Apoptotic response of spermatogenic cells to the germ cell mutagens etoposide, adriamycin, and diepoxybutane

Sjöblom, Tiina; West, Anne; Lähdetie, Jaana

doi:10.1002/(sici)1098-2280(1998)31:2<133::aid-em5>3.0.co;2-n

Cited by 71 publications

(37 citation statements)

References 83 publications

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“…Because doxorubicin treatment destroys stem cells and spermatogonia but spares more of the most differentiated cells of the germ line, such as spermatocytes and spermatids (4,5), the eventual long-term consequences of germ cell death on the testis required a longer period than a few weeks to reach completion. Because a whole spermatogenic cycle takes 63 days in the rat, sufficient time had to be allowed for the preexisting unaffected spermatogenic cells to have the chance to exit from the testis.…”

Section: Resultsmentioning

confidence: 99%

“…In response to several chemotherapeutic agents including anthracyclines, the number of male germ cells undergoing apoptosis increases several fold (4). Because the cells most sensitive to doxorubicin are the early spermatogenic cells, spermatogonia type A and meiotically dividing primary spermatocytes (4,5), doxorubicin treatment may lead to the loss of proliferating nonmature germ cells and eventually of mature spermatozoa. Although it is known that anthracyclines interfere with a number of biochemical and biological functions within eukaryotic cells, the precise mechanisms responsible for its adverse actions on the testis have not been completely elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…Because ceramide increases in germ cells undergoing apoptosis in seminiferous tubules in vitro (21) and because treatments with doxorubicin induce apoptotic death of specific spermatogenic cells in vivo (4,5), one of the first questions was how doxorubicin treatment would affect the ceramide and sphingomyelin of testis and their fatty acids. However, we soon realized that doxorubicin produced several quantitative and qualitative effects on virtually all testicular lipids of the rat.…”

Section: Introductionmentioning

confidence: 99%

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Doxorubicin Affects Testicular Lipids with Long-Chain (C18-C22) and Very Long-Chain (C24-C32) Polyunsaturated Fatty Acids

2007

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Doxorubicin disrupts spermatogenesis by causing apoptosis of spermatogonia and primary spermatocytes. The aim of this study was to examine the effect of this agent on adult rat testicular lipids and their fatty acids. A single dose (7.5 mg/kg) and a multidose regime (3 mg/kg once a week for 4 weeks) were evaluated. Both treatments resulted in the gradual loss of spermatogenic cells and determined a marked reduction in testicular size and weight 9 weeks after their start. Germ cell loss was accompanied by a decrease in phospholipids, including glycerophospholipids and sphingomyelin. Concomitantly, glycerophospholipids lost selectively their major polyunsaturated fatty acid (PUFA), 22:5n-6, and sphingomyelin lost its major very long-chain PUFA (VLCPUFA), 28:4n-6 and 30:5n-6. The molecular species from which the lost polyenes originated were thus a trait of germ cells. A transient peak of 16:0-ceramide was observed 48 h after the single dose.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Doxorubicin Affects Testicular Lipids with Long-Chain (C18-C22) and Very Long-Chain (C24-C32) Polyunsaturated Fatty Acids

2007

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“…It is known that ADR inhibits RNA and DNA synthesis through interaction into the double-helix, thereby interfering with cell division Simpkins and Pearlman, 1984) and induces chromosomal aberrations (Russo and Levis, 1992). ADR tended to kill type A spermatogonia at all stages of the spermatogenic cycle (Matsui et al, 1993) and induces apoptotic death (Sjoblom et al, 1998;Shinoda et al, 1999). There is a possibility that HST-1/FGF-4 protects against ADRinduced apoptotic death of spermatogonia.…”

Section: Discussionmentioning

confidence: 99%

HST-1/FGF-4 gene activation induces spermatogenesis and prevents adriamycin-induced testicular toxicity

