title: Molecular characterization of isocyanate-induced male germ-line genomic instability.
abstract: Male reproductive health is exquisitely sensitive to environmental insults as evidenced by the rising incidence of testicular cancers and low and probably declining semen quality. Isocyanates, such as methyl isocyanate (MIC), with their wide industrial applications, are known to exert severe ill health effects. The present study was performed to find out the pathophysiological implications of isocyanate exposure on the male germ line. The investigations were performed in the cultured mouse spermatogonial GC-1 spg cell line using N-succinimidyl N-methylcarbamate, a surrogate chemical to MIC. DNA damage, oxidative stress and apoptosis response parameters increased with time of exposure and dose after treatment. Treated cells also displayed elevated levels of inflammatory cytokines as well as morphological transformation and stress-responsive senescence. Chromosomal aberrations, telomere anomaly, aneuploidy and variable amplification of microsatellite repeats additionally indicated induced genomic instability. This was accompanied by evidence of a deregulation of cell cycle progression, such as substantial fold-changes in the expression of proliferating cell nuclear antigen, Cyclin D1, Bcl-2 and Bax genes; and aberrant expression of p53, cyclin A, cyclin E, CDK-2 and aurora kinase-B proteins. Our results demonstrate that MIC in the form of N-succinimidyl N-methylcarbamate promotes germ-line genomic instability in vitro. We envisage that understanding the interplay between environmental toxin-induced signaling and predisposition to testicular cancers would spur identification of meaningful targets for useful therapeutic translational modalities.
authors.affiliation: Department of Research, Bhopal Memorial Hospital & Research Centre, Bhokal, India.
authors.forename: Gorantla Venkata
authors.initials: GV
authors.lastname: Raghuram
authors.forename: Neelam
authors.initials: N
authors.lastname: Pathak
authors.forename: Deepika
authors.initials: D
authors.lastname: Jain
authors.forename: Hemant
authors.initials: H
authors.lastname: Pandey
authors.forename: Hariom
authors.initials: H
authors.lastname: Panwar
authors.forename: Subodh Kumar
authors.initials: SK
authors.lastname: Jain
authors.forename: Smita
authors.initials: S
authors.lastname: Banerjee
authors.forename: Pradyumna Kumar
authors.initials: PK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D016207:Cytokines / Q000032:analysis; D004249:DNA Damage; D042822:Genomic Instability / Q000187:drug effects*; D017953:Isocyanates / Q000633:toxicity*; D008297:Male; D051379:Mice; D053842:Microsatellite Instability; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D016207:Cytokines; D017953:Isocyanates; D017382:Reactive Oxygen Species