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Mouse Heat-Shock Factor 1 (HSF1) Is Involved in Testicular Response to Genotoxic Stress Induced by Doxorubicin¹

Université Toulouse 3, Unité Mixte de Recherche 5547 (UMR 5547), Centre de Biologie du Développement, Institut Fédératif de Recherche 109 (IFR 109), Centre National pour la Recherche Scientifique (CNRS)-Université Paul Sabatier (UPS), 31062 Toulouse, France

ABSTRACT

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.

apoptosis, heat shock factor, meiosis, spermatogenesis, stress

¹This work was supported by la Fondation pour la Recherche Médicale (FRM), l'Université de Toulouse (UT3), and le Centre National pour la Recherche Scientifique (CNRS).

Correspondence: ²Annie Conter, Université Toulouse 3, UMR 5547, Centre de Biologie du Developpement, IFR 109, CNRS, UPS, 118 Route de Narbonne, 31062 Toulouse Cedex 09, France. FAX: 33 561 556507; e-mail: conter{at}cict.fr

Correspondence: ³Elisabeth S. Christians, Université Toulouse 3, UMR 5547, Centre de Biologie du Developpement, IFR 109, CNRS, UPS, 118 Route de Narbonne, 31062 Toulouse Cedex 09, France. FAX: 33 561 556507; e-mail: Elisabeth.Christians{at}cict.fr

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