Chronic Moderate Alcohol Consumption Research Articles

Chronic Alcohol Exposure Causes Myeloid-Biased Hematopoiesis Via Double-Strand RNA Sensors and Type 1 Interferon Response

Excessive alcohol use is well-known to cause cytopenias and bone marrow (BM) suppression. However, the mechanisms by which alcohol suppresses BM are poorly understood. Moreover, even though the prevalence of moderate drinking is high worldwide, the effects of chronic moderate alcohol consumption on the human hematopoietic system remain unknown. To fill this knowledge gap, we sought to investigate the effects of chronic moderate alcohol consumption on human hematopoiesis using cell-based and animal models. To examine the effects of alcohol on hematopoietic cells in vitro, we tested varying doses of alcohol (0-100 mM) on four leukemia cell lines (Jurkat, MOLM13, MV-4-11, and THP1) and measured population doubling over 6 days. Population doubling levels significantly decreased in a dose-dependent manner in all cell lines tested. We also measured mitochondrial (mt) ROS by MitoSOX-Red flow cytometry in Jurkat, which showed a dose-dependent increase of mtROS (trends only at 10, 25 mM; significantly increased at 50, 100 mM alcohol) compared to untreated. These findings confirm that alcohol negatively affects cell growth and increases mtROS in a physiologic range of doses. To determine the effects of alcohol on human hematopoietic stem progenitor cells (HSPCs) in vitro, we treated human BM CD34+ cells with 0 vs. 50 mM alcohol for 48 hours and performed bulk RNA-sequencing in triplicate. Gene Set Enrichment Analysis (GSEA) revealed that multiple pathways related to platelet activation and coagulation were enriched in alcohol-treated HSPCs, suggesting the induction of inflammation and/or platelet-biased differentiation by alcohol. To assess the effects of chronic moderate alcohol consumption on HSPCs in vivo, we employed a xenotransplant model. In brief, human BM CD34+ cells were transplanted to 5-to-6-week-old female NBSGW mice. We confirmed their engraftment by bone marrow aspiration at six weeks post-transplant, and then they were randomly assigned to the alcohol vs. control groups. After 2 weeks of adjustment, mice were fed a liquid diet (their only source of water and food) containing alcohol 5% vol/vol vs. iso-caloric control diet for 8 weeks. At 4 and 8 weeks, the alcohol-fed group showed significant myeloid bias, reaching greater than 3 times higher myeloid-to-lymphoid ratio than the control group at 8 weeks, while overall engraftment levels were not different. We will report the results of the secondary transplantation of this experiment at the annual meeting. After 8-week alcohol feeding, sorted human CD45+CD34+ cells from mouse BM were subject to 10x Genomics Chromium X 3' HT single-cell RNA-sequencing (scRNA-seq). Complementing the flow data, our transcriptomic data portrayed stark differences between the two groups. Over 50% of cells in the alcohol group comprised granulocyte progenitors, with B cell progenitors representing less than 25%. Inversely, control group data revealed approximately 30% granulocyte progenitors and 55% B cell progenitors, confirming the myeloid bias of HSPC caused by alcohol. Examining differentially expressed genes and GSEA highlighted a significant upregulation of genes associated with the response to virus and type 1 interferon (IFN-1) signature across all HSPC types. A closer look into the gene set showed increased expression of genes tied to cytosolic double-strand (ds) RNA sensing pathways and subsequent interferon type 1 response. Specifically, dsRNA sensors like MDA5, RIG1, PKR, and OAS1-3, as well as interferon regulatory or responsive genes, such as IRF7, ISG15, IFI6, IFI44L, MX1, and STAT1, were notably increased in HSCs and most progenitor populations. Unexpectedly, alcohol-exposed HSCs tended to be in the G0/G1 phase rather than the S or M phase compared to their counterpart upon cell cycle analysis using scRNA-seq data. This may be due to the activation of the PKR pathway, a known cell cycle inhibitor in mouse HSCs. In summary, our findings demonstrate that chronic moderate alcohol consumption can significantly reshape the hematopoietic system through myeloid-biased differentiation and potentiate inflammation by activating the cytosolic dsRNA sensing pathways and IFN-1 response.

Impact and potential mechanism of effects of chronic moderate alcohol consumption on cardiac function in aldehyde dehydrogenase 2 gene heterozygous mice.

