Low paternal dietary folate alters the sperm epigenome and is associated with negative pregnancy outcomes

We hypothesized that the availability of folate, a soluble B vitamin, would alter the levels of DNA methylation in spermatogenesis with consequences for the sperm epigenome and pregnancy outcomes. We fed male mice with either a folate-deficient or a folate-sufficient diet throughout life. Males fed the folate-deficient diet had offspring with increased birth defects, which included craniofacial and musculoskeletal malformations. These phenotypes corresponded to developmental genes with altered methylation in sperm. To determine if there was transmission of epigenetic effects from sires to offspring, global gene expression levels were assessed in placenta from 18.5 dpc fetuses sired by either a folate-sufficient or folate-deficient male. Gene expression was measured in placenta of 18.5 dpc fetuses sired by either a folate sufficient male (n=4 placentas from different litters and different fathers) or a folate deficient (FD) male (n=4 placentas from different litters and different fathers).

我们提出假说：可溶性B族维生素叶酸（folate）的可获得性，可改变精子发生过程中的DNA甲基化（DNA methylation）水平，进而对精子表观基因组（epigenome）与妊娠结局产生影响。本研究让雄性小鼠终生饲喂叶酸缺乏膳食或叶酸充足膳食。结果显示，饲喂叶酸缺乏膳食的雄性小鼠，其后代的出生缺陷发生率显著升高，此类缺陷涵盖颅面畸形与肌肉骨骼畸形。上述表型与精子中甲基化水平发生改变的发育相关基因存在对应关系。为明确表观遗传效应是否可由父本传递给后代，我们对18.5天交配后天数（days post coitum, dpc）胎鼠的胎盘组织开展了全局基因表达水平检测，这些胎鼠分别由饲喂叶酸充足膳食的雄性小鼠，以及饲喂叶酸缺乏（FD）膳食的雄性小鼠所生育。我们分别检测了由叶酸充足雄性亲本（n=4，样本取自不同胎仔与不同父本的胎盘）、叶酸缺乏（FD）雄性亲本（n=4，样本取自不同胎仔与不同父本的胎盘）所生育的18.5 dpc胎鼠的胎盘基因表达水平。