You are what your grandmother ate, potentially, but maybe not what your great grandmother consumed. A study in mice shows that undernourishment during pregnancy increases the chances that the next two generations will develop obesity and diabetes. But by then the slate is wiped clean.

If the same holds true for humans, it may mean that stressful events in our lives affect our grandchildren's health, but not great-grandchildren.

Environmental stresses cause chemical changes to DNA that turn genes on and off. Many researchers believe that these changes can be passed down through sperm and eggs – a mechanism known as epigenetic inheritance.

Low-calorie diet

For example, studies have linked pregnant mothers that were undernourished during the second world war with gene changes in their children that put them at higher risk of becoming obese or getting cancer. But what happens to later generations is not clear.

To model this effect, Anne Ferguson-Smith at the University of Cambridge and her colleagues fed pregnant mice a diet containing 50 per cent fewer calories than usual from the 12th day of gestation until the birth, which is normally after about 20 days. Offspring were smaller than average and developed diabetes when fed a healthy diet. When the male pups had offspring, they were also at higher risk of becoming diabetic.

The team analysed the sperm of the offspring from the undernourished mothers to see how many genes had had their expression altered by the addition or removal of a methyl group – an epigenetic change. The team found a decrease in methylation in 111 regions of the DNA compared with sperm from mice born to mothers fed a healthy diet.


Unknown mechanism

When these mice, which had normal diets, had pups, however, the methylation patterns disappeared from their offspring's DNA. This was surprising – because the grandpups still proved to be more likely to get diabetes. "It suggests that methylation is a marker but probably not the key mechanism causing the disease," says Ferguson-Smith. She says it is not yet clear what other mechanism might be at work.

She hypothesises that epigenetic inheritance is a short-term adaptation that allows the offspring to be programmed for a stressful environment, but one that can easily be erased if the stressor disappears. "It would make sense to have evolved mechanisms to sense short-term changes in the environment, such that when nutrition became normal again this adaptation wouldn't persist," says Ferguson-Smith.

The team is now investigating whether further generations have an increased risk of developing diabetes to shed some light on how many generations the impact of a parent's diet can last.


参考译文：
一项小鼠实验表明，母亲孕期营养不足会增高子代和孙代发生肥胖及患上糖尿病的机会，但再下一代的健康将不再受影响。

如果这项结果对人类也适用的话，这就可能意味着我们生命中所遭遇的艰难困苦会影响我们孙辈的健康，但对我们的重孙辈没有影响。

环境压力能导致DNA发生化学变化，使得基因被打开或关闭。许多研究者相信，这些变化能通过精子或卵子遗传到下一代——这种机制称为“后成的遗传”或“表观遗传”。

喂养

例如，已有研究表明二战期间一些孕妇的营养不良跟她们的孩子的一些基因变化有关，这些变化会提高肥胖发生与罹患癌症的风险。然而，从她们的孙辈起会有什么变化，则不得而知。

为了建立研究该种影响的模型，剑桥大学的Anne Ferguson-Smith和她的同事对怀孕的小鼠进行了喂养实验。在小鼠妊娠12天后至产仔这段时间内（历时约20天）以热量比正常所需含量低一半的食物进行喂养，结果子代小鼠的体型小于平均水平，并在正常的喂养条件下患上了糖尿病，而且其中的子代雄鼠的儿女们（即营养不良雌鼠的孙辈）患糖尿病的风险也提高了。

该研究小组分析了营养不良雌鼠的儿孙们的精子DNA，结果发现，与母亲得到正常喂养的雄鼠的精子DNA相比，前者有111个区域发生了甲基化或去甲基化——一种常见的表观遗传学变化。

机制不明

然而，在正常喂养的条件下，上述变化（甲基化或去甲基化）从第四代小鼠的DNA中消失了。这一结果令人惊异，因为直到第三代小鼠，它们仍是更容易患糖尿病的。Ferguson-Smith说，“这个结果暗示，甲基化只是一个标志，但很可能并不是导致糖尿病的关键机理。”她还说，尚不明确是否另有其他致病机理。

她猜想，表观遗传是一种短期的适应性，它使得小鼠后代得以应对逆境，但一旦逆境压力消失，这种适应性也就随之被清除。“合理的推断是，它们进化出了一些机制来感知短期的环境变化，因此当小鼠的营养供应恢复正常后，这种适应性也就不再持续。”

该研究小组将继续研究更多代小鼠患糖尿病的风险是否会增高，以期探明母亲的饮食对后代健康的影响到底能持续多少代。

原始来源：http://www.newscientist.com/article/dn25884-famine-puts-next-two-generations-at-risk-of-obesity.html#.VCUYUdyn8ZF