Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
J Nutr. 2012 Jul;142(7):1329-35. doi: 10.3945/jn.111.155903. Epub 2012 May 30.
Prenatal environmental exposures play a critical role in determining late-life chronic disease susceptibility. However, the mechanisms linking the in utero environment and disease development in the offspring are poorly understood. Recent investigations have confirmed a central pathogenic role of T cell chemokine receptors, particularly C-C chemokine receptor (CCR) 2 and CCR5, in chronic inflammatory conditions. This study was designed to determine the effect of a synthetic prenatal micronutrient supplementation (MS) diet rich in methionine pathway metabolites on the T cell chemokine system in F1 C57Bl/6 mice. Female mice were fed either an MS or control diet 3 wk prior to mating, during pregnancy, and lactation. At 4 wk of age, F1 mice were killed for experiments or were fed the standard NIH-31 diet and allowed to age. Food consumption, maternal weight gain, and litter size were similar in dams fed the control and MS diets. However, the F1 offspring of dams fed the MS diet were smaller in size (P < 0.001). T cells from the MS F1 offspring had global hypermethylation compared with control F1 offspring (P < 0.005), corresponding to lower T cell chemokine receptor expression [CCR2 (P < 0.001), CCR5 (P < 0.001), and C-x-C chemokine receptor 3 (P < 0.01)] and cytokine expression [TNFα (P < 0.05), IL-2 (P < 0.001), and IL-4 (P < 0.01)]. Reduced T cell chemokine receptor gene expression in MS F1 mice was associated with decreased chemotaxis in vitro to C-C chemokine ligand (CCL) 2 and C-X-C chemokine ligand 10 (P < 0.01) and in vivo to CCL2 (P < 0.01). Taken together, the results suggest that epigenetic alteration through prenatal diet manipulation reduces the response to proinflammatory signals in mice.
产前环境暴露在决定晚年慢性疾病易感性方面起着关键作用。然而，将宫内环境与后代疾病发展联系起来的机制还知之甚少。最近的研究证实，T 细胞趋化因子受体，特别是 C-C 趋化因子受体（CCR）2 和 CCR5，在慢性炎症状态中具有核心致病作用。本研究旨在确定富含蛋氨酸途径代谢物的合成产前微量营养素补充（MS）饮食对 F1 C57Bl/6 小鼠 T 细胞趋化因子系统的影响。雌性小鼠在交配前 3 周、怀孕期间和哺乳期接受 MS 或对照饮食喂养。在 4 周龄时，F1 小鼠被处死进行实验，或接受标准 NIH-31 饮食并允许其衰老。与对照组相比，接受 MS 饮食的母鼠的食物消耗、体重增加和产仔数相似。然而，接受 MS 饮食的母鼠的 F1 后代体型较小（P < 0.001）。与对照组 F1 后代相比，MS F1 后代的 T 细胞具有全基因组高甲基化（P < 0.005），对应于 T 细胞趋化因子受体表达降低[CCR2（P < 0.001）、CCR5（P < 0.001）和 C-x-C 趋化因子受体 3（P < 0.01）]和细胞因子表达[TNFα（P < 0.05）、IL-2（P < 0.001）和 IL-4（P < 0.01）]。MS F1 小鼠 T 细胞趋化因子受体基因表达降低与体外对 C-C 趋化因子配体（CCL）2 和 C-X-C 趋化因子配体 10 的趋化性降低（P < 0.01）以及体内对 CCL2 的趋化性降低（P < 0.01）有关。总之，这些结果表明，产前饮食干预通过表观遗传改变降低了小鼠对促炎信号的反应。
