Project description:Background: The most important risk factors for head and neck squamous carcinoma (HNSCC) are tobacco smoking and alcohol consumption, while subgroups are caused by infection with human papillomaviruses (HPV) or Epstein-Barr virus (EBV). Here, we studied alterations of somatic copy-number in whole genome, p16 protein and TP53 mutations by alcohol drinking, smoking and viral infections. Methods: We conducted a prospective cohort study. DNA obtained from tumors and margin samples as well as peripheral blood was assayed by array comparative genomic hybridization using Agilent Whole Human Genome 180K. Mutations of p53 gene by direct sequencing, detection of HPV by polymerase-chain-reaction (PCR), quantification of EBV by reverse transcription-PCR and p16 immunohistochemical (IHC) staining were also performed. prospective cohort study: 225 tumor samples were analyzed by Agilent-022060 SurePrint G3 Human CGH miroarray 4x180K. Log2 Ratio (tumor sample DNA/normal DNA) were compared among none alcohol drinkers, moderate alcohol drinkers, heavy alcohol drinkers, none smokers, moderate smokers, heavy smokers and both. Sample characteristics weres scored as following; Human Papilloma Virus Infection (gene detected by PCR in tumor sample): positive=1; negative=0 p16 protein immunohistochemistry: positive=1; negative=0 tumor grade: matured=0; moderate=1; immature=2 Radiotherapy with or without chemotherapy after operation: performed =1; not performed =0 Recurrence/relapse: rec =1; not rec =0 suvival status:death=1; survive=0 smoking status (Pack year of smoking): none smoker=0; pack-year <20 = 1 (moderate smoker); pack-year <=20 = 2 (heavy smoker) alcohol drinking: Alcohol drinkers were divided into non-drinker or less than one drink per day =0: one and more but less than two drinks per day = moderate drinker 1: two and more drinks per day=heavy drinker 2: during the 20 years preceding their treatment for HNSCC. One drink was defined as containing approximately 10g of alcohol, which is considered equal to 30 ml of hard liquor, 100 ml of wine containing 12% alcohol, or 360 ml of beer.

Project description:Background Chronic preconception paternal alcohol use modifies the sperm epigenome, inducing fetoplacental growth defects in the offspring of exposed males. A crucial outstanding question in the field of paternal epigenetic inheritance concerns the resilience of the male reproductive tract and the germline's capacity to recover and correct sperm-inherited epigenetic errors after stressor withdrawal. Objectives We set out to determine if measures of the sperm-inherited epigenetic program revert to match the control treatment one month after withdrawing daily alcohol treatments. Materials and Methods Using a voluntary access model, we exposed C57Bl6/J males to 10% alcohol for ten weeks, withdrew alcohol treatment for four weeks, and used RNA sequencing to examine gene expression patterns in the caput section of the epididymis. We then compared the abundance of sperm small RNA species between treatments. Results In the caput section of the epididymis, chronic alcohol exposures induced changes in the transcriptional control of genetic pathways related to mitochondrial function, oxidative phosphorylation, the generalized stress response (EIF2 signaling), and Sirtuin signaling. Subsequent analysis identified region-specific, alcohol-induced changes in mitochondrial DNA copy number across the epididymis, which correlated with increases in the mitochondrial DNA content of alcohol-exposed sperm. Notably, in the corpus section of the epididymis, increases in mitochondrial DNA copy number persisted one month after alcohol cessation. Analysis of sperm noncoding RNAs between Control and Alcohol-Exposed males one month after alcohol withdrawal revealed a ~100-fold increase in mir-196a, a microRNA induced as part of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)-driven cellular antioxidant response. Discussion and Conclusion Our data reveal that alcohol-induced epididymal mitochondrial dysfunction and differences in sperm noncoding RNA content persist after alcohol withdrawal. Further, differences in mir-196a and sperm mitochondrial DNA copy number may serve as viable biomarkers of adverse alterations in the sperm-inherited epigenetic program.

