Sex Difference in Alcohol-Related Organ Injury (original) (raw)
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Alcoholic liver injury: Influence of gender and hormones
World Journal of Gastroenterology: WJG, 2010
This article discusses several subjects pertinent to a consideration of the role of gender and hormones in alcoholic liver injury (ALI). Beginning with an overview of factors involved in the pathogenesis of ALI, we review changes in sex hormone metabolism resulting from alcohol ingestion, summarize research that points to estrogen as a cofactor in ALI, consider evidence that gut injury is linked to liver injury in the setting of alcohol, and briefly review the limited evidence regarding sex hormones and gut barrier function. In both women and female animals, most studies reveal a propensity toward greater alcohol-induced liver injury due to female gender, although exact hormonal influences are not yet understood. Thus, women and their physicians should be alert to the dangers of excess alcohol consumption and the increased potential for liver injury in females.
Increased severity of alcoholic liver injury in female verses male rats: A microarray analysis
Experimental and Molecular Pathology, 2008
Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines. Am J Physiol Gastrointest Liver Physiol 281: G1348-G1356, 2002.-Alcoholic liver injury is more severe and rapidly developing in women than men. To evaluate the reason(s) for these gender-related differences, we determined whether pathogenic mechanisms important in alcoholic liver injury in male rats were further upregulated in female rats. Male and age-matched female rats (7/group) were fed ethanol and a diet containing fish oil for 4 wk by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. We analyzed liver histopathology, lipid peroxidation, cytochrome P-450 (CYP)2E1 activity, nonheme iron, endotoxin, nuclear factor-B (NF-B) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-␣ (TNF-␣), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). Alcohol-induced liver injury was more severe in female vs. male rats. Female rats had higher endotoxin, lipid peroxidation, and nonheme iron levels and increased NF-B activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-␣ and COX-2 levels were similar in male and female rats. Remarkably, female rats fed fish oil and dextrose also showed necrosis and inflammation. Our findings in ethanol-fed rats suggest that increased endotoxemia and lipid peroxidation in females stimulate NF-B activation and chemokine production, enhancing liver injury. TNF-␣ and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences.
Life Sciences, 2004
Evidence has been presented suggesting that females are significantly more susceptible to alcohol-induced liver damage (ALD) than males. In the current study, we examined sexual dimorphism in hepatic pathology, metabolism and cytokine profiles using two different rat models of ALD. Male and female Sprague-Dawley or Wistar rats were fed ethanol-containing low-carbohydrate liquid diets using oral or intragastric methods for 42 or 60 days. In both models, ethanol treatment produced similar significant liver hyperplasia accompanied by increases in plasma ALT, steatosis, inflammation and necrosis (p < 0.05). Greater pathology scores were observed in the intragastrically infused rats. Males did not differ significantly from females in serum ALT values or pathology despite greater elevations in TNFa and IL-1h mRNAs in ethanol-treated female rat livers ( p < 0.05). Furthermore, there was no sexual dimorphism in blood ethanol concentrations or CYP2E1-induction even though sexually dimorphic alterations in other hepatic cytochrome P450 enzymes were observed. These data do (M.J.J. Ronis). www.elsevier.com/locate/lifescie Life Sciences 75 (2004) 469 -483 not support previous observations that female rats have a greater susceptibility to ethanol-induced hepatotoxicity than males. D 2004 Elsevier Inc. All rights reserved.
Estrogen is involved in early alcohol-induced liver injury in a rat enteral feeding model
Hepatology, 2000
The aim of this study was to investigate whether reduction in blood estrogen by removal of the ovaries would decrease the sensitivity of female rats to early alcoholinduced liver injury using an enteral ethanol feeding model, and if so, whether estrogen replacement would compensate. Livers from ovariectomized rats with or without estrogen replacement after 4 weeks of continuous ethanol exposure were compared with nonovariectomized rats in the presence or absence of ethanol. Ethanol increased serum alanine transaminase (ALT) levels from 30 ؎ 6 to 64 ؎ 7 U/L. This effect was blocked by ovariectomy (31 ؎ 7) and totally reversed by estrogen replacement (110 ؎ 23). Ethanol increased liver weight and fat accumulation, an effect that was minimized by ovariectomy and reversed partially by estrogen replacement. Infiltrating leukocytes were increased 6.7-fold by ethanol, an effect that was blunted significantly by ovariectomy and reversed by estrogen replacement. Likewise, a similar pattern of changes was observed in the number of necrotic hepatocytes. Blood endotoxin and hepatic levels of CD14 messenger RNA (mRNA) and protein were increased by ethanol. This effect was blocked in ovariectomized rats and elevated by estrogen replacement. Moreover, Kupffer cells isolated from ethanol-treated rats with estrogen replacement produced more tumor necrosis factor ␣ (TNF-␣) than those from control and ovariectomized rats. It is concluded, therefore, that the sensitivity of rat liver to alcohol-induced injury is directly related to estrogen, which increases endotoxin in the blood and CD14 expression in the liver, leading to increased TNF-␣ production. (HEPATOLOGY 2000;31:117-123.)
