DNA methylation-independent growth restriction and altered developmental programming in a mouse model of preconception male alcohol exposure
DNA methylation-independent growth restriction and altered developmental programming in a mouse model of preconception male alcohol exposure
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DOI：
10.1080/15592294.2017.1363952
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发表时间：
2017-01-01
期刊：
影响因子：
3.7
通讯作者：
Golding, Michael C.
中科院分区：
文献类型：
--
作者：
Chang, Richard C.;Skiles, William M.;Golding, Michael C.
孕前环境是发育不良和环境诱发疾病发展的重要调节因素。到目前为止，胎儿酒精谱系障碍（FASD）已经完全与母亲的暴露，但新出现的证据表明，男性遗传的精子发育程序的改变可能与这种情况的生长限制表型。使用自愿消费的小鼠模型，我们发现慢性孕前男性乙醇暴露与胎儿生长受限，胎盘效率降低，胆固醇运输异常，调节肝纤维化的遗传途径的性别特异性改变，以及印记基因调节的破坏有关。在酒精精子的临床研究中，已经发现了印记基因座DNA甲基化谱的改变，这表明父亲饮酒的遗产可能通过印记基因调控中的遗传性破坏来传播。然而，精子遗传的DNA甲基化改变广泛传播环境诱导的表型的能力仍然没有得到证实。使用亚硫酸氢盐诱变和第二代深度测序，我们没有发现任何证据表明这些表型或任何相关的转录变化与精子遗传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男性传播一致，并强调了DNA甲基化以外的父系遗传表观遗传机制的重要性。这项研究挑战了母亲酒精暴露的独特重要性，并表明父亲酒精滥用是一个重要的，但被忽视的流行病学因素，在酒精诱导的生长缺陷的成因同谋，并可能提供机制的洞察力失败FASD儿童茁壮成长出生后。
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.