Primary mediastinal germ cell tumor with intratubular germ cell neoplasia of the testis--further support for germ cell origin of these tumors
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Hailemariam et al.1 described the simultaneous occurrence of a mediastinal germ cell tumor and intratubular germ cell neoplasia in the testis in a patient age 32 years. They postulated that both lesions originated in a common germ cell source. A germ cell line can certainly give rise to two different germ cell neoplasms. This explanation was actually offered to account for the association between hematopoietic malignancy and mediastinal germ cell tumor in the same host.2 Other examples of somatic neoplasms arising in patients with germ cell tumors abound.3, 4 In fact, to carry this hypothesis even further back on the histogenesis pathway, it is possible that all multiple tumors occurring in a given patient, be they simultaneous or metachronous, represent different neoplastic manifestations of a pluripotent stem cell element, be the element germ cell3 or otherwise.5 Had the young patient survived the mediastinal germ cell tumor, he may indeed have been at increased risk of developing malignancies other than the tumor of the left testis. The specific type of subsequent cancer may depend partly on alterations in the microenvironment that is "bathing" the stem cell in question.6 In fact, changes in the cellular milieu caused by irradiation6 and/or chemotherapeutic agents3 may explain the occurrence of treatment-related cancers in general. It is important, however, to point out that despite advances in molecular genetics, we are not quite able to delineate, clearly, the clonality of cells within a single tumor,7, 8 let alone track genetic changes that can occur during the progression, including metastasis9, 10 and recurrence,11 of a given tumor; and we are even less prepared to track such changes in different tumors arising in the same patient. K. C. Lee M.D.*Germ plasm
Germ line development
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Approaches for identifying germ cell mutagens: Report of the 2013 IWGT workshop on germ cell assays☆
This workshop reviewed the current science to inform and recommend the best evidence-based approaches on the use of germ cell genotoxicity tests. The workshop questions and key outcomes were as follows. (1) Do genotoxicity and mutagenicity assays in somatic cells predict germ cell effects? Limited data suggest that somatic cell tests detect most germ cell mutagens, but there are strong concerns that dictate caution in drawing conclusions. (2) Should germ cell tests be done, and when? If there is evidence that a chemical or its metabolite(s) will not reach target germ cells or gonadal tissue, it is not necessary to conduct germ cell tests, notwithstanding somatic outcomes. However, it was recommended that negative somatic cell mutagens with clear evidence for gonadal exposure and evidence of toxicity in germ cells could be considered for germ cell mutagenicity testing. For somatic mutagens that are known to reach the gonadal compartments and expose germ cells, the chemical could be assumed to be a germ cell mutagen without further testing. Nevertheless, germ cell mutagenicity testing would be needed for quantitative risk assessment. (3) What new assays should be implemented and how? There is an immediate need for research on the application of whole genome sequencing in heritable mutation analysis in humans and animals, and integration of germ cell assays with somatic cell genotoxicity tests. Focus should be on environmental exposures that can cause de novo mutations, particularly newly recognized types of genomic changes. Mutational events, which may occur by exposure of germ cells during embryonic development, should also be investigated. Finally, where there are indications of germ cell toxicity in repeat dose or reproductive toxicology tests, consideration should be given to leveraging those studies to inform of possible germ cell genotoxicity.
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Much research has been conducted in recent years to elucidate the mechanisms underlying the crucial developmental process of sex determination. It has now been shown that somatic sex is principally determined by the chromosomal sex and the molecular mechanisms involved in this process have become relatively well understood in both human and mouse. However, the pathways involved in the sex determination of the germ cells remain largely unknown except for the fact that the somatic cues surrounding these cells play a significant role. Moreover, which sexual pathway of the germ cells is induced or suppressed has long been a subject of some dispute. Recent findings indicate that the key molecule that influences this choice is retinoic acid. In addition, the Nanos protein has been shown to play a critical role in promoting male germ cell differentiation. In this review, the possible mechanisms underlying these events, which have been brought to light by recent findings, are summarized to provide a better and more precise understanding of our current knowledge of the sex determination and subsequent differentiation of germ cells.
