The Experts below are selected from a list of 83433 Experts worldwide ranked by ideXlab platform
Renee Reijo A Pera - One of the best experts on this subject based on the ideXlab platform.
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human dazl daz and boule genes modulate primordial Germ Cell and haploid gamete formation
Nature, 2009Co-Authors: Kehkooi Kee, Vanessa T Angeles, Martha Flores, Ha Nam Nguyen, Renee Reijo A PeraAbstract:Defects in Germ-Cell (oocyte and sperm) development are a leading cause of infertility in men and women. Several studies have shown that Germ Cells can be differentiated from mouse and human embryonic stem Cells, but human Germ Cells produced in this way generally fail to develop beyond the earliest stages and do not enter meiosis. Now a team from Stanford's Institute for Stem Cell Biology and Regenerative Medicine has developed a system in which primordial Germ Cells can be derived from both male and female human embryonic stem Cells. By silencing and overexpressing Germ-Cell-specific genes, human Germ-Cell formation and developmental progression can be modulated. Specifically, the human DAZL gene, which is implicated in infertility, is shown to function in primordial Germ-Cell formation, whereas closely related family members, DAZ and BOULE, modulate later stages of meiosis and development of haploid male gametes. This system can be used to study Germ-Cell defects and the potential to correct them therapeutically. Defects in human Germ-Cell (oocyte and sperm) development are the leading cause of infertility in men and women. A Germ-Cell reporter is now used to quantify and isolate primordial Germ Cells derived from both male and female human embryonic stem Cells. Human DAZL is observed to function in primordial Germ-Cell formation, whereas the closely related genes DAZ and BOULE promote later stages of meiosis and development of gametes. The leading cause of infertility in men and women is quantitative and qualitative defects in human Germ-Cell (oocyte and sperm) development. Yet, it has not been possible to examine the unique developmental genetics of human Germ-Cell formation and differentiation owing to inaccessibility of Germ Cells during fetal development. Although several studies have shown that Germ Cells can be differentiated from mouse and human embryonic stem Cells, human Germ Cells differentiated in these studies generally did not develop beyond the earliest stages1,2,3,4,5,6,7,8. Here we used a Germ-Cell reporter to quantify and isolate primordial Germ Cells derived from both male and female human embryonic stem Cells. By silencing and overexpressing genes that encode Germ-Cell-specific cytoplasmic RNA-binding proteins (not transcription factors), we modulated human Germ-Cell formation and developmental progression. We observed that human DAZL (deleted in azoospermia-like) functions in primordial Germ-Cell formation, whereas closely related genes DAZ and BOULE (also called BOLL) promote later stages of meiosis and development of haploid gametes. These results are significant to the generation of gametes for future basic science and potential clinical applications.
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human dazl daz and boule genes modulate primordial Germ Cell and haploid gamete formation
Nature, 2009Co-Authors: Kehkooi Kee, Vanessa T Angeles, Martha Flores, Ha Nam Nguyen, Renee Reijo A PeraAbstract:The leading cause of infertility in men and women is quantitative and qualitative defects in human Germ-Cell (oocyte and sperm) development. Yet, it has not been possible to examine the unique developmental genetics of human Germ-Cell formation and differentiation owing to inaccessibility of Germ Cells during fetal development. Although several studies have shown that Germ Cells can be differentiated from mouse and human embryonic stem Cells, human Germ Cells differentiated in these studies generally did not develop beyond the earliest stages. Here we used a Germ-Cell reporter to quantify and isolate primordial Germ Cells derived from both male and female human embryonic stem Cells. By silencing and overexpressing genes that encode Germ-Cell-specific cytoplasmic RNA-binding proteins (not transcription factors), we modulated human Germ-Cell formation and developmental progression. We observed that human DAZL (deleted in azoospermia-like) functions in primordial Germ-Cell formation, whereas closely related genes DAZ and BOULE (also called BOLL) promote later stages of meiosis and development of haploid gametes. These results are significant to the generation of gametes for future basic science and potential clinical applications.
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human embryonic stem Cells and Germ Cell development
2009Co-Authors: Nina Kossack, J Gromoll, Renee Reijo A PeraAbstract:Embryonic stem Cells (ESCs) are derived from the inner Cell mass (ICM) of blastocysts and are characterized by the ability to differentiate into the three primary Germ layers. Evidence shows, however, that the Cells of the ICM and derived ESCs are not identical. Expression of early Germ Cell–specific markers in undifferentiated ESCs and the ability of ESCs to differentiate into functional Germ Cells in vitro suggest that early Germ Cells and ESCs may be closely related Cell types. Proteins such as Dazl, Pumilio, and Nanos are essential for specification, maintenance, and maturation of the Germ Cell population and are conserved from invertebrates to vertebrates. Homologs of these RNA-binding proteins have recently been identified in human Germ Cells as well as in human ESCs, suggesting a role in differentiation of ESCs towards the Germ Cell lineage. This review summarizes properties of ESCs and Germ Cells and highlights the importance of protein complex formation in differentiation of ESCs towards the Germ Cell lineage.
