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Binge Alcohol Exposure in Adolescence Impairs Normal Heart Growth.

ABSTRACT: Background Approximately 1 in 6 adolescents report regular binge alcohol consumption, and we hypothesize it affects heart growth during this period. Methods and Results Adolescent, genetically diverse, male Wistar rats were gavaged with water or ethanol once per day for 6 days. In vivo structure and function were assessed before and after exposure. Binge alcohol exposure in adolescence significantly impaired normal cardiac growth but did not affect whole-body growth during adolescence, therefore this pathology was specific to the heart. Binge rats also exhibited signs of accelerated pathological growth (concentric cellular hypertrophy and thickening of the myocardial wall), suggesting a global reorientation from physiologic to pathologic growth. Binge rats compensated for their smaller filling volumes by increasing systolic function and sympathetic stimulation. Consequently, binge alcohol exposure increased PKA (protein kinase A) phosphorylation of troponin I, inducing myofilament calcium desensitization. Binge alcohol also impaired in vivo relaxation and increased titin-based cellular stiffness due to titin phosphorylation by PKC? (protein kinase C ?). Mechanistically, alcohol inhibited extracellular signal-related kinase activity, a nodal signaling kinase activating physiology hypertrophy. Thus, binge alcohol exposure depressed genes involved in growth. These cardiac structural alterations from binge alcohol exposure persisted through adolescence even after cessation of ethanol exposure. Conclusions Alcohol negatively impacts function in the adult heart, but the adolescent heart is substantially more sensitive to its effects. This difference is likely because adolescent binge alcohol impedes the normal rapid physiological growth and reorients it towards pathological hypertrophy. Many adolescents regularly binge alcohol, and here we report a novel pathological consequence as well as mechanisms involved.

SUBMITTER: Ai L

PROVIDER: S-EPMC7428579 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Binge Alcohol Exposure in Adolescence Impairs Normal Heart Growth.

Ai Lizhuo L Perez Edith E Asimes AnnaDorothea A Kampaengsri Theerachat T Heroux Maxime M Zlobin Andrei A Hiske Mark A MA Chung Charles S CS Pak Toni R TR Kirk Jonathan A JA

Journal of the American Heart Association 20200422 9

Background Approximately 1 in 6 adolescents report regular binge alcohol consumption, and we hypothesize it affects heart growth during this period. Methods and Results Adolescent, genetically diverse, male Wistar rats were gavaged with water or ethanol once per day for 6 days. In vivo structure and function were assessed before and after exposure. Binge alcohol exposure in adolescence significantly impaired normal cardiac growth but did not affect whole-body growth during adolescence, therefore ...[more]

