The Science | Begin Before Birth

Evolution


It is interesting to ask why all this should happen. Why does what a mother eats, or how she feels, change the development of her baby in the womb?


These changes may be an evolutionary mechanism to prepare the baby to be ready for the environment into which they are going to be born. This has been called the Predictive Adaptive Response (see Gluckman and Hanson 2004).


Snake

If, in prehistoric times, a mother was living in a dangerous environment, she would have felt stressed.


Many of the changes caused to her fetus by prenatal stress may have helped her child to survive. (See Glover 2011).


For example being more anxious, can make one more vigilant, and thus quicker to spot something dangerous in the distance, like a snake. Having readily distracted attention, as happens with ADHD, may make one notice a rustle in the undergrowth more easily, whilst being more aggressive may make it easier to quickly get rid of the danger.


Importantly, the degree to which offspring are affected is directly related to the severity of the mother’s stress during pregnancy. This supports the above theory, in which a more dangerous environment will cause the mother more stress, thereby increasing the severity of the effects on the offspring. In these circumstances a child whose attention is even more readily distracted may be better equipped to deal with the prevailing danger, e.g. a large number of predators.


What is also interesting is that maternal stress during pregnancy appears to have sex-specific effects on the resulting offspring. Animal models have demonstrated that male offspring are more likely to display learning deficits and increased aggression, whilst females are more prone to anxious behaviour and hyper-responsiveness of the HPA axis (See Weinstock 2007).


These sex-specific differences can potentially be explained by extending the theory above. Since females are traditionally the primary care givers, then an increased level of anxiety may help them to remain vigilant in a dangerous environment, whilst exploratory males would experience greater exposure to threats and increased aggression may increase their chances of quickly and successfully resolving conflict.


However, what was helpful in dangerous prehistoric times is not so helpful in our modern society, in which education and concentration are highly prized.


 

Epigenetics


Background


We are starting to understand the fundamental biological changes which underlie fetal programming. Of particular importance is the field of epigenetics, which means ‘on top’ of genetics.


Epigenetic changes are modifications of DNA, which occur without any alteration in the underlying DNA sequence and can control whether a gene is turned on or off and how much of a particular message is made. Every cell in our body has the same DNA sequence but different genes are turned on or off to make our different tissues, such as muscle or liver.


Epigenetic changes can also be caused by the environment and lead to differences in individual characteristics. In the womb both the mother’s diet and her stress can cause epigenetic changes in the fetus.


The effects of maternal licking and grooming on the epigenetic regulation of GR expression in pups. (Image taken from Feder and Colleagues 2009)

The early emotional environment can lead to long lasting epigenetic changes in the brain. One of the first examples of this came from animal studies of maternal care. Rats pups who were licked and groomed a lot by their mother, showed reduced anxiety and lower stress responses in adulthood. These effects were due to epigenetic changes within the brain of the offspring, specifically at the receptor for the stress hormone cortisol (Weaver and Colleagues, 2004 ). Similar epigenetic modifications of the cortisol receptor were identified in the brain of rat fetuses whose mother’s were exposed to prenatal stress during pregnancy see Mueller and Bale, 2008


In human studies, child abuse has been shown to alter the epigenetic profile of the brain when examined post-mortem (McGowan and Colleagues, 2009), and maternal prenatal stress, caused by violence from the partner, promotes epigenetic changes in the DNA for this same cortisol receptor, in the blood of their adolescent children (Radtke and colleagues, 2011).


These epigenetic changes can be passed down from the mother or the father (see Franklin, 2010 and Champagne, 2008) and may even persist across multiple generations, being passed on from grandparents to grandchildren. Thus, acquired characteristics can sometimes be inherited. However, whilst certain epigenetic changes can last a lifetime, others are much more temporary, and a lot of research is currently being conducted to establish how epigenetic changes can be reversed.


The Molecular Basis of Epigenetics


The two main epigenetic mechanisms are shown below. These are termed DNA methylation and histone modification, and both determine whether the underlying DNA code can be read or not, and thus whether the DNA is able to make RNA. In particular, the methylation of target genes is usually associated with a dramatic reduction in their level of expression.



