- Alcohol consumption during pregnancy can cause foetal alcohol spectrum disorder (FASD).
- Until now, a diagnostic test specific for FASD has not been available.
- To prevent irreversible damage of the baby’s brain, an early FASD diagnosis is necessary.
- Dr Bruno Gonzalez at the Institute of Research and Innovation in Biomedicine, France, has been studying the effects of alcohol on the foetus’s blood vessels, placenta, and brain for many years.
- His studies have brought to light new information, including molecular markers of neurodevelopmental lesions that could be used as diagnostic tools.
Foetal alcohol spectrum disorder (FASD) is a group of abnormalities caused by exposure to alcohol in utero. Alcohol consumption during pregnancy can affect the baby’s development, causing physical and mental problems, such as low body weight, behavioural issues, learning disabilities, damage to vital organs including eyes and kidneys, and abnormal facial features.
How is FASD diagnosed?
Although the syndrome has been known for years, there is still no direct diagnostic test for FASD. The diagnosis is usually established by a multidisciplinary team after evaluating all the available data, including the characteristic abnormal facial features, the mother’s alcohol intake during pregnancy, and the structure and function of the child’s brain following tests.
Unfortunately, most FASD infants don’t have the characteristic facial traits which include a thin upper lip and a smooth philtrum (the groove between the base of the nose and the upper lip). Also, there is no established safe amount of alcohol for the pregnant mother. This means that when these infants develop behavioural and developmental issues, it is often very difficult to identify the cause. This can contribute to a late FASD diagnosis, if any at all. Since the early childhood years are the most crucial ones for brain development and growth, identifying FASD early would give clinicians the opportunity to follow these children and reduce permanent brain damage. Dr Bruno Gonzalez and his team at the Institute of Research and Innovation in Biomedicine in Rouen, France, have been studying the ways in which alcohol causes damage to the foetus for over 12 years now. Considering neuroplacentology and neurovascular development, the team believe they might be very close to developing a FASD diagnostic tool with the power to improve the lives of millions of people.
Alcohol vs baby
When a pregnant woman drinks alcohol, this passes from her blood to the baby through the placenta and umbilical cord. The placenta is an organ that develops inside the uterus during pregnancy and provides oxygen and nutrients from the mother to the baby, while at the same time removing waste products from the baby’s blood.
Early childhood years are the most crucial ones for brain development and growth, so identifying FASD early offers an opportunity to follow these children and reduce permanent brain damage.
The alcohol can directly act on the developing baby’s nervous system and cause damage to the nerves and brain. Alcohol also disrupts the communication between nerve cells by blocking their ability to form synapses, the functional connections between them.
Besides directly affecting the foetus’s nervous system, alcohol is also known to indirectly affect the nervous system by causing changes and imbalance in the gut microbiota, the community of friendly bacteria that live in our gut, and also by affecting the development of new vessels in both the placenta and the developing baby brain.
Alcohol damages brain vessels
But how exactly does alcohol affect the brain’s blood vessels? Gonzalez and his team decided to find out more by initially studying the structure and characteristics of the tiny brain vessels in both human and mice foetuses with FASD by imaging with the help of special molecular probes. They also used quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), a test to accurately measure the expression of members of the vascular endothelial growth factor (VEGF) family and its cell receptors. VEGF members constitute a family of molecules responsible for stimulating the development of new blood vessels (angiogenesis).
This repeatable pattern could become the base for building a diagnostic toolkit for infants with FASD.
The team compared the results and found that the exposure of the foetus to alcohol resulted in fewer and deformed blood vessels in the cerebral cortex. Their molecular tests also showed that the FASD mice tissues had fewer VEGF receptors, a finding that could explain the vascular changes. Because recent evidence demonstrated the pivotal role of vessels in brain development, the team focused to neurovascular consequences.