PMID: 32319345

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Project description:Adolescent binge alcohol exposure has been previously shown to have long-lasting effects on the expression of hypothalamic genes that regulate the stress response, even in the absence of subsequent adult alcohol exposure. Those data suggested that alcohol can induce permanent gene expression changes, potentially through epigenetic modifications. Importantly, epigenetic modifications can be transmitted to future generations therefore, in these studies we investigated the effects of adolescent binge alcohol exposure on hypothalamic gene expression patterns in the F1 generation offspring. It has been well documented that maternal alcohol exposure during fetal development can have devastating neurological consequences. However, less is known about the consequences of maternal and/or paternal alcohol exposure outside of the gestational time frame. Here, we exposed adolescent male and female rats to a repeated binge EtOH exposure paradigm and then mated them in adulthood. Hypothalamic samples were taken from the offspring of these animals at postnatal day (PND) 7 and subjected to a genome-wide microarray analysis followed by qRT-PCR for selected genes. Importantly, the parents were not intoxicated at the time of mating and were not exposed to EtOH at any time during gestation therefore, the offspring were never directly exposed to EtOH. Our results showed that the offspring of alcohol-exposed parents had significant differences in the expression of hypothalamic genes that mediate neurogenesis and synaptic plasticity during neurodevelopment, genes important for directing chromatin remodeling, posttranslational modifications or transcription regulation, as well as genes involved in regulation of obesity and reproductive function. These data demonstrate that repeated binge alcohol exposure during pubertal development can potentially have detrimental effects on future offspring even in the absence of direct fetal alcohol exposure. Male and female Wistar rats were purchased from Charles River Laboratories (Wilmington, MA) at weaning (postnatal day (PND) 23) and allowed to acclimate for 7 days after arrival. Animals were handled for 5 min./once/day beginning at PND 30. Pubertal EtOH exposure began on PND 37, which is defined as peri-puberty. Animals were undisturbed following the first exposure of our binge EtOH exposure paradigm until PND 68 (late puberty/early adult) at which time they received a second exposure to the same treatment paradigm. During the duration of the experiment, males and females were separately housed in pairs on a 12:12 light/dark cycle with lights on at 0700 h with food and water available ad libitum. Binge Exposure Paradigm and Treatment Design. Rats were handled 5min./once/day for 7 d prior to treatment to control for nonspecific stress responses. At 37 d, animals were given 3 g/kg EtOH (20% v/v in tap water; N = 3/sex), or tap water alone (N = 3/sex), once/day via oral gavage at 10:00 AM to avoid disrupting normal feeding patterns. This process was repeated according to the following schedule for a total duration of 8 consecutive days: 3 d EtOH, 2 d tap water, 3 d EtOH. Control animals were given tap water alone once/day for 8 consecutive days. Our previous studies showed that this repeated binge-pattern EtOH paradigm does not affect body weight/growth curves and consistently results in blood alcohol concentrations (BAC) of 150-180 mg/dl in males and 210-240 mg/dl in females. We and others have previously used this paradigm as a model for the pattern of binge alcohol consumption observed in adolescents and BAC achieved are similar to those observed in humans following a binge drinking episode . After peri-pubertal treatments, animals were left undisturbed in their home cage until PND 68 when each group was again exposed to their respective treatment (i.e. control or binge EtOH. We waited 24 hours after the last dose of EtOH to ensure that blood alcohol concentrations in the parents were undetectable at the time of mating (data not shown). Animals were grouped into mating pairs: binge male + binge female (N = 3 pairs); water male + water female (N = 3 pairs). All of the females gave birth to 12-16 pups approximately 28 d after being housed with a male, indicating that conception took place approximately 6 d after pairing; therefore, the pups were never directly exposed to alcohol at any time. At PND 7 pups were deeply anesthetized on ice and sacrificed. Brains were rapidly removed, the hypothalamus microdissected on ice, and then stored in -80ºC until further processing for a genome-wide analysis on hypothalamic total RNA samples using a chip-based microarray (Southern California Genotyping Consortium, SCGC, Illumina Rat Ref-12). The PND 7 time point was chosen because the extent of rat neurodevelopment at PND 7 is roughly equivalent to that of a human infant at birth

Project description:IntroductionAlcohol use disorders are major risk factors for the development of and susceptibility to acute respiratory distress syndrome. Although these risks of alcohol consumption on the lung are well described, mechanisms by which alcohol abuse promotes acute lung injury are poorly understood. These gaps in our understanding are due, at least in part, to limitations of animal models to recapitulate human alcohol consumption. Recently, a new model of chronic plus binge alcohol exposure was developed that is hypothesized to better model drinking patterns of individuals with alcohol use disorders. Specifically, this paradigm models chronic consumption coupled with periodic bouts of heavy drinking. The impacts of this alcohol-exposure regimen on the lung are uncharacterized. Therefore, the goal of this study was to examine lung injury and inflammation in a well-characterized experimental model of chronic + binge alcohol exposure.Methods10-week-old male C57Bl6/J mice were administered ethanol-containing (or isocaloric control) liquid diet for 10 days, followed by a single ethanol gavage (5 g/kg). Lung inflammation and pulmonary function were assessed.ResultsTen days of ethanol-containing liquid diet alone (chronic) did not detectably affect any variables measured. However, ethanol diet plus gavage (chronic + binge) caused neutrophils to accumulate in the lung tissue and in the bronchoalveolar lavage fluid 24 h post-binge. This inflammatory cell recruitment was associated with airway hyper-responsiveness to inhaled methacholine, as indicated by elevated resistance, Newtonian resistance, and respiratory resistance.ConclusionsTaken together, the novel findings reveal that ethanol alone, absent of any secondary inflammatory insult, is sufficient to produce inflammation in the lung. Although these changes were relatively mild, they were associated with functional changes in the central airways. This animal model may be useful in the future for identifying mechanisms by which alcohol abuse sensitizes at-risk individuals to lung injury.

