28 April 2014
Head of developmental biology group, University of SouthamptonAppeared in BioNews 751
Preparing for pregnancy is important. Timing when to have a family is hard enough for a woman with the conflicting needs of modern life, fitting around her career aspirations and those of her partner.
Biology also comes into the equation, of course. Delaying pregnancy can be a problem since decreased fertility coincides with increasing age and with it the risk of abnormal chromosome segregation (aneuploidy) in eggs and early embryos. Moreover, the woman's health can be critical since it is known that high body mass index and obesity reduces fertility.
Preparing for pregnancy has even added responsibility beyond fertility. Increasing evidence, mainly from animal studies, suggests that eggs and very early embryos in the first few days after conception can be particularly sensitive to their environment with lifetime consequences including risk of diseases into adulthood, and that's what I want to talk about here.
Our studies in rodents show that what a mother eats during this short time window from conception up to before implantation can be 'sensed' by the early embryo which uses this information to adjust how it develops.
If the diet is low in protein, this changes the composition of the uterine fluids that the embryo is bathed in. The embryo has sensing mechanisms that can tell it if maternal nutrients are low and is capable of adapting how it develops to compensate for nutrient deficiencies, a way of protecting itself even if the mother's diet is poor. Our work suggests that low levels of key amino acids and insulin may be factors the embryo monitors within its mother.
The embryo can be ingenious in how it responds. Poor nutrients result in activation of signalling pathways that promote the development and function of those cell lineages that make the placenta, both the main placenta and the yolk sac (an additional organ used to absorb maternal nutrients for pregnancy).
These compensatory responses include increased proliferation of these lineages and the capacity of the cells to capture and take up more nutrients, a process called endocytosis. This is a fascinating dialogue going on between mother and embryo. The embryo has its own agenda for survival; if the mother doesn't eat enough to sustain growth and development for pregnancy, it will just go out and take more, 'without asking'.
It makes sense that these decisions by the embryo to compensate maternal nutrition are made early on, as this allows for construction of the most optimal placental system for nutrient delivery dependent upon the circumstances experienced at the time - just as it is wise to have a finalised blueprint for an office block before you start building it!
Also, it seems sensible that the decisions made by the early embryo are stuck to. We find that the cellular changes responsible for increased nutrient capture by the embryo are heritable throughout gestation; there is therefore a 'memory' of the environment experienced before implantation that protects the embryo thereafter.
Whilst this all sounds like a sensible developmental strategy, there is a sting in the tail, a price to pay. From our rodent models we find that a poor maternal diet just during those few days between conception and implantation - and with a normal diet thereafter - the offspring develop metabolic and cardiovascular disease markers (high blood pressure, excessive body fat, for example) and dysfunctional behaviour.
Why is this happening? This is likely caused by developing a metabolism designed for a frugal environment with emphasis on nutrient storage whenever possible as would have been 'predicted' by the embryo from its mother's poor nutrition around the time of conception. However, this would be an unsuitable physiological state if entering a postnatal world with nutrients aplenty, a maladaptation prone to increase disease risk, and an evolutionary trade-off for early protection provided during development.
Do these memories and legacy of embryo environment have any relevance to humans? We believe they do. Similar nutritional study designs in sheep also indicate adverse adult cardiovascular, metabolic and behavioural consequences may derive from the environment around the time of conception. And historically, people conceived near to the end of the five-month famine in Amsterdam in the second world war showed a comparable disease risk in later life.
There is also some evidence from children conceived via IVF that the conditions and composition of the embryo culture medium can influence early postnatal growth rates and increase the risk of cardiometabolic dysfunction.
All of these suggestions of early 'programming' of health also relate to wider epidemiological studies, particularly from Professor David Barker and colleagues, showing the major risk for acquiring metabolic and cardiovascular disease in later life is not so much your adult lifestyle but by your birth weight.
The early embryo development may 'interrogate' the maternal environment not just for nutritional factors but also for other criteria. Our mouse studies show that maternal sickness (equivalent to a relatively mild systemic bacterial infection) at the time of conception also changes how the embryo develops and alters adult phenotype.
Here, however, there is no enduring consequence for cardiovascular health; rather, the offspring's innate immune system becomes suppressed. This, we think, may be a mechanism to optimise the functioning of the immune system in a world 'predicted' by the embryo to be pathogen-rich and where protection against autoimmune disease is an advantage.
These early sensing mechanisms by the embryo before implantation occur before a woman would even know she is pregnant. Conditions during development can help determine your metabolism for life, a sobering message.