Academic journal article Alcohol Research

Focus On: Epigenetics and Fetal Alcohol Spectrum Disorders

Academic journal article Alcohol Research

Focus On: Epigenetics and Fetal Alcohol Spectrum Disorders

Article excerpt

Epigenetic changes-stable but potentially reversible alterations in a cell's genetic information that result in changes in gene expression but do not involve changes in the underlying DNA sequence-may mediate some of the detrimental effects of prenatal alcohol exposure and contribute to the deficits and abnormalities associated with fetal alcohol spectrum disorders. These epigenetic processes are linked to the chromatin (i.e., DNA, histone proteins, and other associated proteins) and commonly involve chemical modifications (e.g., methylation) of these molecules, which may result in altered expression of the affected genes. Even alcohol exposure prior to conception appears to be able to induce epigenetic changes in the parental genetic material that can be passed on to the offspring and affect offspring outcome. Similarly, epigenetic processes may occur as a result of maternal alcohol consumption during the period between fertilization of the egg and implantation in the uterus. The period most sensitive to alcohol's adverse effects appears to be gastrulation, which corresponds to prenatal weeks 3 to 8 in the human and prenatal days 7 to 14 in the mouse, when cells are differentiating to form organs. One way in which alcohol exposure may induce epigenetic changes, particularly abnormal DNA methylation, is by affecting a set of biochemical reactions called the methionine-homocysteine cycle. KEY WORDS: Maternal alcohol consumption; prenatal alcohol exposure; fetal alcohol spectrum disorders; birth defects; teratogenesis; gastrulation; preconception; conception; pregnancy; genetics; epigenetics

Children born to women who consume alcohol during pregnancy may exhibit a range of abnormalities and developmental deficits that together are termed fetal alcohol spectrum disorders (FASD) (Manning and Hoyme 2007; Stratton et al. 1996). Fetal alcohol syndrome (FAS), which can occur with chronic consumption of high doses of alcohol, represents the most severe end of the spectrum (Jones et al. 1973). Consumption of alcohol at levels that do not produce full FAS can result in more limited deficits that are classified under different categories. These include the following (Stratton et al. 1996):

* Partial FAS, where only some of the growth or central nervous system (CNS) deficits or characteristic facial features are present;

* Alcoholrelated birth defects (ARBD), which primarily are characterized by physical abnormalities; or

* Alcoholrelated neurodevelopmental disorder (ARND), which primarily is characterized by neurobehavioral deficits.

Although the timing and level of alcohol exposure clearly affect the type and severity of the resulting effects, the specific alcoholinduced deficits observed and their extent can vary quite substantially, even among individuals with similar levels of exposure. It appears that multiple direct and indirect mechanisms, likely activated at different stages of development or at different dose thresholds of exposure, may contribute to this varying pattern of deficits (Goodlett et al. 2005). Furthermore, increasing evidence indicates that both genetic and epigenetic mechanisms may play a role in mediating the broad range of effects reported in children with FASD. After providing a brief overview of some of the genetic mechanisms contributing to FASD, this article will take a closer look at the epigenetic mechanisms that may underlie alcohol's detrimental effect during prenatal development.

GENETIC MECHANISMS

Several lines of evidence cumulatively point to a role for genetic variables that may contribute to the diverse adverse outcomes related to alcohol exposure in utero (for reviews, see Green et al. 2007; Warren and Li 2005). Several promising approaches have been developed to elucidate genetic involvement in the susceptibility to or protection from alcoholinduced prenatal toxicity and birth defects (i.e., teratogenesis). Three areas of investigation will be discussed briefly here. …

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