Gillis Rob F, Palmour Roberta M
Department of Human Genetics, McGill University, Montreal, Canada.
Department of Psychiatry, McGill University, Montreal, Canada.
J Neurodev Disord. 2022 Mar 19;14(1):21. doi: 10.1186/s11689-022-09427-z.
Fetal alcohol spectrum disorders (FASD) are common, yet preventable developmental disorders that stem from prenatal exposure to alcohol. This exposure leads to a wide array of behavioural and physical problems with a complex and poorly defined biological basis. Molecular investigations to date predominantly use rodent animal models, but because of genetic, developmental and social behavioral similarity, primate models are more relevant. We previously reported reduced cortical and hippocampal neuron levels in an Old World monkey (Chlorocebus sabaeus) model with ethanol exposure targeted to the period of rapid synaptogenesis and report here an initial molecular study of this model. The goal of this study was to evaluate mRNA expression of the hippocampus at two different behavioural stages (5 months, 2 years) corresponding to human infancy and early childhood.
Offspring of alcohol-preferring or control dams drank a maximum of 3.5 g ethanol per kg body weight or calorically matched sucrose solution 4 days per week during the last 2 months of gestation. Total mRNA expression was measured with the Affymetrix GeneChip Rhesus Macaque Genome Array in a 2 × 2 study design that interrogated two independent variables, age at sacrifice, and alcohol consumption during gestation.
Statistical analysis identified a preferential downregulation of expression when interrogating the factor 'alcohol' with a balanced effect of upregulation vs. downregulation for the independent variable 'age'. Functional exploration of both independent variables shows that the alcohol consumption factor generates broad functional annotation clusters that likely implicate a role for epigenetics in the observed differential expression, while the variable age reliably produced functional annotation clusters predominantly related to development. Furthermore, our data reveals a novel connection between EFNB1 and the FASDs; this is highly plausible both due to the role of EFNB1 in neuronal development as well as its central role in craniofrontal nasal syndrome (CFNS). Fold changes for key genes were subsequently confirmed via qRT-PCR.
Prenatal alcohol exposure leads to global downregulation in mRNA expression. The cellular interference model of EFNB1 provides a potential clue regarding how genetically susceptible individuals may develop the phenotypic triad generally associated with classic fetal alcohol syndrome.
胎儿酒精谱系障碍（FASD）是常见但可预防的发育障碍，源于孕期接触酒精。这种接触会导致一系列行为和身体问题，其生物学基础复杂且定义不明确。迄今为止的分子研究主要使用啮齿动物模型，但由于遗传、发育和社会行为的相似性，灵长类动物模型更具相关性。我们之前报道过，在一个将乙醇暴露靶向快速突触发生期的旧世界猴（绿猴）模型中，皮质和海马神经元水平降低，在此报告该模型的初步分子研究。本研究的目的是评估在对应人类婴儿期和幼儿期的两个不同行为阶段（5个月、2岁）海马体的mRNA表达。
在妊娠的最后2个月，偏好酒精的母猴或对照母猴的后代每周4天饮用每千克体重最多3.5克乙醇或热量匹配的蔗糖溶液。在一个2×2研究设计中，使用Affymetrix基因芯片恒河猴基因组阵列测量总mRNA表达，该设计探究了两个独立变量，即处死时的年龄和孕期酒精摄入量。
统计分析表明，在探究“酒精”因素时，表达存在优先下调，而独立变量“年龄”的上调与下调作用平衡。对两个独立变量的功能探索表明，酒精摄入因素产生了广泛的功能注释簇，这可能意味着表观遗传学在观察到的差异表达中起作用，而变量年龄可靠地产生了主要与发育相关的功能注释簇。此外，我们的数据揭示了EFNB1与FASD之间的新联系；这非常合理，因为EFNB1在神经元发育中的作用以及它在颅额鼻综合征（CFNS）中的核心作用。关键基因的倍数变化随后通过qRT-PCR得到证实。
孕期酒精暴露导致mRNA表达整体下调。EFNB1的细胞干扰模型为遗传易感性个体如何发展出通常与经典胎儿酒精综合征相关的表型三联征提供了一个潜在线索。
