Developmental exposure to ethanol leads to a constellation of cognitive and behavioral abnormalities known as Fetal Alcohol Spectrum Disorders (FASDs). Many cell types throughout the central nervous system are negatively impacted by gestational alcohol exposure, including inhibitory, GABAergic interneurons. Little evidence exists, however, describing the long-term impact of fetal alcohol exposure on survival of interneurons within the hippocampal formation, which is critical for learning and memory processes that are impaired in individuals with FASDs. Mice expressing Venus yellow fluorescent protein in inhibitory interneurons were exposed to vaporized ethanol during the third trimester equivalent of human gestation (postnatal days 2-9), and the long-term effects on interneuron numbers were measured using unbiased stereology at P90. In adulthood, interneuron populations were reduced in every hippocampal region examined. Moreover, we found that a single exposure to ethanol at P7 caused robust activation of apoptotic neurodegeneration of interneurons in the hilus, granule cell layer, CA1 and CA3 regions of the hippocampus. These studies demonstrate that developmental ethanol exposure has a long-term impact on hippocampal interneuron survivability, and may provide a mechanism partially explaining deficits in hippocampal function and hippocampus-dependent behaviors in those afflicted with FASDs.
Millions of people suffer mild traumatic brain injuries (mTBIs) every year, and there is growing evidence that repeated injuries can result in long-term pathology. The acute symptoms of these injuries may or may not include the loss of consciousness but do include disorientation, confusion, and/or the inability to concentrate. Most of these acute symptoms spontaneously resolve within a few hours or days. However, the underlying physiological and cellular mechanisms remain unclear.
Excessive alcohol consumption is a risk factor associated with colorectal cancer; however, some epidemiological studies have reported that moderate alcohol consumption may not contribute additional risk or may provide a protective effect reducing colorectal cancer risk. Prior research highlights the importance of proliferation, differentiation, and apoptosis as parameters to consider when evaluating colonic cell growth and tumorigenesis. The present study investigated whether chronic low-to-moderate ethanol consumption altered these parameters of colonic cell growth and expression of related genes. Twenty-four nondeprived young adult (109 days old) and 24 nondeprived middle-aged (420 days old) Wistar rats were randomly assigned to an ethanol-exposed or a water control group (n = 12/group). The ethanol group was provided voluntary access to a 20% v/v ethanol solution on alternate days for 13 weeks. Colon tissues were collected for quantitative immunohistochemical analyses of cell proliferation, differentiation and apoptosis using Ki-67, goblet cell and TUNEL, respectively. Gene expression of cyclin D1 (Ccnd1), Cdk2, Cdk4, p21waf1/cip1 (Cdkn1a), E-cadherin (Cdh1) and p53 were determined by quantitative real-time polymerase chain reaction in colonic scraped mucosa. Ethanol treatment resulted in a lower cell proliferation index and proliferative zone, and lower Cdk2 expression in both age groups, as well as trends toward lower Ccnd1 and higher Cdkn1a expression. Cell differentiation was modestly but significantly reduced by ethanol treatment only in older animals. Overall, older rats showed decreases in apoptosis and gene expression of Cdk4, Cdh1, and p53 compared to younger rats, but there was no observed effect of ethanol exposure on these measures. These findings suggest that low-to-moderate ethanol consumption improves at least one notable parameter in colonic tumorigenesis (cell proliferation) and associated gene expression regardless of age, however, selectively decreased cell differentiation among older subjects.
Our previous research showed that moderate ethanol consumption reduced colonic cell proliferation regardless of age. To examine the underlying mechanism, this study examined gene expression related to colonic cell growth. Twenty‐four nondeprived young adult (109 days old) Wistar rats and twenty‐four nondeprived middle‐aged (420 days old) Wistar rats were randomly assigned to an ethanol‐exposed or a non ethanol‐exposed (water control) group (n = 12 per group). The ethanol group was provided voluntary access to a 20% v/v ethanol solution on alternate days for 13 weeks (45 ethanol drinking sessions total), a paradigm which results in mean blood alcohol levels of ~30–50 mg/dl (0.03–0.05 mg%) in the outbred Wistar strain when measured 30–120 min into a standard drinking session. The control group was provided with standard drinking water during the same period. Gene expression of cyclin D1, cyclin dependent kinase 2 (CDK2), cyclin dependent kinase 4 (CDK4), p21, E‐cadherin and p53 were determined by real time polymerase chain reaction in colonic scraped mucosa. CDK2 was downregulated in ethanol‐fed rats compared to the control group (P = 0.017). Cyclin D1 trended toward lower expression (P = 0.095), and p21 trended toward higher expression (P = 0.095) in ethanol‐fed rats compared to controls, with no observed effect of age for either gene. Older rats showed significant decreases in CDK4 (P = 0.001), E cadherin (P = 0.013), and p53 (P = 0.005), with no observed effect of ethanol exposure. These results indicate that moderate ethanol consumption may improve expression of some genes related to important parameters of colonic cell growth and tumorigenesis. Support or Funding Information NIH AA023291
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