Alcohol exposure during development: Impact on the epigenome.

Fetal alcohol spectrum disorders represent a wide range of symptoms associated with in utero alcohol exposure. Animal models of FASD have been useful in determining the specific neurological consequences of developmental alcohol exposure, but the mechanisms of those consequences are unclear. Long-lasting changes to the epigenome are proposed as a mechanism of alcohol-induced teratogenesis in the hippocampus. The current study utilized a three-trimester rodent model of FASD to examine changes to some of the enzymatic regulators of the epigenome in adolescence. Combined pre- and post-natal alcohol exposureresulted in a significant increase in DNA methyltransferase activity (DNMT), without affecting histone deacetylase activity (HDAC). Developmental alcohol exposure also caused a change in gene expression of regulators of the epigenome, in particular, DNMT1, DNMT3a, and methyl CpG binding protein 2 (MeCP2). The modifications of the activity and expression of epigenetic regulators in the hippocampus of rodents perinatally exposed to alcohol suggest that alcohol's impact on the epigenome and its regulators may be one of the underlying mechanisms of alcohol teratogenesis.

Selective effects of perinatal ethanol exposure in medial prefrontal cortex and nucleus accumbens.

Ethanol exposure during development is the leading known cause of mental retardation and can result in characteristic physiological and cognitive deficits, often termed Fetal Alcohol Spectrum Disorders (FASD). Previous behavioral findings using rat models of FASD have suggested that there are changes in the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC) following ethanol exposure during development. This study used a rat model of FASD to evaluate dendritic morphology in both the NAC and mPFC and cell number in the NAC. Dendritic morphology in mPFC and NAC was assessed using a modified Golgi stain and analyzed via three dimensional reconstructions with Neurolucida (MBF Bioscience). Cell counts in the NAC (shell and core) were determined using an unbiased stereology procedure (Stereo Investigator (MBF Bioscience)). Perinatal ethanol exposure did not affect neuronal or glial cell population numbers in the NAC. Ethanol exposure produced a sexually dimorphic effect on dendritic branching at one point along the NAC dendrites but was without effect on all other measures of dendritic morphology in the NAC. In contrast, spine density was reduced and distribution was significantly altered in layer II/III neurons of the mPFC following ethanol exposure. Ethanol exposure during development was also associated with an increase in soma size in the mPFC. These findings suggest that previously observed sexually dimorphic changes in activation of the NAC in a rat model of FASD may be due to altered input from the mPFC.

Effects of intrauterine 2,3,7,8-tetrachlorodibenzo-p-dioxin on the development and function of the gonadotrophin releasing hormone neuronal system in the male rat.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental disrupter that continues to be generated from numerous industrial processes. In utero and lactational exposure of rats to levels of TCDD similar to those encountered by human populations have profound and persistent effects on growth, the reproductive axis and spatial learning and memory. TCDD is thought to act through the aryl hydrocarbon receptor, which displays crosstalk with estrogen-mediated genomic activation. An in vitro superfusion system was used to evaluate the effects of TCDD exposure on GnRH-release from hypothalamic explants at three developmental time points in male rats. Pregnant dams were treated with 5 microg/kg TCDD on gestational day 15, and male offspring displayed a marked reduction in GnRH release. However, total mediobasal hypothalamus/preoptic area (MBH/POA) GnRH content was significantly greater in dioxin-exposed animals. These results suggest deficits in release rather than production of GnRH. Confocal microscopy was used to characterize anatomical features of individual GnRH-positive neurons, as well as the organization of the neuronal network governing GnRH release. Differences in cellular structures were apparent in discrete regions of the GnRH neural network, specifically the lateral preoptic area and septal region. We propose that developmental reproductive effects in males treated in utero and lactionally with dioxin, results from a suppressive effect of TCDD on mechanisms governing GnRH release. These effects coincide with changes in growth and development, indicating that TCDD may induce a syndrome of effects by modifying hypothalamic structures regulating growth and reproductive development.