Abstract
Jegou et al. (2012) have reported prenatal alcohol exposure (PAE)-induced reductions of angiogenesis-related proteins in mouse placenta. These effects were associated with striking alterations in microvascular development in neonatal cerebral cortex. Here, we employed a rat model of moderate PAE to search for additional proteins whose placental and fetal cortical expression is altered by PAE, along with a subsequent examination of fetal cerebral cortical alterations associated with altered protein expression. Long-Evans rat dams voluntarily consumed either a 0 or 5% ethanol solution 4 h each day throughout gestation. Daily ethanol consumption, which resulted in a mean peak maternal serum ethanol concentration of 60.8 mg/dL, did not affect maternal weight gain, litter size, or placental or fetal body weight. On gestational day 20, rat placental: fetal units were removed by Caesarian section. Placental protein expression, analyzed by 2D-PAGE – tandem mass spectroscopy, identified a total of 1,117 protein spots, 20 of which were significantly altered by PAE. To date, 14 of these PAE-altered proteins have been identified. Western blotting confirmed the alterations of two of these placental proteins, namely, annexin-A4 (ANX-A4) and cerebral cavernous malformation protein 3 (CCM-3). Specifically, PAE elevated ANX-A4 and decreased CCM-3 in placenta. Subsequently, these two proteins were measured in fetal cerebral cortex, along with radiohistochemical studies of VEGF binding and histofluorescence studies of microvascular density in fetal cerebral cortex. PAE elevated ANX-A4 and decreased CCM-3 in fetal cerebral cortex, in a pattern similar to the alterations observed in placenta. Further, both VEGF receptor binding and microvascular density and orientation, measures that are sensitive to reduced CCM-3 expression in developing brain, were significantly reduced in the ventricular zone of fetal cerebral cortex. These results suggest that the expression angiogenesis-related proteins in placenta might serve as a biomarker of ethanol-induced alterations in microvascular development in fetal brain.
Highlights
Moderate drinking during pregnancy can cause subtle, longterm cognitive impairments in affected offspring, even in the absence of the physical defects associated with Fetal Alcohol Syndrome (Hanson et al, 1978; Shaywitz et al, 1980; Abel, 1984; Conry, 1990; Streissguth et al, 1990)
We examined whether ANX-A4 and cerebral cavernous malformation protein 3 (CCM-3) would be altered in fetal cerebral cortex of prenatal alcohol exposure (PAE) offspring in a manner similar to the alterations observed in placenta
Given that CCM-3 impacts angiogenesis and regulates VEGFR2 endocytosis and expression in vascular endothelium (Fisher and Boggon, 2014), we investigated the effect of ethanol exposure on [125I]-VEGF binding to VEGF receptors in fetal cerebral cortex
Summary
Moderate drinking during pregnancy can cause subtle, longterm cognitive impairments in affected offspring, even in the absence of the physical defects associated with Fetal Alcohol Syndrome (Hanson et al, 1978; Shaywitz et al, 1980; Abel, 1984; Conry, 1990; Streissguth et al, 1990). Various biochemical species and processes have been examined, some using high throughput screening procedures such as DNA methylation (Lussier et al, 2018), mRNA expression profiles (Rosenberg et al, 2010; Downing et al, 2012; Carter et al, 2018), miRNA expression profiles (Balaraman et al, 2014, 2016; Gardiner et al, 2016) and proteomic approaches (Datta et al, 2008; Ramadoss and Magness, 2012; Davis-Anderson et al, 2017) While these approaches have identified a large array of novel targets affected by drinking during pregnancy, to date, there have been very few efforts to link these PAE-induced alterations in a biomarker to specific downstream consequences in brain that could be directly associated with altered neurodevelopment and adverse behavioral consequences
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