Desai M, Hales C N
Department of Clinical Biochemistry, University of Cambridge.
Biol Rev Camb Philos Soc. 1997 May;72(2):329-48. doi: 10.1017/s0006323196005026.
Fetal growth and development is dependent upon the nutritional, hormonal and metabolic environment provided by the mother. Any disturbance in this environment can modify early fetal development with possible long-term outcomes as demonstrated by extensive work on 'programming'. Growth restriction resulting from a deficit in tissue/organ cell number (as measured by tissue DNA content) is irrecoverable. However, when the cell size (or cell protein content) is reduced, the effects on growth may not be permanent. Recent epidemiological studies using archival records of anthropometric measurements related to early growth in humans have shown strong statistical associations between these indices of early development and diseases in later life. It has been hypothesised that the processes explaining these associations involve adaptive changes in fetal organ development in response to maternal and fetal malnutrition. These adaptations may permanently alter adult metabolism in a way which is beneficial to survival under continued conditions of malnutrition but detrimental when nutrition is abundant. This hypothesis is being tested in a rat model which involves studying the growth and metabolism in the offspring of rat dams fed a low-protein diet during pregnancy and/or lactation. Using this rat model, it has been demonstrated that there is: (i) Permanent growth retardation in offspring nursed by dams fed a low-protein diet. (ii) Permanent and selective changes in organ growth. Essential organs like the brain and lungs are relatively protected from reduction in growth at the expense of visceral organs such as the liver, pancreas, muscle and spleen. (iii) Programming of liver metabolism as reflected by permanent changes in activities of key hepatic enzymes of glycolysis and gluconeogenesis (glucokinase and phosphoenolpyruvate carboxykinase) in a direction which would potentially bias the liver towards a 'starved' setting. We have speculated that these changes could be a result of altered periportal and perivenous regions of the liver which may also affect other aspects of hepatic function. (iv) Deterioration in glucose tolerance with age. (v) An increase in the life span of offspring exposed to maternal protein restriction only during the lactation period, and a decrease in life span when exposed to maternal protein restriction only during gestation. These studies show that hepatic metabolism and even longevity can be programmed by events during early life.
胎儿的生长发育依赖于母亲提供的营养、激素和代谢环境。正如大量关于“编程”的研究所表明的，这种环境中的任何干扰都可能改变胎儿早期发育，并可能产生长期后果。由组织/器官细胞数量不足（通过组织DNA含量测量）导致的生长受限是不可恢复的。然而，当细胞大小（或细胞蛋白质含量）减小时，对生长的影响可能不是永久性的。最近利用与人类早期生长相关的人体测量档案记录进行的流行病学研究表明，这些早期发育指标与晚年疾病之间存在很强的统计学关联。据推测，解释这些关联的过程涉及胎儿器官发育因母体和胎儿营养不良而发生的适应性变化。这些适应可能会以一种有利于在持续营养不良条件下生存但在营养丰富时有害的方式永久改变成年后的新陈代谢。这个假设正在一个大鼠模型中进行测试，该模型涉及研究在怀孕和/或哺乳期喂食低蛋白饮食的大鼠母鼠后代的生长和代谢。利用这个大鼠模型，已经证明：（i）由喂食低蛋白饮食的母鼠哺育的后代出现永久性生长迟缓。（ii）器官生长出现永久性和选择性变化。像大脑和肺这样的重要器官相对受到保护，不会因牺牲肝脏、胰腺、肌肉和脾脏等内脏器官而出现生长减少。（iii）肝脏代谢的编程，表现为糖酵解和糖异生关键肝酶（葡萄糖激酶和磷酸烯醇式丙酮酸羧激酶）活性的永久性变化，这种变化可能会使肝脏倾向于“饥饿”状态。我们推测这些变化可能是肝脏门静脉周围和肝静脉周围区域改变的结果，这也可能影响肝功能的其他方面。（iv）随着年龄增长，葡萄糖耐量恶化。（v）仅在哺乳期暴露于母体蛋白质限制的后代寿命增加，而仅在妊娠期暴露于母体蛋白质限制的后代寿命减少。这些研究表明，肝脏代谢甚至寿命都可以由生命早期的事件进行编程。