Yamamoto¹,

Ochiya²,

Tamamushi³

et al. 2002

Oncogene

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We previously demonstrated expression of the HST-1/ FGF-4 gene in the testis of normal adult animals, which suggests its possible role in spermatogenesis. For an understanding of its functional signi®cance in the testis, conditional transgene expression was used. Precise genetic switches can be eciently generated in a straightforward manner using adenovirus-carrying Cre recombinase, which means our new strategies promise to contribute substantially to a better and prompt understanding of the functions of genes in vivo by controlling the expression of any gene to any organ at any desired time. Our new method demonstrated for the ®rst time that the speci®c gain of function of the HST-1/FGF-4 gene in the testis resulted in markedly enhanced spermatogenesis. To further investigate the function and therapeutic potency of HST-1/FGF-4, transgenic mice with enhanced HST-1/FGF-4 expression in the testis were exposed to adriamycin (ADR), an anticancer drug causing severe testicular toxicity. Degree of damage to spermatogenesis was assessed by sperm count, testicular weight, histology, and DNA ploidy. Induced expression of HST-1/FGF-4 markedly enhanced the recovery of ADR-induced testicular damage. Furthermore, adenoviruses carrying the HST-1/FGF-4 gene ameliorated testicular toxicity of ADR. These results with new adenovirus-mediated Cre/lox conditional mice indicated that HST-1/FGF-4 could be an important factor for spermatogenesis, presenting a new paradigm to treat impaired fertility.

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“…In vitro cultured PGCs exposed to N-ethyl-N-nitrosourea (ENU) (a classical toxicant and mutagen, with effects on spermatogenic cells) (Lessard et al, 2004) or Doxorubicin (trade name Adramycin, ADR) an anthracycline widely used in cancer therapy, with apoptotic effects on spermatogenic cells (Sjoblom et al, 1998) demonstrated growth inhibition and apoptosis induction, whereas exposure to mono (2-ethylhexyl) phthalate (MEHP) (the direct metabolite of the di (2-ethylhexyl) phthalate or DEHP), a widespread plasticizer, ubiquitously found as environmental pollutant affected PGC adhesion to cell monolayers (Iona et al, 2002).…”

Section: Effects Of Endocrine Disruptors On Gene Expression In Pgcs Amentioning

confidence: 99%

Endocrine disruptors, gene deregulation and male germ cell tumors

Mazo¹,

Brieño‐Enríquez²,

García-López³

et al. 2013

Int. J. Dev. Biol.

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Endocrine disruptors (EDs) belong to a large group of compounds, usually present as environmental pollutants, which can alter the homeostasis of living organisms by modifying hormonal balance and changing the normal patterns of gene regulation during development and cell differentiation. Hence, the development of male gonads and their functionality may be affected by exposure to specific EDs or their mixtures. The molecular mechanisms of action of these reprotoxicants leading to pathologies of the reproductive system such as testicular cancer, are complex and not well characterized. It is likely, however, that these compounds alter the interaction between the mechanisms of gene regulation and functional gene networks in windows of risk, mainly during embryonic development. Moreover, such changes could be transmitted through generations by epigenetic mechanisms. There are examples of the action of EDs on the expression of mRNAs, small non-coding RNAs and epigenetic marks in the developing testis associated with cellular and molecular alterations found in germ cell tumors. In the present review, we will discuss various aspects of genetic, transcriptomic and epigenetic changes related to testicular development, exposure to EDs and the occurrence of germ cell tumors.

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Apoptotic response of spermatogenic cells to the germ cell mutagens etoposide, adriamycin, and diepoxybutane

Cited by 71 publications

References 83 publications

Doxorubicin Affects Testicular Lipids with Long-Chain (C18-C22) and Very Long-Chain (C24-C32) Polyunsaturated Fatty Acids

Doxorubicin Affects Testicular Lipids with Long-Chain (C18-C22) and Very Long-Chain (C24-C32) Polyunsaturated Fatty Acids

HST-1/FGF-4 gene activation induces spermatogenesis and prevents adriamycin-induced testicular toxicity

Endocrine disruptors, gene deregulation and male germ cell tumors

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