Master Jordanna S, Thouas George A, Harvey Alexandra J, Sheedy John R, Hannan Natalie J, Gardner David K, Wlodek Mary E
Departments of Physiology and.
Zoology, The University of Melbourne, Parkville, Australia; and.
J Nutr. 2015 May;145(5):876-83. doi: 10.3945/jn.114.205724. Epub 2015 Mar 25.
Low birth weight is associated with increased risk of adult cardiovascular and metabolic disease development, with recent studies highlighting transmission to subsequent generations via both maternal and paternal lines. However, the timing of parent-specific programming of disease risk to the next generation remains to be characterized.
The aim of this study was to examine how paternal low birth weight affects the cellular and molecular physiology of the next-generation [second-generation (F2)] blastocysts, before uterine implantation.
Uteroplacental insufficiency was surgically induced in Wistar Kyoto pregnant rats in late gestation, giving rise to first-generation restricted (born small) and sham-operated control (normal birth weight) male offspring, respectively. First-generation restricted and control male rats were naturally mated with normal females.
Resultant F2 blastocysts derived from restricted males displayed reduced expression of growth regulatory genes of the mammalian target of rapamycin pathway compared with F2 control blastocysts (9-74%; P < 0.05). No differences were found in F2 restricted blastocyst structural characteristics, cell number, or carbohydrate utilization at the time of blastocyst retrieval or after 24 h of in vitro culture. However, histidine, methionine, pyruvate, serine, and tryosine consumption and aspartate and leucine production were greater in F2 restricted outgrowth than in controls (P < 0.05).
The findings from this study clearly indicate that male rat offspring born small, arising from uteroplacental insufficiency, have physiologic alterations that manifest as modifications in gene expression levels and nutrient metabolism of F2 blastocysts, even in the absence of overt cellular growth differences. These data demonstrate that growth restriction and associated disease risk have the capacity to be transmitted to the next generation of offspring via the male germ line and is manifest as early as the blastocyst stage of development.
低出生体重与成年后心血管疾病和代谢性疾病发生风险增加相关，近期研究强调了其可通过母系和父系遗传给后代。然而，亲代特异性疾病风险编程至下一代的时间仍有待明确。
本研究旨在探讨父系低出生体重如何在子宫着床前影响下一代[第二代（F2）]囊胚的细胞和分子生理学。
在妊娠晚期通过手术诱导Wistar Kyoto孕鼠发生子宫胎盘功能不全，分别产生第一代受限（出生体重低）和假手术对照（正常出生体重）雄性后代。第一代受限和对照雄性大鼠与正常雌性大鼠自然交配。
与F2对照囊胚相比，来自受限雄性的F2囊胚中雷帕霉素靶蛋白通路的生长调节基因表达降低（9 - 74%；P < 0.05）。在囊胚获取时或体外培养24小时后，F2受限囊胚的结构特征、细胞数量或碳水化合物利用方面未发现差异。然而，F2受限囊胚体外生长时组氨酸、蛋氨酸、丙酮酸、丝氨酸和酪氨酸的消耗以及天冬氨酸和亮氨酸的产生均高于对照组（P < 0.05）。
本研究结果清楚地表明，由子宫胎盘功能不全导致出生体重低的雄性大鼠后代存在生理改变，表现为F2囊胚基因表达水平和营养代谢的改变，即使在没有明显细胞生长差异的情况下也是如此。这些数据表明，生长受限及相关疾病风险能够通过雄性生殖系传递给下一代后代，并且早在囊胚发育阶段就已显现。