Influence of Sex Hormonal Status on Alcohol-Induced Oxidative Injury in Male and Female Rat Liver
Alcoholism: Clinical and Experimental Research, 2000
Background: Oxidative stress contributes to the development of liver injury after chronic alcohol intake. Women exhibit greater sensitivity to alcohol-induced liver disease than do men. The aim of the study was to determine the relationship between the sex hormone status of male and female rats and the degree of alcohol-induced oxidative stress in the liver.
Sex differences in hepatic gene expression in a rat model of ethanol-induced liver injury
Journal of applied physiology (Bethesda, Md. : 1985), 2002
Sex differences in susceptibility to alcohol-induced liver injury have been observed in both humans and experimental animal models. Using a standard model of alcohol-induced fatty liver injury and microarray analysis, we have identified differential expression of hepatic genes in both sexes. The genes that exhibit differential expression are of three types: those that are changed only in male rats fed alcohol, those that change in only female rats fed alcohol, and those that change in both sexes, although not always in the same manner. Certain of the differentially expressed genes have previously been identified as participants in the induction of alcohol-induced liver injury. However, this analysis has identified a number of genes that heretofore have not been implicated in alcoholic liver injury; such genes may provide new areas of investigation into the pathogenesis of this disease.
Hepatic estrogen receptors and alcohol intake
Molecular and Cellular Endocrinology, 2002
Human liver contains estrogen receptors (ER) which render it sensitive to estrogen. Chronic ethanol ingestion in humans and rats results in alterations of circulating sex steroid levels and expression of sex hormone-dependent phenotype. The analysis and quantitation of hepatic estrogen receptor (ER) activity and sex hormone-responsive proteins have been performed over the past two decades. Alcohol abuse appears to induce an increase in ER content of human liver, especially in patients with alcoholic hepatitis actively drinking. This observation is reproduced in an experimental model of chronic alcohol feeding of rats. In male rat liver, the increased ER expression induced by alcohol is associated with an elevated proliferation rate of the hepatocytes. In female liver, the ER content is not affected by alcohol intake and apoptosis prevails over proliferation. The feminization of the liver in males may protect the liver from the severe alcohol-induced liver injury seen in females. #
Gender differences in early alcohol-induced liver injury: role of CD14, NF-kappaB, and TNF-alpha
American journal of physiology. Gastrointestinal and liver physiology, 2000
The purpose of this study was to determine whether early alcohol-induced liver injury (ALI) in females is associated with changes in CD14 on Kupffer cells, activation of hepatic nuclear factor (NF)-kappaB, and expression of tumor necrosis factor (TNF)-alpha mRNA. Male and female rats were given high-fat control or ethanol-containing diets for 4 wk using the intragastric enteral protocol. Physiological parameters were similar in both genders. Ethanol was increased as tolerance developed with higher blood levels than previously observed, resulting in a fourfold increase in aspartate aminotransferase (males 389 +/- 47 IU/l vs. females 727 +/- 66 IU/l). Hepatic pathology developed more rapidly and was nearly twofold greater and endotoxin levels were significantly higher in females after ethanol. Also, expression of CD14 on Kupffer cells was 1.5-fold greater and binding of transcription factor NF-kappaB in hepatic nuclear extracts and TNF-alpha mRNA expression were threefold greater in f...
Gender differences in alcohol-induced neurotoxicity and brain damage
Toxicology, 2013
Considerable evidence has demonstrated that women are more vulnerable than men to the toxic effects of alcohol, although the results as to whether gender differences exist in ethanol-induced brain damage are contradictory. We have reported that ethanol, by activating the neuroimmune system and Toll-like receptors 4 (TLR4), can cause neuroinflammation and brain injury. However, whether there are gender differences in alcohol-induced neuroinflammation and brain injury are currently controversial. Using the brains of TLR4 +/+ and TLR4 −/− (TLR4-KO) mice, we report that chronic ethanol treatment induces inflammatory mediators (iNOS and COX-2), cytokines (IL-1, TNF-␣), gliosis processes, caspase-3 activation and neuronal loss in the cerebral cortex of both female and male mice. Conversely, the levels of these parameters tend to be higher in female than in male mice. Using an in vivo imaging technique, our results further evidence that ethanol treatment triggers higher GFAP levels and lower MAP-2 levels in female than in male mice, suggesting a greater effect of ethanol-induced astrogliosis and less MAP-2 + neurons in female than in male mice. Our results further confirm the pivotal role of TLR4 in alcoholinduced neuroinflammation and brain damage since the elimination of TLR4 protects the brain of males and females against the deleterious effects of ethanol. In short, the present findings demonstrate that, during the same period of ethanol treatment, females are more vulnerable than males to the neurotoxic/neuroinflammatory effects of ethanol, thus supporting the view that women are more susceptible than men to the medical consequences of alcohol abuse.