BackgroundMitochondrial aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in alcohol metabolism. The ALDH2*2 mutations are found in approximately 45% of East Asians, with 40% being heterozygous (HE) ALDH2*1/*2 and 5% homozygous (HO) ALDH2*2/*2. Studies have shown that HO mice lack cardioprotective effects induced by moderate alcohol consumption. However, the impact of moderate alcohol consumption on cardiac function in HE mice is unknown.MethodsIn this study, HO, HE, and wild‐type (WT) mice were subjected to a 6‐week moderate alcohol drinking protocol, following which myocardial tissue and cardiomyocytes of the mice were extracted.ResultsWe found that moderate alcohol exposure did not increase mortality, myocardial fibrosis, apoptosis, or inflammation in HE mice, which differs from the effects observed in HO mice. After exposure to the 6‐week alcohol drinking protocol, there was impaired cardiac function, cardiomyocyte contractility, and intracellular Ca2+ homeostasis and mitochondrial function in both HE and HO mice as compared to WT mice. Moreover, these animals showed overt oxidative stress production and increased levels of the activated forms of calmodulin‐dependent protein kinase II (CaMKII) and ryanodine receptor type 2 (RYR2) phosphorylation protein.ConclusionWe found that moderate alcohol exposure impaired cardiac function in HE mice, possibly by increasing reactive oxygen species (ROS)/CaMKII/RYR2‐mediated Ca2+ handling abnormalities. Hence, we advocate that people with ALDH2*1/*2 genotypes rigorously avoid alcohol consumption to prevent potential cardiovascular harm induced by moderate alcohol consumption.

Effects of moderate alcohol consumption on behavior and neural systems of Wistar rats.

Chronic alcohol consumption affects various neurotransmitters, especially those implicated in the transitioning to alcohol use disorders (particularly dopaminergic and CRFergic systems). Few studies have investigated moderate alcohol consumption and its harmful consequences. The objective of this work was to analyze behavioral and neurochemical (dopaminergic and CRFergic systems) alterations during chronic moderate alcohol consumption. Twelve male Wistar rats were submitted to an intermittent alcohol ingestion protocol (alcohol group) for four weeks. The control group consisted of six rats. Open Field and Elevated Plus Maze tests were used for analysis of motor and anxiety-like behaviors. Immunohistochemistry analysis was performed in dopaminergic and CRFergic systems. Animals exposed to alcohol consumed moderate doses, chronic and intermittently. Behavioral tests detected fewer fecal boli in the alcohol exposed group, and immunohistochemical analysis indicated fewer dopamine-immunoreactive cells in the ventral tegmental area, and more CRF-immunoreactive cells in the anterior cingulate cortex and dorsolateral septum in this group. Thus we concluded that Wistar rats that consumed moderate doses of alcohol voluntarily and chronically showed a discreet anxiolytic effect in behavior, and a hypodopaminergic and hyperCRFergic neurochemical condition, which together are strong inducers of alcohol consumption predisposing to the development of alcohol use disorder (AUD).

Effects of chronic moderate alcohol consumption on right ventricle and pulmonary remodelling

What is the central question of this study? Does the consumption of a moderate amount of alcohol differentially impact the heart ventricles and pulmonary vasculature. What is the main finding and its importance? Moderate alcohol consumption for a short period of time impaired pulmonary vascular cellular renewal through an apoptosis resistance pattern that ultimately affected the right ventricular function and structure. These findings support the need for a deeper understanding of effects of moderate alcohol consumption on the overall cardiovascular and pulmonary systems. Over the past decades, observational studies have supported an association between moderate alcohol consumption and a lower risk of cardiovascular disease and mortality. However, recent and more robust meta-analyses have raised concerns around the robustness of the evidence for the cardioprotective effects of alcohol. Also, studies of the functional, structural and molecular changes promoted by alcohol have focused primarily on the left ventricle, ignoring the fact that the right ventricle could adapt differently. The aim of this study was to evaluate the bi-ventricular impact of daily moderate alcohol intake, during a 4-week period, in a rodent model. Male Wistar rats were allowed to drink water (Control) or a 5.2% ethanol mixture (ETOH) for 4weeks. At the end of the protocol bi-ventricular haemodynamic recordings were performed and samples collected for further histological and molecular analysis. ETOH ingestion did not impact cardiac function. However, it caused right ventricle hypertrophy, paralleled by an activation of molecular pathways responsible for cell growth (ERK1/2, AKT), proteolysis (MURF-1) and oxidative stress (NOX4, SOD2). Furthermore, ETOH animals also presented remodelling of the pulmonary vasculature with an increase in pulmonary arteries' medial thickness, which was characterized by increased expression of apoptosis-related proteins expression (BCL-XL, BAX and caspases). Moderate alcohol consumption for a short period of time impaired the lungs and the right ventricle early, before any change could be detected on the left ventricle. Right ventricular changes might be secondary to alcohol-induced pulmonary vasculature remodelling.

