Panchenko Polina E, Voisin Sarah, Jouin Mélanie, Jouneau Luc, Prézelin Audrey, Lecoutre Simon, Breton Christophe, Jammes Hélène, Junien Claudine, Gabory Anne
UMR BDR, INRA, ENVA, Université Paris Saclay, 78350 Jouy en Josas, France ; Ecole Doctorale 394 "Physiologie, physiopathologie et thérapeutique", Université Pierre et Marie Curie, 75252 Paris, France.
UMR BDR, INRA, ENVA, Université Paris Saclay, 78350 Jouy en Josas, France.
Clin Epigenetics. 2016 Feb 27;8:22. doi: 10.1186/s13148-016-0188-3. eCollection 2016.
Maternal obesity impacts fetal growth and pregnancy outcomes. To counteract the deleterious effects of obesity on fertility and pregnancy issue, preconceptional weight loss is recommended to obese women. Whether this weight loss is beneficial/detrimental for offspring remains poorly explored. Epigenetic mechanisms could be affected by maternal weight changes, perturbing expression of key developmental genes in the placenta or fetus. Our aim was to investigate the effects of chronic maternal obesity on feto-placental growth along with the underlying epigenetic mechanisms. We also tested whether preconceptional weight loss could alleviate these effects.
Female mice were fed either a control diet (CTRL group), a high-fat diet (obese (OB) group), or a high-fat diet switched to a control diet 2 months before conception (weight loss (WL) group). At mating, OB females presented an obese phenotype while WL females normalized metabolic parameters. At embryonic day 18.5 (E18.5), fetuses from OB females presented fetal growth restriction (FGR; -13 %) and 28 % of the fetuses were small for gestational age (SGA). Fetuses from WL females normalized this phenotype. The expression of 60 epigenetic machinery genes and 32 metabolic genes was measured in the fetal liver, placental labyrinth, and junctional zone. We revealed 23 genes altered by maternal weight trajectories in at least one of three tissues. The fetal liver and placental labyrinth were more responsive to maternal obesity than junctional zone. One third (18/60) of the epigenetic machinery genes were differentially expressed between at least two maternal groups. Interestingly, genes involved in the histone acetylation pathway were particularly altered (13/18). In OB group, lysine acetyltransferases and Bromodomain-containing protein 2 were upregulated, while most histone deacetylases were downregulated. In WL group, the expression of only a subset of these genes was normalized.
This study highlights the high sensitivity of the epigenetic machinery gene expression, and particularly the histone acetylation pathway, to maternal obesity. These obesity-induced transcriptional changes could alter the placental and the hepatic epigenome, leading to FGR. Preconceptional weight loss appears beneficial to fetal growth, but some effects of previous obesity were retained in offspring phenotype.
母体肥胖会影响胎儿生长和妊娠结局。为了抵消肥胖对生育和妊娠问题的有害影响，建议肥胖女性在孕前减肥。这种体重减轻对后代是有益还是有害，目前仍未得到充分研究。表观遗传机制可能会受到母体体重变化的影响，从而干扰胎盘或胎儿中关键发育基因的表达。我们的目的是研究慢性母体肥胖对胎儿-胎盘生长的影响以及潜在的表观遗传机制。我们还测试了孕前减肥是否可以减轻这些影响。
给雌性小鼠喂食对照饮食（CTRL组）、高脂饮食（肥胖（OB）组）或在受孕前2个月改为对照饮食的高脂饮食（体重减轻（WL）组）。交配时，OB组雌性小鼠呈现肥胖表型，而WL组雌性小鼠的代谢参数恢复正常。在胚胎第18.5天（E18.5），OB组雌性小鼠的胎儿出现胎儿生长受限（FGR；-13%），28%的胎儿小于胎龄（SGA）。WL组雌性小鼠的胎儿使这种表型恢复正常。在胎儿肝脏、胎盘迷路和交界区测量了60个表观遗传机制基因和32个代谢基因的表达。我们发现至少在三个组织之一中，有23个基因因母体体重轨迹而发生改变。胎儿肝脏和胎盘迷路对母体肥胖的反应比交界区更敏感。三分之一（18/60）的表观遗传机制基因在至少两个母体组之间存在差异表达。有趣的是，参与组蛋白乙酰化途径的基因尤其发生了改变（13/18）。在OB组中，赖氨酸乙酰转移酶和含溴结构域蛋白2上调，而大多数组蛋白去乙酰化酶下调。在WL组中，这些基因中只有一部分的表达恢复正常。
本研究强调了表观遗传机制基因表达，特别是组蛋白乙酰化途径，对母体肥胖的高度敏感性。这些肥胖诱导的转录变化可能会改变胎盘和肝脏的表观基因组，导致FGR。孕前减肥似乎对胎儿生长有益，但先前肥胖的一些影响在后代表型中仍然存在。
