a Department of Veterinary Physiology & Pharmacology, College of Veterinary Medicine and Biomedical Sciences , Texas A&M University , College Station , Texas , USA.
Epigenetics. 2017;12(10):841-853. doi: 10.1080/15592294.2017.1363952. Epub 2017 Dec 7.
The preconception environment is a significant modifier of dysgenesis and the development of environmentally-induced disease. To date, fetal alcohol spectrum disorders (FASDs) have been exclusively associated with maternal exposures, yet emerging evidence suggests male-inherited alterations in the developmental program of sperm may be relevant to the growth-restriction phenotypes of this condition. Using a mouse model of voluntary consumption, we find chronic preconception male ethanol exposure associates with fetal growth restriction, decreased placental efficiency, abnormalities in cholesterol trafficking, sex-specific alterations in the genetic pathways regulating hepatic fibrosis, and disruptions in the regulation of imprinted genes. Alterations in the DNA methylation profiles of imprinted loci have been identified in clinical studies of alcoholic sperm, suggesting the legacy of paternal drinking may transmit via heritable disruptions in the regulation of imprinted genes. However, the capacity of sperm-inherited changes in DNA methylation to broadly transmit environmentally-induced phenotypes remains unconfirmed. Using bisulphite mutagenesis and second-generation deep sequencing, we find no evidence to suggest that these phenotypes or any of the associated transcriptional changes are linked to alterations in the sperm-inherited DNA methylation profile. These observations are consistent with recent studies examining the male transmission of diet-induced phenotypes and emphasize the importance of epigenetic mechanisms of paternal inheritance beyond DNA methylation. This study challenges the singular importance of maternal alcohol exposures and suggests paternal alcohol abuse is a significant, yet overlooked epidemiological factor complicit in the genesis of alcohol-induced growth defects, and may provide mechanistic insight into the failure of FASD children to thrive postnatally.
孕前环境是发育异常和环境诱导疾病发展的重要修饰因子。迄今为止，胎儿酒精谱系障碍（FASD）仅与母体暴露有关，但新出现的证据表明，精子发育程序中的男性遗传改变可能与这种疾病的生长受限表型有关。使用自愿摄入的小鼠模型，我们发现慢性孕前雄性乙醇暴露与胎儿生长受限、胎盘效率降低、胆固醇转运异常、调节肝纤维化的遗传途径的性别特异性改变以及印迹基因调节的中断有关。在酒精性精子的临床研究中已经发现印迹基因座的 DNA 甲基化谱的改变，这表明父亲饮酒的遗传可能通过印迹基因调节的遗传破坏来传递。然而，精子遗传的 DNA 甲基化变化是否具有广泛传递环境诱导表型的能力仍未得到证实。使用亚硫酸氢盐诱变和第二代深度测序，我们没有发现证据表明这些表型或任何相关的转录变化与精子遗传的 DNA 甲基化谱的改变有关。这些观察结果与最近研究饮食诱导表型的雄性传播一致，并强调了除 DNA 甲基化之外，父系遗传的表观遗传机制的重要性。这项研究挑战了母体酒精暴露的单一重要性，并表明父亲酒精滥用是酒精引起的生长缺陷产生的一个重要但被忽视的流行病学因素，并可能为 FASD 儿童出生后不能茁壮成长提供机制上的见解。
