Abstract：
Increased consumption of folic acid is prevalent due to its beneficial effects, but growing evidence emphasizes the side effects pointing to excessive dietary folate intake. The effects of excessive paternal folic acid consumption on offspring and its transgenerational inheritance mechanism have not been elucidated. We hypothesize that excessive folic acid consumption will alter sperm DNA N6-methyladenine (6mA) and 5-methylcytosine (5mC) methylation and heritably influence offspring metabolic homeostasis. Here, we fed roosters either folic acid-control or folic acid-excess diet throughout life. Paternal chronic folic acid excessive supplementation increased hepatic lipogenesis and lipid accumulation but reduced lipolysis both in the roosters and their offspring, which was further confirmed to be induced by one-carbon metabolism inhibition and gene expression alteration associated with the Peroxisome proliferator-activated receptor pathway. Based on the spermatozoal genome-wide DNA methylome identified by Nanopore sequencing, multi-omics association analysis of spermatozoal and hepatic DNA methylome, transcriptome, and metabolome suggested that differential spermatozoal DNA 6mA and 5mC methylation could be involved in regulating lipid metabolism-related gene expression in offspring chickens. This model suggests that sperm DNA N6-methyladenine and 5-methylcytosine methylation were involved in epigenetic transmission and that paternal dietary excess folic acid leads to hepatic lipid accumulation in offspring.
摘要：
由于其有益作用，叶酸的消费增加是普遍的，但是越来越多的证据强调了过量摄入叶酸的副作用。父系过量摄入叶酸对后代的影响及其跨代遗传机制尚未阐明。我们假设过量的叶酸消耗会改变精子DNAN6-甲基腺嘌呤（6mA）和5-甲基胞嘧啶（5mC）甲基化，并影响后代代谢稳态。这里,我们一生都在喂公鸡叶酸控制或叶酸过量饮食。父系慢性叶酸过量补充增加了公鸡及其后代的肝脏脂肪生成和脂质积累，但减少了脂解。这被进一步证实是由与过氧化物酶体增殖物激活受体途径相关的单碳代谢抑制和基因表达改变引起的。基于通过纳米孔测序鉴定的精子全基因组DNA甲基化，精子和肝脏DNA甲基化的多组学关联分析，转录组，和代谢组表明，差异精子DNA6mA和5mC甲基化可能参与调节子代鸡脂代谢相关基因的表达。该模型表明，精子DNAN6-甲基腺嘌呤和5-甲基胞嘧啶甲基化与表观遗传传递有关，并且父本饮食中过量的叶酸会导致后代肝脏脂质积累。
