乙醇引起的神经退行性变介导的。未成熟的大脑对乙醇神经毒性更敏感。我们假设，未成熟大脑对乙醇的敏感性增加是由于其缓解细胞应激的能力有限。使用相当于人类妊娠晚期的小鼠乙醇暴露模型，我们证明了皮下注射乙醇会在出生后第 4 天（PD4）C57BL/6 小鼠中引起广泛的神经细胞凋亡，但对 PD12 小鼠的大脑几乎没有影响。我们分析了在这些对乙醇敏感和耐受的时期（PD4 与 PD12）中调节细胞凋亡的基因的表达谱，以及内质网应激反应（也称为未折叠蛋白反应，UPR）和自噬的途径。促凋亡基因，如 caspase-3 的表达在 PD4 时比 PD12 时高得多；相反，调节 UPR 和自噬的基因，如 atf6、atg4、atg9、atg10、beclin1、bnip3、cepbp、ctsb、ctsd、ctss、grp78、ire1α、lamp、lc3 perk、pik3c3 和 sqstm1 的表达在 PD12 时比 PD4 时高得多。这些结果表明，未成熟大脑对乙醇的易感性可能是由于促凋亡蛋白的高表达和应激反应系统（如 UPR 和自噬）的缺乏所致。
