Liyanage Vichithra R B, Curtis Kyle, Zachariah Robby M, Chudley Albert E, Rastegar Mojgan
Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba, R3E 0J9, Canada.
Curr Top Med Chem. 2017;17(7):808-828. doi: 10.2174/1568026616666160414124816.
Prenatal alcohol (ethanol) exposure (PAE) is the underlying cause for a variety of birth defects and neurodevelopmental deficits referred to as "Fetal Alcohol Spectrum Disorders (FASD)". The more visible phenotypes caused by PAE include growth retardation, and characteristic craniofacial abnormalities associated with functional and structural damage to the central nervous system. Ethanol is a teratogenic agent itself; but it can also alter gene expression. These changes may contribute to the spectrum of effects and different phenotypes that are dependent on alcohol metabolism, as well as the timing and duration of alcohol exposure. Evidence from both human patients and animal models show that genetic factors and epigenetic mechanisms such as DNA methylation, histone post-translational modifications and noncoding RNAs, contribute to the gene expression changes caused by ethanol. Not all embryos that are exposed to alcohol during development exhibit FASD symptoms after birth. FASD patients may present severe birth defects, while others are normal in physical appearance but present a variety of cognitive and behavioral difficulties. It has been hypothesized that maternal and paternal genetic factors may contribute to the sensitivity, resistance or vulnerability of the fetus to alcohol. Moreover, the epigenome is highly sensitive to a multitude of environmental insults including PAE. Studies also show 'transgenerational' effects of alcohol. In such cases, maternal or paternal preconception alcohol consumption could lead to FASD-like phenotypes in the newborn. Thus, the phenotypes in FASD can be modified by interplay between maternal/paternal genetic factors and epigenetic mechanisms. This current review summarizes the contribution of genetic and epigenetic mechanisms in FASD pathobiology, and how this information could be utilized for prevention, early diagnosis and potentially treatment of the affected individuals.
产前酒精（乙醇）暴露（PAE）是导致各种出生缺陷和神经发育缺陷的根本原因，这些缺陷被称为“胎儿酒精谱系障碍（FASD）”。PAE导致的更明显的表型包括生长发育迟缓，以及与中枢神经系统功能和结构损伤相关的特征性颅面异常。乙醇本身就是一种致畸剂；但它也可以改变基因表达。这些变化可能导致一系列依赖于酒精代谢以及酒精暴露时间和持续时间的效应和不同表型。来自人类患者和动物模型的证据表明，遗传因素和表观遗传机制，如DNA甲基化、组蛋白翻译后修饰和非编码RNA，促成了乙醇引起的基因表达变化。并非所有在发育过程中暴露于酒精的胚胎出生后都会出现FASD症状。FASD患者可能出现严重的出生缺陷，而其他患者外观正常，但存在各种认知和行为困难。据推测，母体和父体遗传因素可能导致胎儿对酒精的敏感性、抵抗力或易感性。此外，表观基因组对包括PAE在内的多种环境损伤高度敏感。研究还表明酒精存在“跨代”效应。在这种情况下，母体或父体孕前饮酒可能导致新生儿出现类似FASD的表型。因此，FASD中的表型可以通过母体/父体遗传因素与表观遗传机制之间的相互作用来改变。本综述总结了遗传和表观遗传机制在FASD病理生物学中的作用，以及如何利用这些信息对受影响个体进行预防、早期诊断和潜在治疗。
