Late morfofunctional alterations of the Sertoli cell caused by doxorubicin administered to prepubertal rats

Brilhante, Otávio de Sousa; Okada, Fatima Kazue; Sasso-Cerri, Estela; Stumpp, Taiza; Miraglia, Sandra Maria

doi:10.1186/1477-7827-10-79

Cited by 44 publications

(33 citation statements)

References 74 publications

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“…Furthermore, DXR can induce chromosomal damage in the testis not only via oxidative stress but also by intercalation into DNA and disrupting topo-II-mediated DNA repair. It was also shown that DXR may induce enhanced testicular toxicity in prepubertal rats due to disruption of the supporting Sertoli cells (Brilhante et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Dexrazoxane exacerbates doxorubicin-induced testicular toxicity

Levi¹,

Tzabari²,

Savion³

et al. 2015

Reproduction

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Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we studied its potential effect in reducing DXR-induced testicular toxicity. Male mice were injected with 5 mg/kg DXR, 100 mg/kg DEX, combination of both or saline (control) and sacrificed either 1, 3 or 6 months later. Testes were excised and further processed. Glutathione and apoptosis assays were performed to determine oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effects of the drugs on testicular histology and on spermatogonial reserve. DXR and the combined treatment induced a striking decline in testicular weight. DEX prevented DXR-induced oxidative stress, but enhanced DXR-induced apoptosis within the testes. Furthermore, the combined treatment depleted the spermatogonial reserve after 1 month, with impaired recovery at 3 and 6 months post-treatment. This resulted in compromised sperm parameters, testicular and epididymal weights as well as significantly reduced sperm motility, all of which were more severe than those observed in DXR-treated mice. The activity of DEX in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR exacerbates DXR-induced testicular toxicity. Reproduction (2015) 150 357-366

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Section: Discussionmentioning

confidence: 99%

Dexrazoxane exacerbates doxorubicin-induced testicular toxicity

Levi¹,

Tzabari²,

Savion³

et al. 2015

Reproduction

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“…Indeed, our group has been showing that chemotherapeutic treatments during pre-puberty can lead to irreversible damage to the seminiferous epithelium of rats, although some degree of spermatogenesis restoration is frequently observed (Stumpp et al, 2004;Okada et al, 2009;Vendramini et al, 2010Vendramini et al, , 2012Brilhante et al, 2011Brilhante et al, , 2012. Among the chemotherapeutic drugs studied, etoposide (Stumpp et al, 2004;Okada et al, 2009) and doxorubicin (Vendramini et al, 2010(Vendramini et al, , 2012Brilhante et al, 2011Brilhante et al, , 2012 appear to be particularly aggressive to the reproduction.…”

Section: Discussionmentioning

confidence: 99%

“…However, its harmful effects on other cells, such as spermatogonial stem cells (Tanigaki et al, 2013) and Sertoli cells (Brilhante et al, 2012), cannot be excluded when doxorubicin is administered during pre-puberty, because the spermatogenic damage is still observed in adulthood.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, a reduction of transferrin labeling in the seminiferous epithelium was also observed in the 40 and 64-day-old doxorubicin-treated rats. Such alterations, although secondary to the germ cell primary injury, may have contributed to enhance the spermatogenic harm caused by this drug and it should be also related to a transient damage in the Sertoli cell function caused by doxorubicin (Brilhante et al, 2012). In this study, it is likely that part of the protective action provided by carnitine to the seminiferous epithelium was mediated by Sertoli cells, by maintaining the blood-testis barrier function, as the Sertoli cells express OCTN2, the Carnitine/ Organic Cation Transporter 2, commonly found in blood-tissue barriers (Kobayashi et al 2005).…”