Experimental alcoholism primes structural and functional impairment of the glymphatic pathway

Alcoholism is a risk factor for the development of cognitive decline and dementia. Here we demonstrated that the glymphatic function in the brain was impaired by alcohol administration. Acute moderate alcohol administration substantially retarded and reduced the entry of subarachnoid cerebrospinal fluid (CSF) via the paravascular space into the cerebral parenchyma, thus impaired CSF-interstitial fluid (ISF) exchange and parenchymal amyloid β (Aβ) peptide clearance. The elevated release of β-endorphin and reduced cerebrovascular pulsatility after acute alcohol administration may account for the impairment of the glymphatic function. Chronic moderate alcohol consumption led to pronounced activation of astrocytes and a widespread loss of perivascular AQP4 polarization in the brain, which results in an irreversible impairment of the glymphatic function. The results of the study suggest that impaired glymphatic functions and reduced parenchymal Aβ clearance found in both acute and chronic alcohol treatment may contribute to the development of cognitive decline and dementia in alcoholism.

Chronic moderate alcohol consumption relieves high-fat high-cholesterol diet-induced liver fibrosis in a rat model.

Nonalcoholic fatty liver disease is a worldwide health issue and chronic alcohol consumption may have different effects on this disease. This study explored the role of chronic moderate alcohol consumption on high-fat high-cholesterol (HFHC) diet-induced liver fibrosis in a rodent model. Male Sprague-Dawley rats were divided into five groups: standard chow group, standard chow plus Er Guo Tou (EGT, a Chinese spirit made from fermented cereals) group, HFHC group, HFHC plus EGT group, and HFHC plus pure ethanol (EtOH) group. Rats were fed standard chow or HFHC chow for 12weeks. EGT or pure ethanol was administrated at a daily dose of 4g/kg body weight via intra-gastric gavage from week 4. At the end of week 12, hematoxylin and eosin staining, Sirius red and immunohistochemistry of liver sections were examined. The hepatic expression of F4/80, TNF-α, IL-1β, IL-6, CXCL1, CXCL2, α-SMA, Collagen, TGF-β, MMP2, MMP9, and TIMP1 was calculated. Both moderate EGT and pure ethanol did not increase plasma endotoxin in the portal vein comparing with the FHFC group. EGT and pure ethanol did not improve hepatic inflammation, but ameliorated liver fibrosis in histology. Moderate EGT and pure ethanol ameliorated HFHC diet-induced activation of Kupffer cells and hepatic stellate cells. In conclusion, chronic moderate EGT and pure ethanol could ameliorate HFHC diet-induced liver fibrosis.

Chronic moderate alcohol drinking alters insulin release without affecting cognitive and emotion-like behaviors in rats.

