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Alcohol and Fetal Brain Development: An Interview with Dr. Rajesh C. Miranda - July 2014

This month's Ask the Expert features an interview with Dr. Rajesh C. Miranda, a Professor with the Department of Neuroscience and Experimental Therapeutics, the Interdisciplinary Program in Neuroscience at Texas A&M's Health Science Center (TAMHSC) and a past-President of the FASD Study Group (FASDSG). He has performed extensive research into the effects of alcohol on fetal brain development, and has agreed to answer a few questions about his work and current research on FASD.

Please note: This article discusses complex research topics, and contains some difficult terminology. The FASD Center and the author have tried to provide explanations and definitions where possible.

1. We often refer to FASD as a brain-based disorder. Can you describe the 'basics' of what alcohol does to the brain?

The effects of alcohol on the brain are dependent on the stage of fetal development. During the first trimester, the basic body plan is laid out. For the brain this means that the embryo sets down a layer of primitive cells that we will call ‘neural stem cells,’ in the shape of a tube (the neural tube). The neural tube starts off as a flat sheet of cells that is rolled up to form the tube. The front (or anterior) end of the tube will form the brain and the rear (or posterior) end will form the spinal cord. During this period, alcohol can interfere with the closure of the neural tube and the pre-placement of neural stem cells to cause what are termed ‘neural tube defects’ and brain malformations.

During the second trimester, these neural stem cells generate most of the 80-100 billion neurons of the adult brain. To do so, they must work very fast, and are capable of generating 2,000 to 3,000 new neurons every minute! Neural stem cells do not directly generate neurons, however. Within a zone of the neural tube called the ‘Ventricular Zone’ neural stem cells produce a series of daughter, granddaughter, and great granddaughter cells by cell division, which finally become neurons. This process amplifies the capacity of an individual neural stem cell to produce a large number of neurons. Drugs like alcohol interfere with this process of neuron production. If enough new neurons are not created by the end of the second trimester, the window of opportunity closes forever and the fetus can never again build enough brain capacity to support the ability of the future child to learn and adapt to the environment. A second major feature of the second trimester is that the granddaughters and great granddaughters of the neural stem cells have to migrate away from the ventricular zone where they were born, to their final positions in the developing brain. Alcohol interferes with the migration of these cells, causing them to either over- or under-migrate. When that happens, these misplaced groups of cells form what are termed ‘heterotopias’ that may result in increased susceptibility to seizures later in life.

During the third trimester, neural stem cells change their task; instead of producing neurons, they turn their attention to producing supporting cells of the brain that ensure that neurons function normally. The newly formed neurons start to form connections with each other. They grow out long processes (some can be a meter or more in length) and seek out other neurons and make contact with them by a structure called the ‘synapse.’ Each neuron can make 10,000 or more connections with other neurons. Some of these fibers connecting distant regions of the brain run together to form giant cables. One such giant cable, the ‘corpus callosum,’ is often damaged by prenatal alcohol exposure. This network of connections is vital for the future child to walk, talk, learn, show emotion, and any number of other behaviors. During this trimester, alcohol can interfere with the production of support cells, kill young neurons, and interfere with the wiring and cables that are being laid down between groups of neurons. The great majority of this wiring is laid down once during the third trimester, and mistakes will never be repaired. Therefore, it is not surprising that children prenatally exposed to alcohol will have difficulties with walking, balance, learning, and processing emotions.

It is important to remember that the reason alcohol is so damaging to brain development is that development is a series of one-time events that will never happen again. Disrupting one event in this series (the creation of new neurons, for example) will make it difficult for the fetus to execute subsequent events (e.g., the wiring of neurons together) without error. The severity of defects depends on the timing of alcohol exposure and the dose and pattern of exposure.

2. You've described the maternal-fetal environment as complex, containing a variety of toxic agents that can damage the fetus. Teratogens besides alcohol are known to include other drugs of abuse, tobacco, lead, radiation, and exposure to infectious disease. To what extent does the interplay of these teratogens--knowing which ones cause what type of damage and to what extent--complicate research into the impact of alcohol on the fetus?

The real world experience of the developing fetus is immeasurably complex. Many but not all women who consume large amounts of alcohol during pregnancy may also abuse other drugs and be exposed to adverse life events, including spousal abuse, poverty, poor nutrition, and poor environment. These experiences translate into increased stress and toxicity and burden on several organ systems in the pregnant woman, including endocrine and immune systems. All of these can impair fetal development, and are therefore termed ‘modifiers’ of the teratogenic effects of alcohol. Consideration of the effects of ‘modifiers’ makes research very complex. The field of alcohol teratology is making slow progress towards understanding this complexity. One promising avenue has been studies on the role of nutrition as modifiers of fetal alcohol effects. Multi-vitamin supplements and micronutrients are currently being tested in both laboratory models and in human clinical trials as a way to lessen the effects of maternal alcohol exposure on fetal development.

3. Your research has shown that alcohol promotes stem cell maturation and consequent depletion. Can you elaborate on what this means?