Section: Discussionmentioning

confidence: 99%

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Carnitine partially protects the rat testis against the late damage produced by doxorubicin administered during pre‐puberty

et al. 2014

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SUMMARYDoxorubicin, an anticancer drug, is widely included in chemotherapy protocols to combat childhood cancer. Carnitine, an important quaternary amine, is present in testis and epididymis and is involved in sperm maturation; it has been used in infertility treatment. In a previous study, our group observed that L-carnitine given before etoposide, another chemotherapeutic drug, reduces the spermatogenic damage and protects germ cells against apoptosis. This study aimed to evaluate the antiapoptotic and cytoprotective actions of L-carnitine in long-and mid-term basis, on the seminiferous epithelium of doxorubicin-treated pre-pubertal rats. Fortyeight 30-day-old male Wistar rats were distributed into four groups: sham-control; doxorubicin; carnitine; carnitine/doxorubicin (L-carnitine injected 1 h before doxorubicin). The rats were submitted to euthanasia at 64 and 100 days of age and their testes were collected for biometric, morphometric, and histopathological analyses. The numerical density of apoptotic germ cells was obtained (TUNEL method). In adult phase (100 days), the following spermatic parameters were analyzed: mature spermatid (19 step) count and sperm daily production per testis; sperm number and transit time through the epididymal caput/corpus and cauda; frequency of morphologically abnormal spermatozoa (from epididymal fluid), as well as sperm DNA integrity (Comet assay). The testicular and spermatic parameters at both ages were improved in rats treated with carnitine before doxorubicin. At 64 days, the TUNEL-positive germ cell frequency was lower in the carnitine/doxorubicin-treated rats comparatively to the doxorubicin-treated rats. At 100 days of age, the sperm DNA fragmentation was also lower in the previously carnitine-treated rats, as evidenced by the analysis of three parameters. Carnitine reduced the late testicular and spermatic damages caused by doxorubicin, probably providing a partial cytoprotection against the deleterious action of doxorubicin administration to pre-pubertal rats. However, further studies shall be undertaken to investigate the protective mechanisms involved in such germ cell preservation.

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“…Indeed, Sertoli cells play a key role in the control of spermatogenesis and in germ cell development (Fritz 1973, Carreau et al 1994 and any alteration in these cells can cause severe damage to spermatogenesis (Hess et al 1991, Brilhante et al 2012. However, there are very few studies about the effects of nicotine on late spermatogenesis (Lagunov et al 2011) in animals exposed during whole intrauterine (21-22 days in rats) period and lactation (from the birth to weaning).…”

Section: Introductionmentioning

confidence: 99%

Prenatal and lactation nicotine exposure affects Sertoli cell and gonadotropin levels in rats

Paccola¹,

Miraglia²

2016

Reproduction

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Nicotine is largely consumed in the world as a component of cigarettes. It can cross the placenta and reach the milk of smoking mothers. This drug induces apoptosis, affects sex hormone secretion, and leads to male infertility. To investigate the exposure to nicotine during the whole intrauterine and lactation phases in Sertoli cells, pregnant rats received nicotine (2 mg/kg per day) through osmotic minipumps. Male offsprings (30, 60, and 90 days old) had blood collected for hormonal analysis (FSH and LH) and their testes submitted for histophatological study, analysis of the frequency of the stages of seminiferous epithelium cycle, immunolabeling of apoptotic epithelial cells (TUNEL and Fas/FasL), analysis of the function and structure of Sertoli cells (respectively using transferrin and vimentin immunolabeling), and analysis of Sertoli-germ cell junctional molecule (b-catenin immunolabeling). The exposure to nicotine increased the FSH and LH plasmatic levels in adult rats. Although nicotine had not changed the number of apoptotic cells, neither in Fas nor FasL expression, it provoked an intense sloughing of epithelial cells and also altered the frequency of some stages of the seminiferous epithelium cycle. Transferrin and b-catenin expressions were not changed, but vimentin was significantly reduced in the early stages of the seminiferous cycle of the nicotine-exposed adult rats. Thus, we concluded that nicotine exposure during all gestational and lactation periods affects the structure of Sertoli cells by events causing intense germ cell sloughing observed in the tubular lumen and can compromise the fertility of the offspring.

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Late morfofunctional alterations of the Sertoli cell caused by doxorubicin administered to prepubertal rats

Cited by 44 publications

References 74 publications

Dexrazoxane exacerbates doxorubicin-induced testicular toxicity

Dexrazoxane exacerbates doxorubicin-induced testicular toxicity

Carnitine partially protects the rat testis against the late damage produced by doxorubicin administered during pre‐puberty

Prenatal and lactation nicotine exposure affects Sertoli cell and gonadotropin levels in rats

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