title: Epigenetic dimension of oxygen radical injury in spermatogonial epithelial cells.
abstract: The present work reports a direct role of mitochondrial oxidative stress induced aberrant chromatin regulation, as a central phenomenon, to perturbed genomic integrity in the testicular milieu. Oxygen-radical injury following N-succinimidyl N-methylcarbamate treatment in mouse spermatogonial epithelial (GC-1 spg) cells induced functional derailment of mitochondrial machinery. Mitophagy resulted in marked inhibition of mitochondrial respiration and reduced mtDNA copy number. Impaired cell cycle progression along with altered H3K9me1, H4K20me3, H3, AcH3 and uH2A histone modifications were observed in the treated cells. Dense heterochromatin foci and aberrant expression of HP1α in nuclei of treated cells implied onset of senescence associated secretory phenotype mediated through nuclear accumulation of NF-κB. Neoplastic nature of daughter clones, emerged from senescent mother phenotypes was confirmed by cytogenetic instability, aberrant let-7a and let-7b miRNA expression and anchorage independent growth. Together, our results provide the first insights of redox-dependent epigenomic imbalance in spermatogonia, a previously unknown molecular paradigm.
authors: Translational Research Lab, School of Biological Sciences, Dr. H.S. Gour Central University, Sagar, India; Division of Translational Research, Tata Memorial Centre, ACTREC, Navi Mumbai, India. Electronic address: pkm_8bh@yahoo.co.uk.
authors: Pradyumna K
authors: PK
authors: Mishra
authors: Translational Research Lab, School of Biological Sciences, Dr. H.S. Gour Central University, Sagar, India.
authors: Neha
authors: N
authors: Bunkar
authors: Translational Research Lab, School of Biological Sciences, Dr. H.S. Gour Central University, Sagar, India; Division of Translational Research, Tata Memorial Centre, ACTREC, Navi Mumbai, India.
authors: Gorantla V
authors: GV
authors: Raghuram
authors: Division of Translational Research, Tata Memorial Centre, ACTREC, Navi Mumbai, India.
authors: Naveen K
authors: NK
authors: Khare
authors: Translational Research Lab, School of Biological Sciences, Dr. H.S. Gour Central University, Sagar, India.
authors: Neelam
authors: N
authors: Pathak
authors: Translational Research Lab, School of Biological Sciences, Dr. H.S. Gour Central University, Sagar, India; Division of Translational Research, Tata Memorial Centre, ACTREC, Navi Mumbai, India.
authors: Arpit
authors: A
authors: Bhargava
mesh_terms: D000818:Animals; D000975:Antioxidants; D002219:Carbamates / Q000633:toxicity; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000032:analysis; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects*; D042421:Histone Code / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D053842:Microsatellite Instability; D008928:Mitochondria / Q000737:chemistry / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity*; D013093:Spermatogonia / Q000187:drug effects* / Q000648:ultrastructure
chemical_list: D000975:Antioxidants; D002219:Carbamates; D004272:DNA, Mitochondrial; D016328:NF-kappa B; D017382:Reactive Oxygen Species
keywords: DNA methylation; Histone modifications; Isocyanate toxicity; Mitochondria; Senescence; miRNA