Exposure of fetus to alcohol
Although most nutrients are affected by alcohol intake, specific nutrients noted from numerous studies are thiamin, riboflavin, vitamin B-12, vitamin E, selenium, vitamin A, vitamin C, folic acid, vitamin D, zinc, and a few trace minerals. Alcohol is metabolized within hepatocytes by 1 of the 3 following pathways:
Alcohol dehydrogenase pathway (ADH): The first pathway, known as ADH, occurs in the cytosol of the hepatocyte (Fig. 2). ADH metabolizes ethanol to acetaldehyde, which is subsequently converted into acetic acid in mitochondria (20). In the ADH pathway, ethanol competes with vitamin A, or retinol, for metabolism because both substrates are metabolized by the same pathway (this is discussed later). Ultimately, ethanol is oxidized, which leads to the production of acetaldehyde and large amounts of NADH.
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Alcohol effects on vitamin A
Alcohol consumption during pregnancy depletes maternal vitamin A stores, which can interrupt normal cell growth of the fetus. The proposed mechanism for this is that when both retinol and alcohol are present, ADH involved in the rate-limiting step of retinol oxidation has a higher affinity to alcohol, therefore preferentially metabolizing alcohol instead of retinol. This results in a deficiency in retinoic acid synthesis (39, 40), which is required to signal and control the cells involved in fetal development, organogenesis, organ homeostasis, cell and neuronal growth and differentiation, development of the CNS, and limb morphogenesis (16, 40).
DHA is highly important during fetal development because it plays an essential role in cognitive and visual development, as well as the development of the CNS (53, 54). DHA is also a precursor of a potent neurotrophic factor (neuroprotectin D1), which protects the brain and retina against injury-induced oxidative stress and enhances cell survivals in these tissues. Thus, it is recognized as a conditionally essential nutrient for infants. There is no RDA for DHA, but the Adequate Intake (AI) for n–3 FAs for pregnancy is 1.4 g/d (55). DHA is esterified to membrane phospholipids to maintain optimal fluidity and cellular integrity. Among phospholipids, phosphatidylserine has been the most studied in association with CNS development (54, 56, 57). Optimal neuronal development of the fetus is dependent on maternal intake and dietary status of DHA. In humans, the accumulation and integration of DHA into phosphatidylserine and cell membranes occurs from 16 wk to term and continues into the early postnatal development period (53). It is specifically during the last trimester in which DHA is rapidly incorporated into phosphatidylserine synthesis and storage in the hippocampus, because it is during this period in which human brain growth rapidly occurs (57, 58).
Folate (folic acid)
Folic acid, a water-soluble vitamin, has been identified as an essential nutrient that may provide a protective effect against gestational ethanol exposure. For folic acid to become metabolically active, it must be reduced to tetrahydrofolic acid (FH4) as a carrier for single-carbon moieties. FH4 is involved in the biosynthesis of the DNA and RNA precursors thymidylate and purine bases (64). Therefore, adequate maternal folic acid status is integral for optimal fetal growth and development. During pregnancy, the demand for folic acid is increased because it is not only required to support the mother for increased RBC formation but also to support the rapid growth of the fetus, including neural tube formation (65). The RDA for folic acid during pregnancy is 600 μg/d (66), and dietary sources are found in green leafy vegetables, beef, liver, pulses, and foods produced from whole wheat.
Alcohol effects on zinc
Alcohol consumption on a chronic basis itself reduces the availability of zinc because there is decreased intake and absorption and increased urinary excretion. When acute zinc deficiency occurs as a result of ethanol exposure, metallothionein, a low-molecular-weight protein body, sequesters plasma zinc to the liver, resulting in a reduction in plasma zinc. This leads to decreased amounts available for placental transport, resulting in fetal zinc deficiency (81, 82).
Choline and its metabolites are invaluable in neurotransmission (acetylcholine), structural integrity of cell plasma membranes (phosphatidylcholine and sphingomyelin), and cell signaling and in folate-independent pathways as a methyl donor via its metabolite, betaine (42, 90). This nutrient is the most-studied nutrient related to brain development and memory function and has been classified as an essential nutrient by the Institute of Medicine and National Academy of Sciences in the United States (66).
Choline supplementation in animal models
A recent study looked at the effect of choline supplementation on specific neurons that are altered in FASD (94). Pregnant rat dams were fed an alcohol-containing liquid diet or a control diet during GDs 7 and 21 with or without choline (642 mg/L choline chloride). The results showed that gestational choline supplementation prevented the adverse effects of alcohol on the neurons (Table 1) (94). Previous research from Thomas and colleagues (95–99) showed that perinatal choline supplementation can reduce the severity of FASD—specifically, hyperactivity and learning deficits in the rat model. The authors found that choline chloride supplementation (250 mg · kg−1 · d−1 choline chloride) prevented ethanol-induced alterations in tasks that require behavioral flexibility such as spontaneous alternation behavior and memory (Table 1) (98).
Antioxidants are compounds that are produced to scavenge free radicals and other compounds that threaten cellular oxidation. Cells can neutralize and scavenge reactive oxygen species through the enzymatic activity of SOD, glutathione peroxidase (GPx), and catalase. Nutrients such as folate, vitamin C (ascorbic acid), vitamin E (α-tocopherol), selenium, and zinc are important contributors to antioxidant activity.
Selenium is a micronutrient that serves as an important component for the generation of the enzyme GPx. GPx inhibits oxidation because it is involved in scavenging free radicals, specifically hydrogen peroxide, and converting them to harmless products such as water. Selenium-based GPx primarily is active within the cytosol or the mitochondria. The amount of selenium obtained from the diet is based on the amount in the soil or water where the food source was grown. Once consumed, it is predominantly stored in the liver, because alcohol metabolism in the liver produces various reactive oxygen species and free radicals. The RDA for selenium during pregnancy is 60 μg/d (105).
Alcohol effects on selenium.
Typically, selenium deposits and plasma concentratons are low in chronic alcoholics because of decreased dietary intake and increased production of free radicals resulting from alcohol metabolism (107). However, selenium concentrations in the plasma were reported to be increased and were significantly greater in women who drank heavily, defined as >140 g/wk, during their pregnancy in comparison to abstinent women and those who consumed alcohol moderately (108).