Fetal alcohol spectrum disorders: can alcohol-related oxidative stress concur to the prenatal damage?

Introduction Alcohol consumed during pregnancy freely crosses the placental barrier and constitutes a significant risk for many adverse outcomes globally defined Fetal Alcohol Spectrum Disorders (FASD) up to the Fetal Alcohol Syndrome (FAS). Many teratogenic mechanisms have been proposed but, to date, one of the most studied and understood is the alcohol-related Oxidative Stress (OS). Alcohol-related OS can affect lipids and proteins and can produce DNA alteration and epigenetic modifications since DNA is very sensitive to the OS effect. Recent animal studies show that alcoholrelated OS can affect mainly the brain that is physiologically more vulnerable than other organs as liver or kidney. Experimental evidence show that alcohol-related OS significantly concur to produce the Fetal Alcohol Spectrum Disorders (FASD) and the Fetal Alcohol Syndrome (FAS). Animal experimentation show that OS is involved in developing FASD and that the individual vulnerability observed in different rat strain may reside, at least in part, in the regulation of REDOX equilibrium. The association between FASD and oxidative stress is confirmed by the evidence that alcohol effects are mitigated when antioxidants are administered. Clinical studies performed by OS biomarkers as plasmatic Malondialdehyde (MDA), Free Oxygen Radicals Testing (FORT) and Free Oxygen Radicals Defense (FORD) in the blood of heavy drinking subjects evidence their OS status. Gender difference are significant since OS level in drinking women is higher than that in drinking men. Conclusion Animal studies show that OS condition have a significant role in impairing pregnancy and in developing the neurobehavioral symptoms of FASD. Evidence from clinical studies suggest that to include the study of OS biomarkers in obstetric and neonatal routine diagnostic procedures could be a good strategy to early detect at-risk situation and to improve treatment. The high reliability and practicability of current available tests for determination of OS biomarkers make easier to reach this goal. Introduction To date because of the widespread habit of drinking in women, the prenatal alcohol exposure should be considered a major public health concern. Alcohol consumed during pregnancy freely crosses the placental barrier and constitutes a significant risk for many adverse outcomes globally defined Fetal Alcohol Spectrum Disorders (FASD) up to the Fetal Alcohol Syndrome (FAS)1. Many teratogenic mechanisms have been proposed but, to date, one of the most studied and understood is the alcohol-related Oxidative Stress. Redox regulation plays a pivotal role for the life and the health of the cell since redox equilibrium between production of the Reactive Oxygen Species (ROS) and the activity of antioxidant defenses is essential for cellular functioning and many of the protein involved in the signal intracellular transductional chains (receptors, kinases, phosphatases and transcriptional factors) depend on it. There are a growing number of studies that show the influence of redox modulation in cellular signaling and that demonstrate how even slight redox modifications serve to modulate cell functions1. Intracellular ROS are produced in mitochondria by means of the electron transport chain that is the main source of free radicals, and in the cytoplasm via xanthine oxidase and reduced nicotinamide adenosine dinucleotide phosphate (NADPH) and NADPH oxidase (NOX) pathways. NOX has a dedicated function of generating reactive oxygen species and experimental evidence suggests that NOX has an important role in signal transduction in cellular stress responses2. Oxidation reactions are crucial for life but they can also be damaging; so there is a complex system including various types of antioxidants, such as glutathione, vitamin C, vitamin A, and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases, that acts as a defense to counteract the production of ROS. When the redox homeostasis is altered by endogenous or exogenous factors such as exposure to chemicals or to ionizing radiation, it is produced the so-called oxidative stress (OS) that is the redox imbalance due to the increase of ROS and the decrease of endogenous antioxidant defenses3,4. When OS condition occurs for a long time, heavy cellular damages such as apoptosis, necrosis and epigenetic modification can be produced. Alcohol drinking can produce redox imbalance both directly by its own metabolism that generates ROS, both indirectly by impairing antioxidant power of the cells5. Alcohol-related OS can affect lipids and proteins and can produce DNA alteration and epigenetic modifications since DNA is very sensitive to the OS effect6. Alcohol is a teratogen and onset and severity of alcohol*Corresponding author Email: [email protected] 1 Istituto Superiore di Sanità, Roma, Italy