Project description:Background Chronic preconception paternal alcohol use modifies the sperm epigenome, inducing fetoplacental growth defects in the offspring of exposed males. A crucial outstanding question in the field of paternal epigenetic inheritance concerns the resilience of the male reproductive tract and the germline's capacity to recover and correct sperm-inherited epigenetic errors after stressor withdrawal. Objectives We set out to determine if measures of the sperm-inherited epigenetic program revert to match the control treatment one month after withdrawing daily alcohol treatments. Materials and Methods Using a voluntary access model, we exposed C57Bl6/J males to 10% alcohol for ten weeks, withdrew alcohol treatment for four weeks, and used RNA sequencing to examine gene expression patterns in the caput section of the epididymis. We then compared the abundance of sperm small RNA species between treatments. Results In the caput section of the epididymis, chronic alcohol exposures induced changes in the transcriptional control of genetic pathways related to mitochondrial function, oxidative phosphorylation, the generalized stress response (EIF2 signaling), and Sirtuin signaling. Subsequent analysis identified region-specific, alcohol-induced changes in mitochondrial DNA copy number across the epididymis, which correlated with increases in the mitochondrial DNA content of alcohol-exposed sperm. Notably, in the corpus section of the epididymis, increases in mitochondrial DNA copy number persisted one month after alcohol cessation. Analysis of sperm noncoding RNAs between Control and Alcohol-Exposed males one month after alcohol withdrawal revealed a ~100-fold increase in mir-196a, a microRNA induced as part of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)-driven cellular antioxidant response. Discussion and Conclusion Our data reveal that alcohol-induced epididymal mitochondrial dysfunction and differences in sperm noncoding RNA content persist after alcohol withdrawal. Further, differences in mir-196a and sperm mitochondrial DNA copy number may serve as viable biomarkers of adverse alterations in the sperm- inherited epigenetic program.

Project description:Background Chronic preconception paternal alcohol use modifies the sperm epigenome, inducing fetoplacental growth defects in the offspring of exposed males. A crucial outstanding question in the field of paternal epigenetic inheritance concerns the resilience of the male reproductive tract and the germline's capacity to recover and correct sperm-inherited epigenetic errors after stressor withdrawal. Objectives We set out to determine if measures of the sperm-inherited epigenetic program revert to match the control treatment one month after withdrawing daily alcohol treatments. Materials and Methods Using a voluntary access model, we exposed C57Bl6/J males to 10% alcohol for ten weeks, withdrew alcohol treatment for four weeks, and used RNA sequencing to examine gene expression patterns in the caput section of the epididymis. We then compared the abundance of sperm small RNA species between treatments. Results In the caput section of the epididymis, chronic alcohol exposures induced changes in the transcriptional control of genetic pathways related to mitochondrial function, oxidative phosphorylation, the generalized stress response (EIF2 signaling), and Sirtuin signaling. Subsequent analysis identified region-specific, alcohol-induced changes in mitochondrial DNA copy number across the epididymis, which correlated with increases in the mitochondrial DNA content of alcohol-exposed sperm. Notably, in the corpus section of the epididymis, increases in mitochondrial DNA copy number persisted one month after alcohol cessation. Analysis of sperm noncoding RNAs between Control and Alcohol-Exposed males one month after alcohol withdrawal revealed a ~100-fold increase in mir-196a, a microRNA induced as part of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)-driven cellular antioxidant response. Discussion and Conclusion Our data reveal that alcohol-induced epididymal mitochondrial dysfunction and differences in sperm noncoding RNA content persist after alcohol withdrawal. Further, differences in mir-196a and sperm mitochondrial DNA copy number may serve as viable biomarkers of adverse alterations in the sperm-inherited epigenetic program.

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Bioenergetic mechanisms of alcohol-associated cirrhosis in patient derived hepatocytes

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