Project description:Brain developmental lesions are a devastating consequence of prenatal alcohol exposure (PAE). We recently showed that PAE affects cortical vascular development with major effects on angiogenesis and endothelial cell survival. The underlying molecular mechanisms of these effects remain poorly understood. This study aimed at characterizing the ethanol exposure impact on the autophagic process in brain microvessels in human fetuses with fetal alcohol syndrome (FAS) and in a PAE mouse model. Our results indicate that PAE induces an increase of autophagic vacuole number in human fetal and neonatal mouse brain cortical microvessels. Subsequently, ex vivo studies using green fluorescent protein (GFP)-LC3 mouse microvessel preparations revealed that ethanol treatment alters autophagy in endothelial cells. Primary cultures of mouse brain microvascular endothelial cells were used to characterize the underlying molecular mechanisms. LC3 and p62 protein levels were significantly increased in endothelial cells treated with 50?mM ethanol. The increase of autophagic vacuole number may be due to excessive autophagosome formation associated with the partial inhibition of the mammalian target of rapamycin pathway upon ethanol exposure. In addition, the progression from autophagosomes to autolysosomes, which was monitored using autophagic flux inhibitors and mRFP-EGFP vector, showed a decrease in the autolysosome number. Besides, a decrease in the Rab7 protein level was observed that may underlie the impairment of autophagosome-lysosome fusion. In addition, our results showed that ethanol-induced cell death is likely to be mediated by decreased mitochondrial integrity and release of apoptosis-inducing factor. Interestingly, incubation of cultured cells with rapamycin prevented ethanol effects on autophagic flux, ethanol-induced cell death and vascular plasticity. Taken together, these results are consistent with autophagy dysregulation in cortical microvessels upon ethanol exposure, which could contribute to the defects in angiogenesis observed in patients with FAS. Moreover, our results suggest that rapamycin represents a potential therapeutic strategy to reduce PAE-related brain developmental disorders.

Project description:Adolescent binge alcohol exposure has long-lasting effects on the expression of hypothalamic genes that regulate the stress response, even in the absence of subsequent adult alcohol exposure. This suggests that alcohol can induce permanent gene expression changes, potentially through epigenetic modifications to specific genes. Epigenetic modifications can be transmitted to future generations therefore, and in these studies we investigated the effects of adolescent binge alcohol exposure on hypothalamic gene expression patterns in the F1 generation offspring. It has been well documented that maternal alcohol exposure during fetal development can have devastating neurological consequences. However, less is known about the consequences of maternal and/or paternal alcohol exposure outside of the gestational time frame. Here, we exposed adolescent male and female rats to a repeated binge EtOH exposure paradigm and then mated them in adulthood. Hypothalamic samples were taken from the offspring of these animals at postnatal day (PND) 7 and subjected to a genome-wide microarray analysis followed by qRT-PCR for selected genes. Importantly, the parents were not intoxicated at the time of mating and were not exposed to EtOH at any time during gestation therefore the offspring were never directly exposed to EtOH. Our results showed that the offspring of alcohol-exposed parents had significant differences compared to offspring from alcohol-naïve parents. Specifically, major differences were observed in the expression of genes that mediate neurogenesis and synaptic plasticity during neurodevelopment, genes important for directing chromatin remodeling, posttranslational modifications or transcription regulation, as well as genes involved in regulation of obesity and reproductive function. These data demonstrate that repeated binge alcohol exposure during pubertal development can potentially have detrimental effects on future offspring even in the absence of direct fetal alcohol exposure.

Dataset Information

Binge Alcohol Exposure in Adolescence Impairs Normal Heart Growth.

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Binge Alcohol Exposure in Adolescence Impairs Normal Heart Growth.

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