Mouse heat-shock factor 1 (HSF1) is involved in testicular response to genotoxic stress induced by doxorubicin.
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 Hsf1(tm1Ijb)/Hsf1(tm1Ijb) 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.
Salmand
Pierre A
PA
Université Toulouse 3, Unité Mixte de Recherche 5547 (UMR 5547), Centre National pour la Recherche Scientifique (CNRS)-Université Paul Sabatier (UPS), 31062 Toulouse, France.
Jungas
Thomas
T
Fernandez
Marylise
M
Conter
Annie
A
Christians
Elisabeth S
ES
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000963:Antimetabolites; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004317:Doxorubicin / Q000633:toxicity*; D000076249:Heat Shock Transcription Factors; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008540:Meiosis / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis / Q000187:drug effects*; D009153:Mutagens / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013076:Sperm Count; D013077:Sperm Head / Q000187:drug effects / Q000502:physiology; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000187:drug effects* / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
D000903:Antibiotics, Antineoplastic; D000963:Antimetabolites; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D009153:Mutagens; D018809:Proliferating Cell Nuclear Antigen; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D001973:Bromodeoxyuridine