Background Prenatal ethanol (EtOH) and prenatal stress have both been independently shown to induce learning deficits and anxiety behavior in adult offspring. However, the interactive effects of these two developmental teratogens on behavioral outcomes have not been systematically evaluated. Methods We combined an established moderate prenatal EtOH consumption paradigm where Long-Evans rat dams voluntarily consume either a 0% or 5% EtOH solution in 0.066% saccharin water (resulting in a mean peak maternal serum EtOH concentration of 84 mg/dL) with a novel prenatal stress paradigm. Pregnant rats were exposed to 3% 2,3,5-trimethyl-3-thiazoline (TMT) for 20 minutes a day on Gestational Days 13, 15, 17, and 19. Adult female offspring were evaluated for anxiety-like behavior using an elevated plus maze and hippocampal-sensitive learning using a two-trial trace conditioning task. Results TMT exposure produced a three-fold increase in maternal serum corticosterone compared to non-exposed, unhandled controls. Neither prenatal exposure paradigm, either alone or in combination, altered maternal weight gain, ethanol consumption, maternal care of litters, litter size, pup birth weight, or pup weight gain up to weaning. Offspring exposed to prenatal stress displayed significant increases in anxiety-like behavior in the elevated plus maze in terms of open arm entries and time spent on the open arms, with no significant effect of prenatal EtOH exposure and no interaction of the two prenatal exposures. Performance in a two-trial trace conditioning task revealed a significant effect of prenatal ethanol exposure on freezing behavior on the testing day, with no significant effect of prenatal stress exposure and no interaction of the two prenatal exposures. Conclusions While each prenatal exposure independently produced different behavioral outcomes, the results indicate that there is no significant interaction of prenatal ethanol and prenatal stress exposures on learning or anxiety at the exposure levels employed in this dual exposure paradigm. Subsequent studies will examine whether similar outcomes occur in male offspring and whether other measures of anxiety or learning are differentially impacted by these prenatal exposure paradigms.

These results suggest that a PAE-induced elevation in H receptor-mediated inhibition of glutamate release from perforant path terminals as 1 mechanism contributing the LTP deficits previously observed in the dentate gyrus of PAE rats, as well as providing a mechanistic basis for the efficacy of H receptor inverse agonists for ameliorating these deficits.

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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-PAGEtandem 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

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