Protection against Cytotoxic-
Induced Testis Damage -
Experimental Approaches

Id, Morris

doi:10.1159/000474583

Cited by 20 publications

(8 citation statements)

References 7 publications

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“…However, hypogonadism does not occur with cisplatin treatment [58,59]. In our experiments, cisplatin caused damage to the testis without significantly changing the circulating levels of testosterone, LH or FSH.…”

Section: Discussioncontrasting

confidence: 47%

Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice1

García

Chen

Guillory

et al. 2015

Biology of Reproduction

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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.

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Section: Discussioncontrasting

confidence: 47%

Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice1

García

Chen

Guillory

et al. 2015

Biology of Reproduction

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“…Animal studies mostly in rats and mice were carried out in an attempt to confirm the protective effect of GnRH analog administered before cytotoxic insults on spermatogenesis. Several researchers successfully demonstrated the protection of spermatogenesis from procarbazine or cyclophosphamide in the rat model 2–4 . However, other researchers found no substantial protective effects in the mouse or in the rat to the same or other drugs 5–7 .…”

Section: Introductionmentioning

confidence: 99%

GnRH analog, leuprorelin acetate, promotes regeneration of rat spermatogenesis after severe chemical damage

et al. 2001

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Background: Future fertility is a major concern for cancer patients who undergo intensive chemotherapy. There has been controversy about whether hormonal treatments may have protective effects against the severe spermatogenic damage caused by chemotherapy or irradiation. Recently, it has been proposed that gonadotrophin-releasing hormone (GnRH) analogs administered after testicular damage stimulate the recovery of spermatogenesis. In this study, we have investigated the effects of GnRH agonist, leuprorelin, on the damage to spermatogenesis induced by busulfan. Methods: Fisher rats were treated with busulfan, 25 mg/kg, intraperitoneally. The effects of subcutaneous injections of leuprorelin before or after treatment were evaluated histologically 18 weeks later. Results:The percentage of 'recovered' seminiferous tubules was 27.7 ± 12.6% in control rats without leuprorelin and 26.9 ± 10.2% in rats with leuprorelin injected 4 weeks before busulfan. Rats in both groups showed poor recovery of spermatogenesis with an increase of intratesticular fluid. However, rats treated with leuprorelin three times (4 weeks apart) after busulfan showed an improvement of up to 56.5 ± 12.0% (P < 0.05). A focal but massive necrotic lesion in the testis was observed only in this group of rats. Conclusions:The results demonstrated that leuprorelin administered after chemical testicular damage enhanced the recovery of spermatogenesis. At the same time, a possible significant side-effect of leuprorelin was noted.

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“…Meanwhile, cisplatin-based chemotherapy is known to induce azoospermia and impairment of fertility in men [3,5,8]. Animal studies in mice and rats have clearly demonstrated that cisplatin impairs spermatogenic and maturational processes [9,12].…”

mentioning

confidence: 99%

Cisplatin-Induced Germ Cell Apoptosis in Mouse Testes

Zhang¹,

Yamamoto²,

Soramoto³

et al. 2001

Archives of Andrology

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The purpose of this study was to investigate whether exposure of male mice to cisplatin induces apoptosis in male germ cells and the possible role of apoptosis in cisplatin-induced testicular damage. Forty-eight male BALB/c mice were divided into cisplatin and control groups. The mice from the cisplatin group received a single intraperitoneal injection of cisplatin of either 1, 5, or 10 mg/kg. The control group received a single intraperitoneal injection of saline alone. The testes were removed on days 1, 3, and 7 after cisplatin administration, respectively. Following histological examination, apoptotic indices (AIs) were measured within seminiferous tubules of the mouse testes by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. A low incidence of spontaneous apoptosis was observed in controls, particularly in spermatogonia and spermatocytes of the mouse testes. After cisplatin administration, both increased Als and decreased spermatozoa and spermatids were found in the seminiferous tubules of the mouse testes. Cisplatin-induced apoptosis was found in spermatogonia, spermatocytes, and spermatids of the mouse testes. In comparison to the control values, AIs increased 2.6- to 6.8-fold in cisplatin-treated mouse testes. AIs reached the highest level on day 1 following 1 mg/ kg, on day 3 following 5 mg/kg, and on day 7 following treatment of 10 mg/kg cisplatin. The study showed that cisplatin-induced germ cell apoptosis in the mouse testes was related to both the dose response and the time course of response. It is suggested that cisplatin-induced germ cell apoptosis may result in decreased spermatogenesis, and the higher dose of cisplatin may delay the occurrence of apoptosis in the mouse testes.

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Protection against Cytotoxic- Induced Testis Damage - Experimental Approaches

Cited by 20 publications

References 7 publications

Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice1

Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice1

GnRH analog, leuprorelin acetate, promotes regeneration of rat spermatogenesis after severe chemical damage

Cisplatin-Induced Germ Cell Apoptosis in Mouse Testes

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