Mouse Heat-Shock Factor 1 (HSF1) Is Involved in Testicular Response to Genotoxic Stress Induced by Doxorubicin

• Published in: Biology of reproduction Vol. 79; no. 6; pp. 1092 - 1101
• Main Authors: Salmand, Pierre A, Jungas, Thomas, Fernandez, Marylise, Conter, Annie, Christians, Elisabeth S
• Format: Journal Article
• Language: English
• Published: Madison, WI Society for the Study of Reproduction, Inc 01.12.2008; Society for the Study of Reproduction
• Subjects: Animals; Antibiotics, Antineoplastic - toxicity; Antimetabolites; Biological and medical sciences; Blotting, Western; Bromodeoxyuridine; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Doxorubicin - toxicity; Fundamental and applied biological sciences. Psychology; Heat Shock Transcription Factors; Hormone metabolism and regulation; Immunohistochemistry; In Situ Nick-End Labeling; Male; Mammalian male genital system; Meiosis - drug effects; Meiosis - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutagenesis - drug effects; Mutagens - toxicity; Proliferating Cell Nuclear Antigen - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sperm Count; Sperm Head - drug effects; Sperm Head - physiology; Spermatogenesis - drug effects; Testis - drug effects; Testis - physiology; Transcription Factors - genetics; Transcription Factors - physiology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology; Vertebrates: reproduction; Spermatogenesis; Rodentia; Male; apoptosis; Meiosis; Germinal cell; Testicle; Male genital system; heat shock factor; Stress; Vertebrata; Mammalia; Mouse
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.108.070334

Heat-shock factor 1 (HSF1) protects cells and organisms against various types of stress, either by triggering a complex response that promotes cell survival or by triggering cell death when stress-induced alterations cannot be rescued. Although this dual role of HSF1 was observed in spermatogenesis exposed to heat shock or proteotoxic stress, HSF1 was also reported to contribute to cell resistance against genotoxic stress, such as that caused by doxorubicin, an anticancer drug in common clinical use. To better understand the stress/cell-dependent functions of HSF1, we used wild-type and Hsf1tm¹Ijb/Hsf1tm¹Ijb males to determine the role of HSF1 in the genotoxic stress response elicited in spermatogenic cells. Within 2 days after a single intraperitoneal injection of doxorubicin (DOXO; 5 mg/kg), proliferation of Hsf1⁺/⁺ but not Hsf1⁻/⁻ spermatogenic cells was significantly reduced, whereas cell death was increased in mitotic germ cells and metaphase I spermatocytes. By 21 days, meiotic cells were depleted in all treated Hsf1⁺/⁺ testes but not in Hsf1⁻/⁻ ones. Nevertheless, after 3 mo, spermatogenesis showed better signs of recovery in Hsf1⁺/⁺ than in Hsf1⁻/⁻ males. Taken together, these data indicate that acute response to genotoxic stress in the testis involves HSF1-dependent mechanisms that induce apoptotic cell death in a TRP53-independent manner, but also intervene on a longer term to restore seminiferous tubules.