Magnetic resonance imaging, in situ hybridization, and immunohistochemistry-based analyses of early prenatal ethanol exposure-induced central nervous system abnormalities.

摘要

Fetal alcohol spectrum disorders (FASD), the collection of defects resulting from prenatal alcohol (ethanol) exposure, has been the subject of basic and clinical investigation for four decades, but remains a major public health problem. At the severe end of the spectrum is fetal alcohol syndrome (FAS), which is characterized by the presence of growth retardation, craniofacial anomalies, and brain deficits. The research described herein was designed to advance our knowledge regarding ethanol's insult to the developing brain, with much of it directed toward testing the hypothesis that the application of magnetic resonance-based imaging to the examination of brain morphology, regional volumes and fiber tracts in ethanol-exposed fetal mice would facilitate new discoveries. As with other teratogens, it is well known that the type and severity of abnormality induced by ethanol is dependent upon the dose, timing, and pattern of maternal exposure. For this study, the CNS dysmorphology resulting from acute gestational day (GD) 7 maternal ethanol administration was examined in fetal mice utilizing state of the art imaging techniques. This time in mouse development is consistent with that in the third week of human gestation. Magnetic resonance microscopy (MRM) allowed for linear, volumetric and 3-dimensional morphologic analyses of ethanol-induced alterations in the fetal CNS and diffusion tensor imaging (DTI) provided for assessment of fiber tract abnormalities. In addition, routine histological techniques were utilized for detailed examination of the ventromedian forebrain in ethanol-exposed embryos and fetuses.;Major new findings from these studies include the following regarding the consequences of acute GD7 ethanol exposure in mice (1) cerebral cortical heterotopias are induced; a discovery that was facilitated by MRM-based analyses, (2) fiber tract abnormalities involving the corpus callosum, anterior commissure, and fornix/fimbria occur, as evidenced by DTI, (3) fiber tract abnormalities, as identified in fetal mice, persist into periadolescent stages, (4) ventral forebrain insult preferentially involving the preoptic area and medial ganglionic eminences reduces Olig2 and GABA expression and alters the morphology of somatostatin-expressing cells. Overall, the results of this work promise to aid in clinical recognition, diagnosis, and prevention of FASD.