title: Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice.
abstract: Cisplatin administration induces DNA damage resulting in germ cell apoptosis and subsequent testicular atrophy. Although 50 percent of male cancer patients receiving cisplatin-based chemotherapy develop long-term secondary infertility, medical treatment to prevent spermatogenic failure after chemotherapy is not available. Under normal conditions, testicular p53 promotes cell cycle arrest, which allows time for DNA repair and reshuffling during meiosis. However, its role in the setting of cisplatin-induced infertility has not been studied. Ghrelin administration ameliorates the spermatogenic failure that follows cisplatin administration in mice, but the mechanisms mediating these effects have not been well established. The aim of the current study was to characterize the mechanisms of ghrelin and p53 action in the testis after cisplatin-induced testicular damage. Here we show that cisplatin induces germ cell damage through inhibition of p53-dependent DNA repair mechanisms involving gamma-H2AX and ataxia telangiectasia mutated protein kinase. As a result, testicular weight and sperm count and motility were decreased with an associated increase in sperm DNA damage. Ghrelin administration prevented these sequelae by restoring the normal expression of gamma-H2AX, ataxia telangiectasia mutated, and p53, which in turn allows repair of DNA double stranded breaks. In conclusion, these findings indicate that ghrelin has the potential to prevent or diminish infertility caused by cisplatin and other chemotherapeutic agents by restoring p53-dependent DNA repair mechanisms.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, Texas Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas Huffington Center on Aging, Baylor College of Medicine, Houston, Texas Jgarcia1@bcm.edu.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Garcia
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, Texas Department of Health Education, College of Preventive Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Ji-an
authors.initials: JA
authors.lastname: Chen
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, Texas Huffington Center on Aging, Baylor College of Medicine, Houston, Texas.
authors.forename: Bobby
authors.initials: B
authors.lastname: Guillory
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas Huffington Center on Aging, Baylor College of Medicine, Houston, Texas Department of Metabolism and Aging, The Scripps Research Institute Florida, Jupiter, Florida.
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
authors.affiliation: Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas Scott Department of Urology, Baylor College of Medicine, Houston, Texas.
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Lamb
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D054439:Ghrelin / Q000494:pharmacology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D054439:Ghrelin; D006657:Histones; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D002945:Cisplatin
keywords: GHSR; growth hormone secretagogue; infertility; testis