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
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 for developing colorectal cancer while others suggest that moderate alcohol consumption may provide a protective effect that reduces colorectal cancer risk. Prior experimental data have indicated the importance of proliferation, differentiation, and apoptosis as parameters to consider when evaluating colonic cell growth and tumorigenesis. Chemopreventative agents are reported to decrease cell proliferation and to increase differentiation and apoptosis. The present study examined whether chronic low‐to‐moderate ethanol consumption had an effect on these parameters of colonic cell growth. Twenty‐four nondeprived young adult (109 days old) Wistar rats (n=12/group) and twenty‐four nondeprived middle‐aged (420 days old) Wistar rats (n=12/group) were allowed to voluntarily consume a 20% v/v ethanol solution on alternate days for 13 weeks (45 ethanol drinking sessions total) or were given access only to water (non ethanol‐exposed control). The intermittent access 20% ethanol drinking paradigm utilized results in mean blood alcohol levels of ~30–50 mg/dl in the outbred Wistar strain when measured 30–120 min into a standard drinking session. Following the final experimental session, colon tissues were collected for quantitative immunohistochemical analyses of cell proliferation, differentiation and apoptosis using Ki‐67, goblet cell and TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling), respectively. Ethanol treatment resulted in a lower cell proliferation index in both young (P = 0.05) and older (P < 0.001) rats, as well as a lower proliferative zone (P < 0.01 for both ages). Older rats had a shorter colon, but there was no significant difference for proliferation index between young and old rats. Cell differentiation between ethanol‐treated animals and controls was not significant for young rats, but older rats had a lower level of differentiation in the ethanol group. For apoptosis, there was no significant effect of ethanol treatment for either young or old rats. Younger rats had higher values than older rats for both differentiation and apoptosis (P < 0.05). These findings suggest that moderate consumption of ethanol improves at least one notable parameter (cell proliferation) in colonic tumorigenesis regardless of age, however, reduced cell differentiation among older animals. Support or Funding Information Support Contributed By: NIH AA023291
Many alcohol‐induced health complications are directly attributable to the toxicity of alcohol or its metabolites, but another potential health impact of alcohol may be on the microbial communities of the human gut. Clear distinctions between healthy and diseased‐state gut microbiota have been observed in subjects with metabolic diseases and recent studies suggest that chronic alcoholism is linked to gut microbiome dysbiosis. Here, we investigated the effects of alcohol consumption on the gut microbiome in both rats and humans. The gut microbiota of rats voluntarily consuming a 20% ethanol solution, on alternate days, were compared to a non‐exposed control group to identify differential taxonomic and functional profiles. Gut microbial diversity profiles were determined using culture‐independent amplification, next‐generation sequencing and bioinformatic analysis of bacterial 16S ribosomal RNA gene sequence libraries. Our results showed that, compared to controls, ethanol‐consuming rats experienced a significant decline in the biodiversity of their gut microbiomes, a state generally associated with dysbiosis. We also observed significant shifts in the overall diversity of the gut microbial communities and a dramatic change in the relative abundance of particular microbes, such as the Lactobacilli. We also compared our results to human fecal microbiome data collected as part of the citizen science American Gut Project. In contrast to the rat data, human drinkers had significantly higher gut microbial biodiversity than non‐drinkers. However, we also observed that microbes that differed among the human subjects displayed similar trends in the rat model, including the Lactobacilli as well as bacteria implicated in metabolic disease.Support or Funding InformationNIH AA023291This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Previous epidemiological studies and experimental data from rodent models have reported a non‐linear relationship between consumption of alcohol and cardiovascular disease risk and colorectal health. These studies indicate that light‐to‐moderate alcohol consumption, in contrast to excessive alcohol use, may provide cardiovascular health benefits as well as a protective effects on risk for colorectal cancer. Although prior studies have examined the effects of moderate ethanol consumption primarily in young adult animals, it is unknown if the results can be extrapolated to older adults or if these effects may be more pronounced in aging animals due to declining indices of health.. This study examined the effects of moderate ethanol consumption on lipid profile and colonic gene expression in older rats. Twenty‐four non deprived middle aged (420 days old) Wistar rats (n=12/group) were allowed to voluntarily consume a 20% v/v ethanol solution on alternate days for 13 weeks or were given access to water as their sole source of fluid (non‐ethanol exposed control). Moderate ethanol consumption significantly increased HDL cholesterol levels (P = 0.016) and ApoA1 (P = 0.048) compared to control. There were no differences in serum triglyceride, total cholesterol, LDL cholesterol, oxidized LDL and glucose between the groups. Blood C‐reactive protein (CRP) was decreased significantly (P = 0.034) in ethanol‐exposed animals. Blood high‐mobility group protein 1 (HMGB1) showed a decreased trend in the ethanol group (P = 0.083). In colon, gene expression of aldehyde dehydrogenase (Aldh) displayed an increased trend in ethanol‐exposed rats (P = 0.073). Colonic superoxide dismutase (Sod) was upregulated with ethanol intervention (P = 0.050). Colonic gene expression of cyclooxygenase 2 (Cox‐2), RelA, b‐catenin, CD68, and Pparr were not different between the groups. These results suggest that moderate consumption of ethanol in older rats may potentially contribute to improved cardiovascular and colorectal cancer risk by improving blood cholesterol, decreasing blood markers of inflammation in and increasing antioxidant enzyme expression in colon. Support or Funding Information NIH AA023291
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