Magnetic resonance microscopy-based analyses of the neuroanatomical effects of gestational day 9 ethanol exposure in mice

Abstract

Animal model-based studies have shown that ethanol exposure during early gestation induces developmental stage-specific abnormalities of the face and brain. The exposure time-dependent variability in ethanol’s teratogenic outcomes is expected to contribute significantly to the wide spectrum of effects observed in humans with fetal alcohol spectrum disorder (FASD). The work presented here employs a mouse FASD model and magnetic resonance microscopy (MRM; high resolution magnetic resonance imaging) in studies designed to further our understanding of the developmental stage-specific defects of the brain that are induced by ethanol. At neurulation stages, i.e. at the beginning of gestational day (GD) 9 and again 4 hours later, time-mated C57Bl/6J dams were intraperitoneally administered 2.9 g/kg ethanol or vehicle. Ethanol-exposed fetuses were collected on GD 17, processed for MRM analysis, and results compared to comparably staged controls. Linear and volume measurements as well as shape changes for numerous individual brain regions were determined. GD 9 ethanol exposure resulted in significantly increased septal region width, reduction of cerebellar volume, and enlargement of all of the ventricles. Additionally, the results of shape analyses showed that many areas of the ethanol-exposed brains including the cerebral cortex, hippocampus and right striatum were significantly misshapen. These data demonstrate that ethanol can induce dysmorphology that may not be obvious based on volumetric analyses alone, highlight the asymmetric aspects of ethanol-induced defects, and add to our understanding of ethanol’s developmental stage-dependent neuroteratogenesis.

Radiological studies of fetal alcohol spectrum disorders in humans and animal models: An updated comprehensive review

“…The cerebellum was 14% smaller with a significant change in shape, and bilaterally asymmetric, while the right and left cortices exhibited a trend towards slightly decreased volume. The cerebral cortex, hippocampus and right striatum were significantly distorted [159].…”

“…Both of these processes have been confirmed in a number of PAE studies using a histological approach (for example [176]). Asymmetric alterations within a single brain structure, such as the cerebellum in the mice following GD9 exposure [159] and the cortical lobes in humans [5;17;27] were also reported. were not consistently observed in animals.…”

Effects of prenatal alcohol exposure (PAE): insights into FASD using mouse models of PAE

“…Seminal research by Sulik and colleagues has shown that a single acute dose of alcohol on each of these 3 days can produce distinct and profound craniofacial malformations that are reminiscent of sentinel clinical features of FAS (Parnell et al 2009, 2013; Godin et al 2010; Lipinski et al 2012). Sulik and colleagues used 2 doses of alcohol = 2.9 g/kg (4 h apart, i.p.)…”

“…Mouse models of early neurulation GD9–10 PAE show brain volume abnormalities compared with the controls but do not result in facial dysmorphologies (O’Leary-Moore et al 2010; Parnell et al 2013). In their MRI studies, Parnell and colleagues demonstrated that in contrast to GD7–8 PAE embryos, GD9–10 PAE embryos have no statistically significant reduction in crown–rump length or total body volume compared with their stage-matched controls (O’Leary-Moore et al 2010; Parnell et al 2013). GD9–10 PAE embryos also have a significant reduction in total brain volume of ~13.6% compared with the stage-matched controls (O’Leary-Moore et al 2010; Parnell et al 2013).…”

Effects of all three trimester moderate binge alcohol exposure on the foetal hippocampal formation and olfactory bulb

“…Further, there is a preferentially selective and dose-dependent effect on the foetal dentate gyrus in response to pre-natal alcohol exposure, with changes exhibited in the density and/or number of dentate gyrus granule cells and with none of these alterations being observed when the exposure period does not include the third trimester-equivalent. In addition, rodent studies using other modalities, such as magnetic resonance imaging and behavioural testing, to evaluate the hippocampus have also found that change in volume may not be a sensitive indicator of pre-natal alcohol exposure, but that functional deficits and surface and shape changes are present that indicate damage does indeed occur [35–37]. The findings from this study utilizing unbiased stereologic analysis highlight the need to critically evaluate the sensitivity as well as specificity of screening methods being developed to assess injury from prenatal alcohol exposure.…”