The corpus callosum (CC) can be absent (agenesis) in children with fetal alcohol syndrome (FAS). Preliminary data show that the CC is reduced, and surviving connections are abnormal, in rats with fetal alcohol exposure. Preliminary data also show that CC development is significantly abnormal following moderate or heavy level, during first or second human trimester equivalent in utero alcohol exposure. Studies in humans have shown that CC abnormalities are correlated with affective and/or developmental disorders. Previous studies have shown that normal development of transitory CC connections in cat is critical for normal functional development of the visual system. Rat data show that transitory CC connections are also present for auditory and somatosensory cortex. Cat and rat results show that CC development includes a transitory extension of many axons and dendrites into all neocortical layers. These cortical CC connections are restructured during a finite period of development that is characteristic for each species. Thus, many of the neurological and psychological consequences of fetal alcohol exposure in humans may be linked to negative consequences of altered CC development. The primary goals of this proposal are to determine the extent to which the rat CC is a model for the affects of fetal alcohol exposure in humans, and to determine if there is a critical threshold and time period for alcohol exposure to produce CC abnormalities. Alcohol doses that produce heavy, moderate and light blood alcohol concentrations (BACs) in pregnant mothers will be tested. Alcohol exposure during human trimester equivalents 1, 2, and 1-2 will be tested in rat. Preliminary data show that each BAC/timing combination leads to differential consequences for CC development. The proposed studies will determine the nature and consistency of the CC abnormality related to timing and BAC level, and quantify the effects on CC development. CC axonal and dendritic morphology, as well as CC cellular polarity and orientation, will be quantified; preliminary data show that all these parameters of CC development are altered by prenatal alcohol exposure. Specific parameters of abnormal CC development will be correlated with different doses and timing of alcohol exposure. The effect of alcohol on initial generation of CC cells will also be determined to provide an index of the consistency of prenatal alcohol effects in humans and rats, as well as determine whether alcohol produces CC abnormalities by indirect, as well as direct, effects on CC cells. These investigations will evaluate the effectiveness of the rat CC model for human FAS and fetal alcohol effects (FAE), also called alcohol related birth defects (ARBD). The results will also provide extensive information that will be useful for studying possible mechanisms by which fetal alcohol exposure affects the developing brain. The results of the proposed studies will be clinically relevant in providing detailed data by which to evaluate the timing and extent of alcohol exposure on fetal development, and may be used by health care professionals in counseling pregnant women on the potential effects of alcohol consumption.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG4-ALTX-3 (01))
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University of Tennessee Health Science Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Livy, Daniel J; Elberger, Andrea J (2008) Alcohol exposure during the first two trimesters-equivalent alters the development of corpus callosum projection neurons in the rat. Alcohol 42:285-93
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