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Why Are Males More at Risk in the Womb?

foetus

Birth weight and poor growth in the womb are associated with conditions appearing decades later, such as heart disease, hypertension, metabolic syndrome, diabetes and psychiatric disorders.

By Sam Buckberry & Claire Roberts

Subtle changes in the placenta before a child’s birth can affect its predisposition to chronic disease and premature death many years later – and unborn boys are most vulnerable.

Tiny and seemingly insignificant deviations from a rocket’s course at take-off can have significant and measurable effects on its ultimate trajectory. In a similar vein, could minute changes in the function of the human placenta before a child’s birth affect its predisposition to chronic disease and premature death many years later? And are males genetically more predisposed to problems while still in the womb than females? These questions are at the forefront of our research into sex differences in placental function and foetal growth.

Significant sex differences in the foetal growth patterns of human babies have long been recognised. For example, baby boys are, on average, larger than girls at birth. One in four pregnancies in Australia will feature an obstetric complication, and a disproportionate number of these pregnancies will be carrying a male baby. Several studies in the 1990s reported sex biases in the incidence and severity of pregnancy complications such as pre-eclampsia, where the mother develops high blood pressure and impaired kidney function.

Not only does this sex bias have consequences during pregnancy – it may be linked to some adult-onset diseases too.

Although the underlying causes of many pregnancy pathologies remain elusive, we do know that abnormal or sub-optimal functioning of the placenta plays a significant role. There seem to be differences in the way the placenta operates when the mother is carrying a boy compared with when she is carrying a girl. Boys are able to grow faster, but this is not without its costs.

The placenta begins to develop once the embryo attaches to the inside of the mother’s uterus 5–6 days after conception. From this point, placental cells begin invading the lining of the uterus, where they colonise and transform the mother’s uterine arteries and also establish their own network of blood vessels to enable the transfer of nutrients and oxygen from mother to child. Although the placenta is a shared organ between a mother and her baby, the maternal and foetal blood do not mix.

If the placenta does not invade deeply enough, the flow of the mother’s blood to the placenta may be inadequate. This may diminish placental function and lead to complications such as foetal growth restriction, pre-term birth and pre-eclampsia. Furthermore, the placenta secretes a variety of hormones into the mother’s bloodstream that modulate how she adapts to pregnancy. This can affect her health.

Since the cells that form placental tissue originate from the fertilised embryo, it is the baby’s genes that largely direct how the placenta develops and functions. By studying the regulation of genes in the placenta we hope to determine how and why male and female babies develop differently.

The baby’s sex is distinguished by the sex chromosomes: XX in females and XY in males. Traits controlled by genes located on the sex chromosomes are the most likely source of differences between the sexes, although genes on the other chromosomes (the autosomes) also matter.

Some genes on the autosomes are known as sex-limited genes, meaning that both males and females possess a certain gene but they are activated in only one sex. Genes responsible for milk production during lactation are a good example: both males and females carry milk production genes but they are only expressed in females.

Genes are not simply switched on or off; rather, control of gene expression is more analogous to a volume dial. Genes are expressed at different levels, and expression can be turned up or turned down to varying degrees.

Genes that are turned up to different levels between the sexes are referred to as sex-influenced genes. These can explain, for example, why some men become bald. Both males and females carry genes affecting a person’s predisposition to lose their hair, but expression of these genes is strongly influenced by the presence of testosterone, which amplifies the gene expression. In contrast to men, even women who carry “baldness genes” do not typically lose hair because they produce very low levels of testosterone.

Although the existence of sex-influenced genes is well recognised, their extent and significance before birth is only beginning to emerge. Ascertaining how many sex-influenced genes operate in the placenta, and what effects these genes have, may provide valuable insights into how males and females develop differently in the womb. More importantly, we may be able to determine how sex-influenced genes place males at greater risk of particular diseases.

Our recent study, published in Molecular Human Reproduction, analysed placental gene expression data from more than 300 babies delivered from normal pregnancies in the United States, Europe and Asia. By scanning the entire human genome, we identified more than 140 genes showing significant sex differences in expression: a result far exceeding previous estimates.

One intriguing group of sex-influenced genes, for which expression levels were significantly lower in placentas from male babies, were the genes that produce human chorionic gonadotropin (hCG) – the hormone measured in pregnancy tests. hCG enables pregnancy to be detected from a very early stage because placental cells release hCG into the mother’s bloodstream soon after conception. Although we do not completely understand the functional repertoire of hCG, there is good evidence to indicate that it plays key roles in developing and maintaining placental tissue, and helps to suppress rejection of the foetus and placenta by the mother’s immune system.

What does this suggest for the fate of male babies? From our research and previous studies showing sex differences in foetal growth, the observation that hCG genes are, on average, expressed at higher levels in placentas from female babies indicates that females invest more of the nutrients supplied from their mother to maintain placental function. Conversely, male babies invest more of these nutrients into body growth, which explains why males are heavier on average than females at birth. Nevertheless, all the nutrients required for growth are acquired from the mother through the placenta, so the right balance must be struck between maintaining placental function and body growth.

In most cases, the increased investment of nutrients towards body growth adopted by male babies does not appear to cause complications in pregnancy. However, if adverse conditions arise during pregnancy, for example as a result of a poor maternal diet, males may be unable to respond as well as females.

It is hypothesised that males push their placenta to the limit by extracting the maximum possible nutrients, leaving nothing in reserve in case something goes wrong. Conversely, female babies appear to grow more slowly in response to adversity as a survival mechanism, maintaining the functional capacity of the placenta. In less than ideal growth conditions, therefore, it is somewhat more risky to be male.

In the context of natural selection, the additional risk that males take may have had significant benefits during mammalian evolution. Bigger babies (but not too big) are more likely to survive to reproductive age and become bigger adults than small babies. In the animal kingdom, males of many species are somewhat expendable, and only the most competitive males will pass on their genes to the next generation. Conversely, most females will reproduce as long as they can survive to adulthood.

In modern humans, the impact of these naturally selected growth strategies extend beyond the womb and may influence health in a myriad of ways. A rapidly growing body of research demonstrates many links between adverse events occurring in utero and in early postnatal life with lifelong physical and mental well-being. Animal and human studies indicate that birth weight and poor growth in the womb are associated with conditions appearing decades later, such as heart disease, hypertension, metabolic syndrome, diabetes and psychiatric disorders. These are all examples of diseases exhibiting sex-bias in terms of incidence, severity and age of onset. We suggest that establishing strong foundations in particular biological systems during early development can help to avoid certain health problems – which would be more difficult or less effective to treat – later in life.

If sex differences in placental function underlie differences in the developmental origins of lifelong health in males and females, then understanding differential placental functions between male and female babies may be central to elucidating the origins and sex-specific risks for many adult-onset diseases.

Piecing together the complex relationships between foetal sex, in utero development, pregnancy outcome and lifelong health is a complex challenge. However, continued research into human placental function and sex-influenced genes will contribute crucial pieces to the puzzle.

Sam Buckberry is a PhD candidate at The University of Adelaide’s Robinson Research Institute, where Claire Roberts directs the Placental Development Laboratory.