Toxicological study of etoposide (VP-16) in rats with special emphasis on testicular alteration

Kadota, Toshihito; Chikazawa, Hirotaka; Takahashi, Norimitsu

doi:10.1016/0378-4274(89)90008-8

Cited by 14 publications

(6 citation statements)

References 9 publications

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“…at 24 h post-treatment, exhibited statistically significant increased percentages of aberrant spermatogonial metaphases and chromosomal aberrations (excluding gaps), mostly chromatid breaks, per 100 spermatogonial metaphases (Table 1). This clastogenic effect of etoposide in mouse spermatogonia is in agreement with earlier reports on its induction of spermatid micronuclei (Kallio and Lahdetie, 1993), spermatogonial cell death, other clastogenic damage, specific locus mutations, dominant lethal mutations (Russell et al, 1998(Russell et al, , 2000, centromeric DNA fragmentation (Kallio and Lahdetie, 1996) during mouse spermatogenesis and micronucleus induction in cultured seminiferous tubules (Sjoblom et al, 1994) and spermatid micromidei and spermatogenic cell damage (Kadota et al, 1989) in rat spermatogenesis. The induction of mostly chromatid breaks by etoposide in the present study is in complete agreement with earlier reports of Palitti et al (1989), Agarwal et al (1994) and our earlier report on mouse bone marrow (Choudhury et al, 2004).…”

Section: Discussionsupporting

confidence: 90%

Etoposide‐induced cytogenotoxicity in mouse spermatogonia and its potential transmission

Palo

Sahu

Choudhury

2005

J of Applied Toxicology

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As cancer chemotherapeutic agents are cytogenotoxic but not target-specific during systemic treatment, they affect all the encountered cells including the non-cancerous ones and consequently lead to the recurrence of second malignancy in post-chemotherapeutic cancer survivors. The effects would be persistent if the stem cells were affected. These drugs also may affect germline cells during therapeutic treatments. There is every chance that the effects are transmitted through the germline cells to the gametes and to the next generation if the gonadal mother cells are affected. Such transmission of effects from the post-chemotherapeutic childhood cancer survivors is of serious concern but very little attention has been given so far to such studies. Etoposide (VP-16)--a semi-synthetic epipodophyllotoxin derivative, a DNA non-intercalating agent and a topoisomerase II inhibitor--is prescribed frequently for the treatment of various types of cancers. It is a potent clastogen inducing chromosomal damage both in vitro and in vivo. Its clastogenic effect is indirect through inhibition of the catalytic activity of topoisomerase II enzymes, which maintain the topology of DNA during replication, recombination, transcription, etc. by forming a 'cleavable complex' and facilitate the cleaving and re-ligation of the cleaved DNA to relieve the torsional stress during such events. Transient stabilization of the cleavable complex by etoposide leads to illegitimate ligation of the cleaved DNA. Consequently, single- and double-strand breaks occur. In the present study, the clastogenic potential of three different doses of etoposide (10, 15 and 20 mg kg(-1)) in the male germline of mice was assessed from the dividing spermatogonia after a single exposure for one cell cycle duration at 24 h post-treatment. Transmission of such effects was assessed from the frequency of aberrant primary spermatocytes at week 4 post-treatment and of abnormal sperm at week 8 post-treatment. All three doses of etoposide were found to be clastogenic to the dividing spermatogonia of mice, and mostly chromatid breaks were induced. The effects also were transmitted through the male germline of mice, which was evident from the prevalence of statistically significant increased percentages of aberrant primary spermatocytes at week 4 posttreatment and the higher percentages of abnormal sperm at week 8 post-treatment. Thus, there is every chance that the cytogenotoxic effects of etoposide are transmitted to the next generation through the male germline of post-chemotherapeutic cancer survivors, therefore it is essential to make etoposide target-specific or modulate its effects.

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Section: Discussionsupporting

confidence: 90%

Etoposide‐induced cytogenotoxicity in mouse spermatogonia and its potential transmission

Palo

Sahu

Choudhury

2005

J of Applied Toxicology

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“…The irregularities, infolding of the basement membrane, lamellation of the lamina densa, as well as hyperplasia of collagen fibers of the tunica propria have been described in alcohol-fed Sprague Dawley rats, in which testosterone levels in serum and testes declined [49]. A similar effect was observed in the testes of rats injected with etoposide (VP-16) used as a form of chemotherapy [50]. The basement membrane is modified extracellular matrix [51], coexisting side--by-side with anchoring junctions, such as ectoplasmic specializations and desmosome-like junctions [52][53][54].…”

Section: Discussionmentioning

confidence: 85%

Testis morphology in rats chronically treated with letrozole, an aromatase inhibitor

Kondarewicz¹,

Kolasa²,

Zawiślak³

et al. 2012

Folia Histochem Cytobiol.

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Abstract:The aim of this study was to investigate the influence of the long-term treatment of rats with letrozole on the testis morphology. The pharmacologically induced estrogen deficiency caused statistically significant decreases of both intratesticular and serum levels of estradiol, and morphological changes in the seminiferous epithelium and in the interstitial tissue of the testes. Six months of treatment resulted in the sloughing of premature germ cells of the seminiferous epithelium into the tubular lumen and in intraepithelial vacuolization. Multinucleated giant cells composed of premature germ cells, conglomerates of various cell nuclei and cell debris as well as irregularities and infoldings of the tubular basement membrane were also seen. Moreover, deep invaginations of the lamina propria with myoid cells were observed. Cells in the interstitial tissue showed changes similar to that observed in aging processes. The cytoplasm of LH-R-positive Leydig cells was loaded with lipofuscin granules. The number of lipofuscin-loaded cells was significantly increased in the interstitial tissue of testis in letrozole-treated rats. The results indicate the direct influence of estrogens on seminiferous tubules and the interstitial tissue morphology.

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“…However, this drug has also been shown to provoke the death of normal cells via apoptosis (Kadota et al 1989). In the testis, etoposide causes an increase of apoptotic germ cell death, leading to serious damage of the seminiferous epithelium (Sjöblom et al 1998;Stumpp et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Carnitine reduces testicular damage in rats treated with etoposide in the prepubertal phase

2009

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Etoposide is a chemotherapeutic agent that induces cell death by blocking topoisomerase II catalytic function. Although etoposide is effective in the treatment of cancer, it also causes the death of normal proliferating cells, including male germ cells. Administration of etoposide during the prepubertal phase causes diturbances in several testicular morphometric parameters and in Sertoli cells. Cytoprotection of the seminiferous epithelium is the only means of preserving potential male reproduction in prepubertal cancer patients. Carnitine, an amino acid naturally present in normal cells, is a promising cryoprotectant as it is concentrated in the epididymis and promotes sperm maturation. We have therefore investigated whether carnitine protects rat testes against etoposide and, thus, improves fertility in adulthood. Our results suggest that carnitine partially protects the testis against damage caused by etoposide, although the mechanism by which it happens remains unknown.

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Toxicological study of etoposide (VP-16) in rats with special emphasis on testicular alteration

Cited by 14 publications

References 9 publications

Etoposide‐induced cytogenotoxicity in mouse spermatogonia and its potential transmission

Etoposide‐induced cytogenotoxicity in mouse spermatogonia and its potential transmission

Testis morphology in rats chronically treated with letrozole, an aromatase inhibitor

Carnitine reduces testicular damage in rats treated with etoposide in the prepubertal phase

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