From vessels to brain
These eye-opening results motivated the team to take their experiments to the next level. They knew that the inner lining of the blood vessels (endothelium) fine-tunes the maturation of the nerve cells that control the activity of important regions of the brain (interneurons) by releasing a messenger molecule called gamma-aminobutyric acid or GABA (GABAergic neuron differentiation). A further experiment on mice and human foetal tissues suggested that alcohol interferes with the endothelium and the vessel-associated migration of GABA interneurons, leading to their cortical mispositioning, something that may contribute to the neurodevelopmental issues associated with FASD including memory, thinking, learning, and sensing. These findings were reinforced by a later study on human foetal FASD tissues that confirmed an insufficient and delayed development of the interneurons during the two first trimesters of pregnancy.
Further experimentation on both human and mice exposed the ways alcohol can affect the maturation (differentiation) of brain oligodendrocytes, the cells that insulate and protect the nerves, by interfering with the vascular endothelium. FASD brains have more immature oligodendrocytes than mature ones, something that was also confirmed by measuring the levels of a protein called platelet-derived growth factor receptor A (PDGFR-α) which is produced by immature oligodendrocytes. These were found to be much higher in the FASD brains than in healthy brains. These oligodendrocyte-related defects are known to be associated with neurodevelopmental issues including long-term mobility problems.
The placenta–brain axis
Having discovered more about how alcohol affects the development of the brain vessels and therefore the brain itself (neurovascular development), the team then took a closer look at growth molecules produced by the placenta. This time, they tested the foetal tissues for the placental growth factor (PlGF), a molecule from the VEGF family that contribute to kick-start angiogenesis. The measurements showed that the levels of PLGF were lower in the alcohol-exposed animals compared to healthy ones. Both the affected placentas and brains had fewer blood vessels developed compared to unexposed animals. Similarly, in a different study, by testing the levels of CD146, a molecule interfering with the PlGF/VEGF family that helps the endothelial cells stick together and form healthy blood vessels, they found low levels of placental CD146, which were also associated with vascular damage typical in FASD.
The next study was even more ambitious, with the team accurately measuring the altered expression by alcohol of a larger number of growth-related factors between placenta and foetal brain (transcriptomic signature study). This study revealed a characteristic pattern of growth-related genes specific to animals previously exposed to alcohol. This repeatable pattern could become the base for building a diagnostic toolkit for infants with FASD.
The findings from the above studies reveal a series of new candidate molecules involved in FASD neurovascular impairments. They also confirm that neuroplacentology is a rising research field and can help better understand the mechanisms involved in the development of neurodevelopmental diseases.
Could a new generation of biomarkers for the accurate and early diagnosis of FASD emerge from the above scientific data? Very likely so.
What led you to study the connection between alcohol, the vessels, and the developing brain?
This project started with the first discovery that in human neonates in utero exposed to alcohol, the cortical vasculature is disorganised (Jégou et al, 2012). Concurrently, other research groups (not involved in alcohol research) showed that microvessels were guiding different nervous cell populations: GABA interneurons (Won et al, 2013) and subsequently, oligodendrocytes (Tsai et al, 2016). Consequently, it was tempting to speculate that alcohol-induced vascular defects could impact neurodevelopment.
What is one common misconception people have about the effects of drinking during pregnancy on the developing baby?
It is not clear for people that there is no safe dose or duration of alcohol that may not lead to brain toxicity for the foetus. Indeed, during pregnancy, there are different windows of vulnerability for different nervous cell types. This can explain the large panel of deleterious effects of alcohol in the developing brain.
Did you have any unexpected/surprising findings in any of your relevant studies? What were they?
Yes we did. We found that several neurovascular defects observed in the developing brain were also observed in the developing retina, supporting that eye imagery in neonates would provide a promising research avenue to identify neurovascular alterations in babies.
What is the next step necessary towards developing a FASD-specific diagnostic toolkit?
By using behavioural approaches, we need to determine if the neurovascular abnormalities that we evidenced after prenatal alcohol exposure are reflecting the progressive apparition of behavioural troubles.