Two epigenetic mechanisms are described above, histone modifications and DNA methylation both of which determine whether the underlying DNA code can be read or not


The Agouti Mice


One example of the effect of epigenetic changes is shown in a special type of mouse called the Agouti mouse. These animals have the same genes, but have different epigenetic modifications to a single gene, which controls coat colour. During pregnancy, the mother of the smaller mouse with the brown coat was fed a diet rich in supplements, including folic acid. Folic acid serves as a methyl donor, and this allows the agouti gene to become methylated and switched off, resulting in brown fur.


However, the mother of the mouse with the yellow coat was not fed these supplements. As a result, the agouti gene remained unmethylated and expressed in all cells, leading to a yellow colouration of the fur, as well as adult-onset obesity, diabetes, and tumorigenesis. So these genetically identical mice look so radically different due to epigenetic changes, caused in the womb, by their pregnant mothers’ diet.



The Agouti mice above show the effects of different diets during pregnancy

The Agouti mice above show the effects of different diets during pregnancy


Why not take a look at our film for more information on epigenetics and how it relates to fetal programming





Epigenetics

Click here to see the video

 

Placenta and Fetal Brain

The human placenta


Research is showing that the placenta is very important in filtering what passes from the mother through to the fetus (see O’Donnell and colleagues, 2009).


It seems that the emotional state of the mother can change this filtering capacity.


If the mother is stressed more of the stress hormone cortisol may pass through, and this in turn can alter the development of the fetal brain.


Cortisol is usually broken down by an enzyme called 11β-HSD2:



Click Here To See How Placental 11β-HSD2 Works


If the mother is stressed there is less of this enzyme in the placenta and so more cortisol can filter through and affect the development of the fetal brain.


This has been shown in animals (see Mairesse and colleagues, 2007) and there is some new evidence that the same happens in humans too (see O’Donnell and colleagues 2011).


There is also evidence that exposure to higher levels of cortisol in the womb can alter the development of the fetal brain (See Bergman and Colleagues 2010).



The Placenta and the Fetal Brain


The primary function of the placenta is to maintain an adequate supply of nutrients to fetus. This is especially important for fetal brain development which undergoes rapid growth in the prenatal period:


neurons

Image courtesy of Sandman and colleagues Univesrity of California Irvine

A 3mm neural tube will grow into a whole brain containing 100 billion neurons and 100 trillion connections.


Proliferation (production of new neurons) starts at 5 weeks continues through 18 months.


Precursor cells give rise to neurons which migrate to specific brain areas and differentiate to perform specialised functions.



New neurons form connections between one another, termed synaptogenesis.


An excess of neurons are produced prenatally. Neural pruning removes the unused neurons, a process which continues at least until puberty.


Although recent evidence has shown that new brain cells are formed well into adulthood, termed adult neurogenesis, the brain experiences the greatest growth before birth as shown in the figure below:




 

Evidence from Animals


It can be hard to establish the effects of prenatal stress on the fetus and the child in humans, because so many problems can occur together. If the mother is stressed, anxious or depressed while she is pregnant she is likely to be the same after the baby is born. Many studies have tried to take account of this, but it is difficult.


But the evidence from animals is quite clear. Prenatal stress has a long term effect on the offspring. It is possible to foster the newborn rat of a stressed mother to a new mother, on the first day after birth and compare their behaviour as they grow up with that of a newborn rat whose mother was not stressed in pregnancy. One method used is shown in the diagram. The pregnant rat is stressed by exposing her to the smell of a cat.


Example of a prenatal stress study using rats


Animal experiments have shown that prenatal stress can cause all the following effects on the offspring:


  • More anxiety
  • Reduced attention
  • Learning deficits
  • Less difference in function between the left and right sides of the brain
  • Effects different on male and female offspring
  • Altered sexual behaviour – males show homosexual behaviour and females are less nurturing mothers.


Importantly, all these effects have also been demonstrated in humans, except for the alterations in sexual behaviour.