A team from Rouen has shown that the placenta constitutes a formidable witness of the neurodevelopmental disorders in children exposed to alcohol during pregnancy. It contains a new biomarker that makes it possible to identify abnormalities in brain angiogenesis.
While it has been known since the 1960s that the consumption of alcohol by pregnant women can cause fetal malformations, clinical research has not yet made it possible to precisely determine the conditions in which these disorders might occur.
Several factors are under debate, including gestation stage, frequency and quantity of alcohol consumption and the binge drinking phenomenon. What is more, the effects of the exposure vary considerably from one individual to another. An uncertainty which unfortunately encourages families to downplay the risks incurred, even in populations which have already been made aware of them. In addition, the "zero alcohol" slogan is sometimes perceived as exaggerated, guilt-inducing and even infantilizing.
"Yet there is no threshold effect for exposure to alcohol. It is toxic from the beginning to end of development," clarifies Inserm Research Director Bruno Gonzalez*. "The form this toxicity takes depends on the period concerned: we call this the window of vulnerability. But consuming only small amounts doesn’t mean that there won’t be any effects." Leader of the NeoVasc team in Rouen, the neuroscience researcher is studying the formation of brain lesions in neonates.
Beyond the syndrome
The prevalence of the problems caused by fetal alcohol exposure is high (19.8 cases per 1,000 in Europe according to a meta-analysis conducted by researchers at the University of Toronto) and no doubt underestimated due to diagnostic difficulties. Only the most severe form, fetal alcohol syndrome, is commonly diagnosed during pregnancy because its resultant facial and cranial deformations can be observed early on by ultrasound. However, many children who are victims of maternal alcohol consumption are only diagnosed towards the age of 5-6 years old, at school, when they display learning and behavioral disorders (hyperactivity, delayed language acquisition, impulsiveness, etc.).
In such cases, several years of treatment have already been lost, in a period where the brain is highly plastic and capable of recovering some its damaged functions. "Without early treatment, many of these children find themselves underperforming at school," deplores Gonzalez. Yet it would be unworkable to monitor all cases of suspected exposure in order to catch the problem early. The research by the Rouen team offers a potential response to this problem with the development of a new generation of alcohol exposure biomarkers. "Until now, we only had exposure biomarkers, i.e. tools to determine whether the child had been exposed to alcohol by screening for compounds reflecting its metabolism or toxicity, notably in the liver," adds the researcher. "We needed a biomarker that could inform us of the quality of neurodevelopment, which is something that did not exist."
In close collaboration with the pediatrics department of University Hospital Rouen headed by Stéphane Marret, his team was able to identify a biomarker in the placenta that indicates abnormalities in brain angiogenesis, namely the formation of the vessels that will irrigate the nervous system. "From the temporal and anatomical points of view, this process is concomitant with neurogenesis. The role of the vessels is not just to supply energy but also act as a guide in the migration of certain nerve cell populations," explains Gonzalez. "In short, correct brain vascularization requires correct neurodevelopment." From a certain stage of development, the researchers observed that angiogenesis was altered in all children exposed to alcohol in utero: the vessels were present but in a disorganized way. Likewise, the nerve cells that use these vessels as a guide presented abnormalities. The next step was to understand the molecular and cellular mechanisms that precede these alterations.
The team studied families of molecules that come into play in controlling angiogenesis, such as vascular endothelial growth factor (VEGF). Alcohol disrupts the VEGF receptors in the brain – notably VEGFR1. Yet it is the sole receptor of another member of the family, placental growth factor (PLGF). While the latter is very difficult to detect in the brain, it is abundant in the placenta, begging the question of what if it is secreted in the fetal blood circulation, playing a role in brain angiogenesis? This led to the team hypothesizing the existence of a placenta-brain connection which would be disrupted by alcohol. "In animals we were able to go yet further by demonstrating how this link works," specifies the researcher.
Placenta and brain - a link
Examination of human and mouse placentas which had and had not been exposed to alcohol revealed that there is indeed a link between vascular disorders of the placenta and those of the brain. PLGF could therefore be measured to determine brain damage in children. And there is more: animal studies have shown that repressing or amplifying PLGF expression made it possible to mimic the damage caused by alcohol or correct it. "What we have is not just have a biomarker but a tool which can have an effect on the organs, and this is something that is totally new," said Gonzalez. "So we filed a therapeutic patent in addition to the initial biomarker patent. At present, in the scope of a third - neurological - patent, we are wondering about the impact of alcohol and placental PLGF on the maturation and positioning of certain nerve cell populations. We will also try to test whether modulating placental PLGF makes it possible to act on behavioral disorders caused by exposure to alcohol in utero." Once again, the placenta has proven to be a particularly interesting organ because, as it is destroyed at birth, taking samples from it is easy and non-invasive. We can therefore imagine a place for this new generation of biomarkers in systematic neonatal screening strategies. In addition, public health policies aiming to reduce the prevalence of alcohol consumption by pregnant women need to be pursued.
*Unit 1245 Inserm/Université de Rouen, Genomics and Personalized Medicine in Cancer and Neurological disorders, NeoVasc team
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