I mentioned earlier that at the end of the first trimester, the basic body plan of the future child was set in place and the neural tube with its complement of neural stem cells was poised to grow and develop into a brain and spinal cord. The fetal neural tube does not start out with enough stem cells to accomplish that task all at once. As mentioned, neural stem cells do not produce neurons directly but instead generate a series of daughter cells, and their daughters and subsequent generations are the ones that produce the neurons. For the purposes of our discussion, the process is a little more complex, because the neural stem cells generate two types of daughters. One type of daughter is identical to the parent and will become a new neural stem cell and take the place of the parent. We call this ‘stem cell renewal or replenishment.’ The second type of daughter cell is a little different (more mature) than the parent and starts down the road towards making a new neuron. We refer to this as the process of ‘maturation’ or ‘differentiation.’ If a parent stem cell creates two daughter cells identical to itself, the neural stem cell population is doubled; on the other hand if a parent cell creates two daughter cells that are a little more mature (i.e., starting to become neurons), then the neural tube has just lost a stem cell. If the neural tube loses too many stem cells all at once and is not able to replenish them, then its future capacity to generate new neurons will be diminished. Our research indicates that alcohol promotes the maturation of neural stem cells and diminishes their renewal capacity. We think that this loss of renewal capacity ultimately results in fewer neurons being produced and may result in diminished brain size (microencephaly).

4. You are a past-President of the FASD Study Group (FASDSG). What are some key recent findings emerging from their work, and have they shaped new research currently underway?

The FASDSG has been an important and exciting educational vehicle to bring together clinicians and researchers who share a common passion for preventing FASD and improving the lives of children affected by FASD and their caregivers. Here are a few examples of important progress:

Early detection of fetal alcohol exposure: There has been a recent and enormous emphasis on developing better and more sensitive methods for detecting fetal alcohol exposure. These include mathematical modeling of the facial asymmetries and deviations, biomarkers from newborn blood or meconium, and high-resolution and functional imaging of brain regions and fiber tracts.

Mechanisms underlying FASD and fetal susceptibility: Perhaps the most exciting recent development has been the identification of a phenomenon termed ‘epigenetics’ as an important mechanism for fetal programming and fetal alcohol effect. Epigenetics (literally, ‘above genetics’) is a mechanism to control the folding and unfolding of our chromosomes to control access to their library of genes. The cellular memory for how to pack and unpack chromosomes can be modified by life experiences in one generation and this modified memory transmitted to future generations. Alcohol has now been shown to affect epigenetic pathways. This has important implications for fetal development and long-term adult effects of fetal exposure. The involvement of epigenetics also means that the effects of excessive alcohol consumption in one generation can influence physiology for many subsequent generations. Finally, research is now showing that male germ cells can also be epigenetically programmed and that there may be a paternal contribution to FASD. This is potentially very important. All preventive efforts now focus on modifying alcohol consumption patterns in the mother and ignore the contribution of the father to developmental defects.

Early intervention for FASD: Remarkable progress has been made towards developing both behavioral and nutrition intervention programs to mitigate effects of fetal alcohol exposure. Following the realization that alcohol may influence epigenetic mechanisms, research has focused on nutrition supplementation that will modify epigenetic pathways.

Developmental origins of adult disease susceptibility: Fetal alcohol exposure can increase the probability of future alcoholism. However, there may be endocrine, cardiovascular, and neural effects that last a lifetime. Recent research has focused on identifying problems including insulin sensitivity and cancer susceptibility that are likely to affect adults with fetal alcohol exposure as they progress through middle age and beyond.

5. What are some important ways that the historic view of FASD has changed through research?

Fetal Alcohol Syndrome (FAS) would not be accepted as a ‘real’ syndrome today without the wealth of human and animal research showing that alcohol is a teratogen. Today there is no question that alcohol is the causing agent in FASD. Early research also delineated the role of dose and timing of alcohol exposure on the severity of outcomes. In this regards, it is important to note the importance of the research showing that binge patterns of alcohol consumption are particularly harmful to fetal development.

Newer research has focused on identifying modifiers of FASD; for example, maternal stress and nutrition. More needs to be done in this area.

We also used to think that alcohol was primarily toxic to fetal tissues, in that it simply killed fetal cells. This thinking is being replaced by a more nuanced view that alcohol is a teratogen because it interferes with epigenetic programming and with regulatory functions of cellular agents like miRNAs, an exciting new class of small regulatory RNA molecules. This change in view will be very important for developing new approaches to biomedical and nutrition interventions.

New research using high resolution imaging technologies is also giving us a more detailed view of the brain affected by alcohol exposure in utero in both humans and in animal models. Using modalities like diffusion tensor imaging and functional magnetic resonance imaging, researchers are trying to determine specific circuitry that is targeted by fetal alcohol exposure. We expect that in time this will lead to new behavioral interventions to teach children with an FASD to better cope with their environment.

Finally, the research showing that alcohol influences epigenetic pathways makes it possible for the first time to consider both the trans-generational effects of alcohol exposure as well as the role of the father in FASD. This type of information is likely to have important and far-reaching consequences for school, child protective services, and the juvenile and adult justice systems.



About the Expert

Rajesh C. Miranda, Ph.D., is a Professor with the Department of Neuroscience and Experimental Therapeutics Interdisciplinary Program in Neuroscience at Texas A&M's Health Science Center (TAMHSC). His research focus areas include fetal brain development, stem cells, microRNAs, and teratology, and his findings have been published in BMC Neuroscience, The Journal of Neuroscience, Plos One, and Alcoholism: Clinical and Experimental Research.


DISCLAIMER: The views, opinions, and content of this column are those of the author/expert and do not necessarily reflect the views, opinions, or policies of SAMHSA, HHS, or TAMHSC.