Because the consumption of alcoholic beverages prevails in society, its effects on diabetes risk is a subject of interest. Extant literature on this issue often disagrees. Here, we probed the effects of chronic moderate ethanol consumption on glucose metabolism in rats. The effect of chronic moderate alcohol drinking on depression- and anxiety-like behaviors and memory was also explored. Adolescent male and female Long-Evans rats consumed saccharin-sweetened 5% (1 week) and 10% ethanol (7 weeks) under a 7.5-h/day (Monday-Friday) access schedule. This exposure was followed by sucrose preference and elevated plus maze (EPM) tests during an intervening week, before a 6-week intermittent-access (Monday, Wednesday, Friday) to 20% unsweetened ethanol in a 2-bottle choice drinking paradigm was implemented (EtOH). A free-feeding control group received water (Water). Our prior work revealed that voluntary ethanol consumption decreases food intake in rats. Hence, a second control group that received water was mildly food-restricted (FR), and their average body weight was matched to that of the EtOH group. During the week following week 6 of intermittent-access to 20% ethanol, rats were submitted to sucrose preference, EPM, and novel object recognition (NOR) tests. Insulin response to a glucose load was subsequently assessed via an oral glucose tolerance test (OGTT). Rats attained and maintained blood ethanol concentrations of ∼55mg/dL that correlated with the dose of sweetened 10% ethanol ingested. Relative to intake by Water controls, EtOH rats consumed less chow. There was no body weight difference between both groups. Neither sex of EtOH rats showed increased depression- and anxiety-like behaviors, as respectively measured by sucrose preference and EPM, nor did they show deficit in object recognition memory during abstinence. Male EtOH rats, however, showed signs of reduced general activity on the EPM. During OGTT, male EtOH rats showed a time-dependent potentiation of insulin release for proper glucose clearance. Such an effect was not observed in females. This landmark study shows that chronic moderate alcohol consumption can have negative metabolic consequences in the absence of overt behavioral deficits, especially in males.

Alcohol Consumption Modulates Host Defense in Rhesus Macaques by Altering Gene Expression in Circulating Leukocytes.

Several lines of evidence indicate that chronic alcohol use disorder leads to increased susceptibility to several viral and bacterial infections, whereas moderate alcohol consumption decreases the incidence of colds and improves immune responses to some pathogens. In line with these observations, we recently showed that heavy ethanol intake (average blood ethanol concentrations > 80 mg/dl) suppressed, whereas moderate alcohol consumption (blood ethanol concentrations < 50 mg/dl) enhanced, T and B cell responses to modified vaccinia Ankara vaccination in a nonhuman primate model of voluntary ethanol consumption. To uncover the molecular basis for impaired immunity with heavy alcohol consumption and enhanced immune response with moderate alcohol consumption, we performed a transcriptome analysis using PBMCs isolated on day 7 post-modified vaccinia Ankara vaccination, the earliest time point at which we detected differences in T cell and Ab responses. Overall, chronic heavy alcohol consumption reduced the expression of immune genes involved in response to infection and wound healing and increased the expression of genes associated with the development of lung inflammatory disease and cancer. In contrast, chronic moderate alcohol consumption upregulated the expression of genes involved in immune response and reduced the expression of genes involved in cancer. To uncover mechanisms underlying the alterations in PBMC transcriptomes, we profiled the expression of microRNAs within the same samples. Chronic heavy ethanol consumption altered the levels of several microRNAs involved in cancer and immunity and known to regulate the expression of mRNAs differentially expressed in our data set.

Abstract 1248: Environmental factors (heavy metal, alcohol) enhance tumor malignant behaviors

Abstract Global cancer incidence and mortality increases dramatically word wild, epically in China, even though significant progress has been made against cancer. Cancer will account for the first most common cause of disease-related death in China. Abundant evidences demonstrated both genetic and environmental factors might contribute to human cancer initiation and progression. In our lab, we focus on role of gain-of-function mutant SHP-2 (genetic factor) and heavy mental contamination or alcohol drinking (environmental factors) on tumor progression. Here, we reported environmental factors like heavy mental arsenic and alcohol consumption promote digestive tumor and breast cancer malignant behaviors. The first, clinic data showed that an increasing arsenic concentration in III/IV TNM stage gastric cancer patient, then an enhanced cancer cell malignant behaviors (proliferation/ motility/ metastasis, etc) were found in gastric cancer or colon cancer cell lines chronic treated with 5-15 nm arsenic in vitro and in vivo. EMT might contribute to this promotion process induced by arsenic. The second: a positive correlation between alcohol consumption and advanced Tumor-Node-Metastasis (TNM) stages, higher vessel invasion and poorer prognosis in Hepatocellular carcinoma (HCC) were found. In vitro and in vivo experiments further indicated that alcohol promoted the progression and migration/invasion of HCC, breast cancer and lewis lung carcinoma (LLC). Specifically, we found that alcohol enhanced the migration/invasion of tumor cells and increased tumor angiogenesis. Consistently, higher expression of VEGF, MCP-1, activated NF-κB and more infiltrated M2 macrophage was observed in tumor tissues of alcohol-drinkers. Alcohol induced the accumulation of intracellular reactive oxygen species (ROS) and the activation of NF-κB signaling in HepG2 cells. Conversely, blockage of alcohol-mediated ROS accumulation and NF-κB signaling inhibited alcohol-induced expression of VEGF and MCP-1, the tumor growth, angiogenesis and metastasis. These results suggested that chronic moderate alcohol consumption may promote the progression and metastasis of tumor; the oncogenic effect may be at least partially mediated by the ROS accumulation and NF-ĸB-dependent VEGF and MCP-1 up-regulation. Even more, an increasing cancer stem cell population was found in tumor cell lines under low dose alcohol induction. Our results make us presume chronic stress induced by environmental factors like alcohol, heavy mental, etc might activate cell signal and enhance tumor progression in a universal way. Those studies will be benefited to tumor prevention. This study was supported by a grant from the National Natural Science Foundation of China (codes: 30873046, 30973424, and 81072663). Note: This abstract was not presented at the meeting. Citation Format: Siying Wang. Environmental factors (heavy metal, alcohol) enhance tumor malignant behaviors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1248. doi:10.1158/1538-7445.AM2015-1248

Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma.

BackgroundHepatocellular carcinoma (HCC), the most common form of primary liver cancer, is the third leading cause of cancer-related death in human. Alcohol is a known risk factor for HCC. However it is still unclear whether and how alcohol enhances the progression and metastasis of existing HCC.Methods and resultsWe first retrospectively investigated 52 HCC patients (24 alcohol-drinkers and 28 non-drinkers), and found a positive correlation between alcohol consumption and advanced Tumor-Node-Metastasis (TNM) stages, higher vessel invasion and poorer prognosis. In vitro and in vivo experiments further indicated that alcohol promoted the progression and migration/invasion of HCC. Specifically, in a 3-D tumor/endothelial co-culture system, we found that alcohol enhanced the migration/invasion of HepG2 cells and increased tumor angiogenesis. Consistently, higher expression of VEGF, MCP-1 and NF-κB was observed in HCC tissues of alcohol-drinkers. Alcohol induced the accumulation of intracellular reactive oxygen species (ROS) and the activation of NF-κB signaling in HepG2 cells. Conversely, blockage of alcohol-mediated ROS accumulation and NF-κB signaling inhibited alcohol-induced expression of VEGF and MCP-1, the tumor growth, angiogenesis and metastasis.ConclusionThis study suggested that chronic moderate alcohol consumption may promote the progression and metastasis of HCC; the oncogenic effect may be at least partially mediated by the ROS accumulation and NF-ĸB-dependent VEGF and MCP-1 up-regulation.

Chronic moderate alcohol consumption induces iNOS expression in the penis: An immunohistochemical study.

To investigate the effect of moderate alcohol consumption on metabolic alterations, inducible nitric oxide synthase (iNOS), immunohistochemical distribution, and morphological damage to penile erectile tissue in rats. Male Wistar albino rats were divided into 2 groups. Group 1 rats (control group, n = 8) received tap water ad libitum, and group 2 rats (n = 8) were fed with 20% ethanol. Increasing levels of alcohol were given to the rats over 12 weeks. Immunohistochemistry was then performed using the avidin-biotin-peroxidase technique on 5-pm thickness tissue sections. Stained sections were examined by imaging microscope. Alcohol consumption resulted in a significant increase in iNOS immunoreactivity in the penile erectile tissue. Increased iNOS expression was determined in the tunica albuginea, cavernosal smooth muscle cells, trabeculae of connective tissue, arterioles, and the urethral epithelium. Moreover, chronic alcohol consumption resulted in decreasing serum testosterone and high density lipoprotein (HDL) levels with increasing cholesterol and triglyceride levels. Chronic moderate alcohol consumption can affect penile erectile tissue by increasing iNOS immunoreactivity and induce histopathological damage such as penile fibrosis. These abnormalities are also related to the defense mechanism against morphological damage.

