Metabolic Research Laboratories, University of Cambridge, Level 4, Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
Prog Biophys Mol Biol. 2011 Jul;106(1):323-36. doi: 10.1016/j.pbiomolbio.2010.12.005. Epub 2010 Dec 13.
The intrauterine environment is a major contributor to normal physiological growth and development of an individual. Disturbances at this critical time can affect the long-term health of the offspring. Low birth weight individuals have strong correlations with increased susceptibility to type 2 diabetes and cardiovascular disease in later-life. These observations led to the Thrifty Phenotype Hypothesis which suggested that these associations arose because of the response of a growing fetus to a suboptimal environment such as poor nutrition. Animal models have shown that environmentally induced intrauterine growth restriction increases the risk of a variety of diseases later in life. These detrimental features are also observed in high birth weight offspring from mothers who were obese or consumed a high fat diet during gestation. Recent advances in our understanding of the mechanisms underlying this phenomenon have elucidated several potential candidates for the long-term effects of the early environment on the function and metabolism of a cell. These include: (1) Epigenetic alterations (e.g. DNA methylation and histone modifications), which regulate specific gene expression and can be influenced by the environment, both during gestation and early postnatal life and (2) Oxidative stress that changes the balance between reactive oxygen species generation (e.g. through mitochondrial dysfunction) and antioxidant defense capacity. This has permanent effects on cellular ageing such as regulation of telomere length. Further understanding of these processes will help in the development of therapeutic strategies to increase healthspan and reduced the burden of age-associated diseases.
宫内环境是个体正常生理生长和发育的主要因素。在此关键时期受到干扰会影响后代的长期健康。低出生体重个体与 2 型糖尿病和心血管疾病的易感性增加密切相关。这些观察结果导致了节俭表型假说，该假说表明，这些关联是由于生长中的胎儿对不良环境（如营养不良）的反应而产生的。动物模型表明，环境诱导的宫内生长受限会增加多种疾病的风险。在怀孕期间肥胖或摄入高脂肪饮食的母亲所生的高出生体重的后代也观察到了这些有害特征。我们对这一现象背后机制的理解的最新进展阐明了早期环境对细胞功能和代谢的长期影响的几个潜在候选因素。这些包括：（1）表观遗传改变（例如 DNA 甲基化和组蛋白修饰），它们调节特定基因的表达，并且可以受到环境的影响，包括在妊娠期间和出生后的早期，以及（2）氧化应激，改变活性氧物质生成的平衡（例如通过线粒体功能障碍）和抗氧化防御能力。这对细胞衰老产生永久性影响，例如调节端粒长度。进一步了解这些过程将有助于制定治疗策略，以增加健康寿命并减少与年龄相关疾病的负担。