Sexual Differentiation
Cell fate determination
Germ line development
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Spermatocyte
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Abstract Spermatogenesis is a highly ordered developmental program that produces haploid male germ cells. The study of male germ cell development in the mouse has provided unique perspectives into the molecular mechanisms that control cell development and differentiation in mammals, including tissue-specific gene regulatory programs. An intrinsic challenge in spermatogenesis research is the heterogeneity of germ and somatic cell types present in the testis. Techniques to separate and isolate distinct mouse spermatogenic cell types have great potential to shed light on molecular mechanisms controlling mammalian cell development, while also providing new insights into cellular events important for human reproductive health. Here, we detail a versatile strategy that combines Cre-lox technology to fluorescently label germ cells, with flow cytometry to discriminate and isolate germ cells in different stages of development for cellular and molecular analyses.
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The Organisation for Economic Co-operation and Development Test Guideline 488 (TG 488) provides recommendations for assessing germ cell and somatic cell mutagenicity using transgenic rodent (TGR) models. However, important data gaps exist for selecting an optimal approach for simultaneously evaluating mutagenicity in both cell types. It is uncertain whether analysis of germ cells from seminiferous tubules (hereafter, tubule germ cells) or caudal sperm within the recommended design for somatic tissues (i.e., 28 days of exposure plus three days of fixation time, 28 + 3d) has enough sensitivity to detect an effect as compared with the analysis of sperm within the recommended design for germ cells (i.e., 28 + 49d and 28 + 70d for mouse and rat, respectively). To address these data gaps, the Germ Cell workgroup of the Genetic Toxicology Technical Committee of the Health and Environmental Sciences Institute reviewed the available TGR mutagenicity data in male germ cells, and, characterized the exposure history of tubule germ cells for different sampling times to evaluate its impact on germ cell mutagenicity testing using TG 488. Our analyses suggest that evaluating mutant frequencies in: i) sperm from the cauda epididymis at 28 + 3d does not provide meaningful mutagenicity data; ii), tubule germ cells at 28 + 3d provides reliable mutagenicity data only if the results are positive; and iii) tubule germ cells at 28 + 28d produces reliable positive and negative results in both mice and rats. Thus, the 28 + 28d regimen may provide an approach for simultaneously assessing mutagenicity in somatic tissues and germ cells from the same animals. Further work is required to support the 28 + 28d protocol for tissues other than slowly proliferating tissues as per current TG 488. Finally, recommendations are provided to guide the experimental design for germ cell mutagenicity data for regulatory submission, as well as other possible approaches to increase the reliability of the TGR assay.
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Extragonadal germ cell tumors are extremely rare and account for only 3%-5% of all germ cell tumors. These tumors are rarely associated with metachronous primary testicular germ cell tumors. We report the fourth case of a primary germ cell tumor occurring after the treatment of a primary CNS germ cell tumor in a 27 year-old male with embryonal cell carcinoma of the testicle 9 years after the treatment of a germ cell tumor of the pineal gland. This represents the first case of a non-seminomatous germ cell tumor of the testicle after a CNS germ cell tumor. This case illustrates the importance of long term follow-up and self-examination in patients with extragonadal germ cell tumors.
Testicle
Embryonal carcinoma
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A variety of in vivo mammalian test models are available for screening of chemicals for mutagenicity at the chromosomal level. These models have been grouped into those focusing on somatic cell effects and those dealing with germ cell effects. An analysis of available literature indicates that 76 compounds have been tested from chromosome effects in both somatic and germ cells. Of these, concordant results (positive-positive or negative-negative) were obtained with 58 compounds. Of the remaining 18 compounds with discordant results, all were positive in somatic cells, but negative in germ cell assays. These results suggest an inherent relative insensitivity of germ cells themselves to mutagenic chemicals. In the context of screening for safety evaluation purposes, this analysis suggests that a negative somatic-cell response can be taken as highly predictive of negative results in a germ cell assessment.
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