Effects of chronic moderate alcohol consumption and novel environment on heart rate variability in primates (Macaca fascicularis)

The effects of chronic moderate alcohol consumption on cardiac function are not understood. Acute stress may affect cardiac function by shifting autonomic cardiac regulation in favor of the sympathetic nervous system. Although alcohol consumption often increases at times of stress, the interactive effects of stress and chronic moderate alcohol consumption on cardiac regulation have not been studied. The objective was to assess the effects of long-term (1-2 years) moderate (a two-drink/day equivalent, 5 days/week) alcohol consumption on heart rate (HR) variability under normal and acutely stressful conditions in small stable groups of ovariectomized adult cynomolgus monkeys (Macaca fascicularis). Monkeys were trained to voluntarily drink their daily alcohol dose (<30 min), and blood levels were determined an hour later. The animals were acutely stressed by removal from the home cage to a novel environment for 30 min. HR in freely moving subjects was recorded via telemetry in the home cage and the novel environment. Acute stress increased HR, decreased HR variability, and decreased the high frequency component of the power spectrum suggesting reduced parasympathetic cardiac modulation. Chronic moderate alcohol consumption decreased HR variability and the low frequency components of the power spectrum. When stressed, monkeys with a history of chronic moderate alcohol consumption had higher HRs than the controls. HR dynamics in monkeys rapidly respond to acute stress. Chronic moderate alcohol consumption may be deleterious to cardiac function. HR response to stress may be exaggerated when accompanied by a history of chronic moderate alcohol consumption.

Health Risks of Chronic Moderate and Heavy Alcohol Consumption: How Much Is Too Much?

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. Most of what we know about the deleterious effects of alcohol in vivo has been gleaned from studies in sober alcoholics recruited from substance abuse treatment programs. Little is known about effects of chronic drinking in the moderate or heavy range encountered in a much larger fraction of modern society. Extrapolation of information on the adverse effects of chronic drinking on organ function from clinical samples to social drinkers in the general population has to be met with great skepticism, as it may lead to wrong conclusions about the chronic effects of alcohol in social drinkers. Several recent studies suggest that moderate alcohol consumption has certain beneficial health effects, whereas heavy social alcohol consumption has recently been associated with organ abnormalities and cognitive deficits. These social drinking effects have attracted great public interest; reports of benefits of moderate drinking have also inspired inappropriate publications by the media, including misleading advertisements by the alcohol producing and distributing industry. Although adverse effects of moderate to heavy drinking on heart, liver, and cancer development have attracted attention by clinicians and researchers for some time, its compromising effects on brain and cognition have only recently been studied. This symposium brought together researchers from different disciplines, who reviewed and presented new data on consequences of social drinking in the areas of clinical neuropsychology and behavior (Drs. Nixon and Meyerhoff), neurophysiology (Dr. Nixon, Ms. De Bruin), neuroimaging (Ms. de Bruin, Dr. Meyerhoff), hepatic disease (Dr. Bode), and cancer (Dr. Seitz). The symposium aimed to clarify both the potential health benefits of moderate alcohol consumption and risks of moderate and heavy drinking on proper organ function and to provide insights and new data to practicing physicians and public health authorities for education on problem drinking.

Effects of social status and moderate alcohol consumption on mammary gland and endometrium of surgically postmenopausal monkeys.

To evaluate the effects of social subordination stress and chronic moderate alcohol consumption on indices of breast and endometrial cancer risk. Forty-six adult, ovariectomized, cynomolgus monkeys (Macaca fascicularis) were trained to voluntarily drink a placebo or a two-drink/day equivalent of ethanol (0.5 g/kg), 5 days a week for 26 months, the latter resulting in average blood alcohol levels of 42 mg/100 mL. Indices of cell proliferation and sex steroid receptor abundance were measured. Compared with dominants, socially subordinate females had increased cell proliferation and proportions of glandular (P < 0.02) and epithelial tissue (P = 0.009) and less stroma (P < 0.02) in endometrium, and increased tissue thickness in breast (P < 0.05). There was no evidence of increased risk of breast or endometrial cancer with chronic moderate alcohol consumption, as indicated by markers of cell proliferation and sex steroid receptor abundance. Chronic moderate alcohol consumption did not effect circulating sex steroid concentrations (all P > 0.10). The adipocyte hormones leptin and adiponectin were correlated with indices of cell proliferation and sex steroid receptor abundance. These observations suggest that social status was more important than chronic moderate alcohol consumption in endometrial and breast biology of surgically postmenopausal females. Endogenous sex steroid metabolism was not significantly affected by chronic moderate alcohol exposure consistent with the lack of estrogen-like effects on breast and endometrium. Social subordination stress was associated with initial cellular changes that may increase endometrial cancer risk. Ovariectomized cynomolgus monkeys may be a useful model for the study of effects of social factors and obesity on breast and endometrial cancer risk.

Effect of acute and chronic moderate alcohol consumption on fasted and postprandial lipemia in the rat

Effects of acute and chronic alcohol intake on fasted and postprandial lipemia in the rat model are reported. In the acute study, fasted rats are loaded with a 30% w/w olive oil emulsion with or without 8% alcohol in the form of ethanol, beer or whisky. After 3 h, either mesenteric lymph or blood is collected and the TAG-rich lipoprotein fractions are isolated. In the chronic study, animals received, for a period of 10 weeks, 3% alcohol in drinking water in the form of ethanol, beer or whisky. Blood samples were collected from animals in either the fasted state or after being loaded with the fat load as described above. Alcohol ingestion along with a fat load increases the number (increased net apoB48 secretion) and reduces the size (reduced TAG/apoB48 ratio) of CM secreted into the mesenteric lymph duct. It also delays gastric emptying, reduces trans-enterocyte TAG flux rates and increases plasma concentrations of TAG, cholesterol and CM. Similar conditions also results in increased total phospholipid and cholesterol content of CM but not of VLDL, indicating an enhanced liver bile secretion into the gut; however, a significant increase in plasma VLDL concentration is observed. Unlike the acute study, an alcohol–fat load in animals put on chronic alcohol intake results in increased HDL cholesterol concentrations and less pronounced postprandial hypertriglyceridemia and hypercholesterolemia but not hyperchylomicronemia. In the fasted state, plasma TAG and total apoB concentrations are not modified in these animals, and an increase in HDL and a decrease in total and LDL cholesterol concentrations are observed. No liver function impairment is observed following the 10-week period of chronic alcohol intake. In conclusion, unlike binge drinking, chronic moderate alcohol consumption appears to have a cardioprotective effect in the fasted state, an effect attenuated by the observed temporary postprandial hyperchylomicronemia and hypertriglyceridemia resulting from a direct effect of alcohol on CM size and number.

Alterations in preimplantation in vivo development after preconceptional chronic moderate alcohol consumption in female mice.

Although many studies have explored the effects of acute or chronic ethanol exposure during the postimplantation period on embryo/fetal development, few reports have described the ethanol effects on preimplantation embryo development. Little is known about the effects of ethanol consumption prior to gestation on embryo growth. Recently, we have shown that chronic moderate ethanol intake by prepubertal female mice reduces the ovulatory response and impairs in vitro fertilization and in vitro embryo preimplantation development. The purpose of the present work was to evaluate the effects of preconceptional chronic moderate ethanol ingestion on preimplantation embryo morphology and differentiation, the timing of cleavage and embryo growth in vivo, and to determine the time pattern in which alterations appear. Prepubertal female mice were treated with 10% (w/v) ethanol for 30 days prior to conception. After inducing ovulation on day 27 and 29 of the ethanol treatment, females were mated with control males and the day of presence of vaginal plug was day 1. On day 1, a decreased percentage of normal fertilized oocytes, elevated parthenogenetic oocyte activation and unfertilized eggs with abnormal metaphase II were found in ethanol-treated, compared to control females. On day 2, while any differences in the total percentage of 2-cell embryos were observed, the treated females had a significantly higher percentage of morphologically abnormal embryos, compared to control females. On day 3, the preconceptional consumption of ethanol produced significantly reduced percentages of compacted morulae and an increased percentage of uncompacted morulae. The total percentage of morulae in the treated females was lower than in controls. On day 4, ethanol-treated females showed significantly decreased percentages of hatched attached blastocysts and increased early blastocyst and morula percentages, compared to controls. Thus, preconceptional chronic moderate ethanol ingestion by prepubertal female mice produced retarded development, impaired blastocyst hatching, abnormal embryo morphology and embryo loss by fragmentation due to alterations induced in the female gamete.

Chronic moderate alcohol consumption results in induction of nitric oxide synthase and cardio-vascular protection : R. Binsack, C.R. White, V. Darley-Usmar, C. Foster, F. Zhou and D.A. Parks. Depts. of Anesthesiology, Physiology, Pathology and UAB Center for Free Radical Biology, Univ. of Alabama at Birmingham, Birmingham, AL 35233 USA

Chronic moderate alcohol consumption results in induction of nitric oxide synthase and cardio-vascular protection : R. Binsack, C.R. White, V. Darley-Usmar, C. Foster, F. Zhou and D.A. Parks. Depts. of Anesthesiology, Physiology, Pathology and UAB Center for Free Radical Biology, Univ. of Alabama at Birmingham, Birmingham, AL 35233 USA

Comparison of plasma lipid and lipoprotein profiles in hypertensive black versus white men

An abnormal plasma lipid and lipoprotein profile is an independent and strong predictor of mortality and morbidity from coronary artery disease (CAD). We report on plasma lipid and lipoprotein profiles with respect to race, age, obesity, blood pressure (BP), smoking, and drinking history in 1,292 male veterans with a diastolic BP of 95 to 109 mm Hg while off antihypertensive medications. Blacks had 24% (p < 0.001) lower triglycerides than whites. In contrast, the following parameters were higher in blacks than in whites by the indicated percentages: high-density lipoprotein (HDL) cholesterol, 16% (p < 0.001); HDL 2 cholesterol, 36% (p < 0.001); apolipoprotein (Apo) A 1, 8% (p < 0.001); HDL/low-density lipoprotein (LDL), 18% (p = 0.018); HDL 2/LDL, 36% (p = 0.031); HDL 2 HDL 3 , 21% (p < 0.001); and Apo A 1 Apo B , 15% (p < 0.001). Triglycerides were unchanged up to age 60, but were lower by 24% (p < 0.001) in those aged ≥70. Apo A 1 levels were higher (p < 0.001), whereas LDL cholesterol was lower (p < 0.008) in moderate alcohol consumers versus abstainers. Triglycerides were higher (p < 0.001), whereas HDL, HDL 2 cholesterol, and Apo A 1 were lower (p < 0.001) with increasing obesity. Moderate alcohol consumption had a strong favorable effect on HDL, HDL 2, and HDL 3 cholesterol among subjects of normal weight, but this effect was diminished in obese subjects. Total and LDL cholesterol were higher by 6.4% (p = 0.001) and 9.4% (p < 0.003), respectively, whereas HDL cholesterol remained unchanged in those with diastolic BP of 105 to 109 mm Hg versus those with diastolic BP of 95 to 99 mm Hg. We conclude that hypertensive black men have lipid and lipoprotein profiles indicative of less CAD risk than white men. Chronic moderate alcohol consumption correlates with a favorable plasma lipid and lipoprotein profile in normal, but not obese, men. Obesity is associated with an adverse plasma lipid and lipoprotein profile. Thus, race, alcohol intake, and obesity may be important modifiers of CAD in untreated hypertensive men.

6 - Gastroduodenal Damage due to Drugs, Alcohol and Smoking

In man, convincing data have been obtained in short-term observations that some drugs can cause acute gastroduodenal damage including gastritis and erosions. Useful clinical and epidemiological studies on the relationship between these acute lesions and peptic ulceration, and between the chronic ingestion of these drugs and peptic ulceration or massive upper gastrointestinal haemorrhage are, however, rare. Even for the most widely used and studied greatest offender--acetylsalicylic acid (ASA)--an association with major bleeding or gastric ulceration could only be established for frequent and heavy ASA intake. The percentage of those ASA users who will experience such a serious event each year is about 0.01 to 0.05 per cent. By the use of special (e.g. enteric-coated) ASA formulations and other precautions, this low rate may be further reduced. Although for most of the other non-steroidal anti-inflammatory drugs (NSAIDs), anecdotal reports on putative drug-related major gastric bleeding or peptic ulceration exist, the ulcerogenicity of these drugs has not yet been conclusively proven in controlled studies. Some of the newer NSAIDs seem at normal dosage to be far less damaging than traditional ASA or indomethacin. Glucocorticoids might enhance ulcer risk to a minor extent when administered at high dosage for prolonged periods to susceptible individuals. Chronic moderate alcohol consumption by itself does not seem to increase the liability to peptic ulceration. With highly concentrated alcoholic beverages, gastric bleeding from acute lesions may, however, be occasionally precipitated under certain circumstances, such as when unbuffered ASA is taken concomitantly. Smoking of cigarettes is associated, and perhaps causally related, with an increased incidence of gastric and duodenal ulcerations, impaired ulcer healing, and more frequent ulcer recurrences. Duodenal ulcer patients in particular should be advised to stop smoking.