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human Germ Cell lineage differentiation from embryonic stem Cells
CSH Protocols, 2008Co-Authors: Kehkooi Kee, Renee Reijo A PeraAbstract:INTRODUCTIONBiological and ethical constraints hinder studies of human Germ Cell development despite its importance to reproductive health, including fertility and tumorigenesis. Thus, most of what we know of human Germ Cell development has been extrapolated from studies in model organisms. Human embryonic stem Cells (hESCs) may provide an ideal system for probing the developmental genetics of Germ Cell formation and differentiation in vitro. The growth factors BMP (bone morphogenetic protein) 4, BMP7, and BMP8b are required for development of primordial Germ Cells (PGCs) in mice. It has been shown that these BMPs significantly increase Germ Cell differentiation from hESCs in vitro. This protocol describes a method to induce Germ Cell differentiation from hESCs by the addition of BMPs to hESC differentiation medium. The protocol can be used to study the basic mechanism of Germ Cell development in human Cells.
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modeling human Germ Cell development with embryonic stem Cells
Regenerative Medicine, 2006Co-Authors: Amander T. Clark, Renee Reijo A PeraAbstract:There has previously been no robust Cell-based model for examining the genetic and epigenetic mechanisms of human Germ Cell formation. Human embryonic stem Cells (hESCs) could potentially fill this need, as all Cell types analyzed to date (including mature Germ Cells) can be identified by marker analysis during hESC differentiation. Furthermore, hESCs could also be used to differentiate mature female Germ Cells (oocytes) in culture as an alternate reprogramming Cell for somatic Cell nuclear transfer. However, to differentiate and isolate a functional Germ Cell from hESCs, the mechanisms that regulate Germ Cell formation need to be understood. The purpose of this review is to summarize the current understanding of the earliest events in human Germ Cell formation and to describe some of the known genetic pathways that regulate Germ Cell specification and development in the mouse. Finally, the current literature on the formation of Germ Cells from ESCs will be described.
Leendert H. J. Looijenga - One of the best experts on this subject based on the ideXlab platform.
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cripto expression epigenetic regulation and potential diagnostic use in testicular Germ Cell tumors
Molecular Oncology, 2016Co-Authors: Cassy M Spiller, Josephine Bowles, Guillaume Burnet, Hans Stoop, Peter Koopman, Ad J. M. Gillis, Leendert H. J. LooijengaAbstract:Type II Germ Cell tumors arise after puberty from a Germ Cell that was incorrectly programmed during fetal life. Failure of testicular Germ Cells to properly differentiate can lead to the formation of Germ Cell neoplasia in situ of the testis; this precursor Cell invariably gives rise to Germ Cell cancer after puberty. The Nodal co-receptor Cripto is expressed transiently during normal Germ Cell development and is ectopically expressed in non-seminomas that arise from Germ Cell neoplasia in situ, suggesting that its aberrant expression may underlie Germ Cell dysregulation and hence Germ Cell cancer. Here we investigated methylation of the Cripto promoter in mouse Germ Cells and human Germ Cell cancer and correlated this with the level of CRIPTO protein expression. We found hypomethylation of the CRIPTO promoter in undifferentiated fetal Germ Cells, embryonal carcinoma and seminomas, but hypermethylation in differentiated fetal Germ Cells and the differentiated types of non-seminomas. CRIPTO protein was strongly expressed in Germ Cell neoplasia in situ along with embryonal carcinoma, yolk sac tumor and seminomas. Further, cleaved CRIPTO was detected in media from seminoma and embryonal carcinoma Cell lines, suggesting that cleaved CRIPTO may provide diagnostic indication of Germ Cell cancer. Accordingly, CRIPTO was detectable in serum from 6/15 patients with embryonal carcinoma, 5/15 patients with seminoma, 4/5 patients with Germ Cell neoplasia in situ Cells only and in 1/15 control patients. These findings suggest that CRIPTO expression may be a useful serological marker for diagnostic and/or prognostic purposes during Germ Cell cancer management.
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complete androgen insensitivity syndrome factors influencing gonadal histology including Germ Cell pathology
Modern Pathology, 2014Co-Authors: Jana Kaprovapleskacova, Hans Stoop, Wolter J Oosterhuis, Martine Cools, Hennie T Bruggenwirth, S L S Drop, Katja P Wolffenbuttel, M Snajderova, Jan Lebl, Leendert H. J. LooijengaAbstract:Patients with complete androgen insensitivity syndrome are at an increased risk for the development of gonadal Germ Cell cancer. Residual androgen receptor (AR) activity and abnormal gonadal location may influence the survival of atypical Germ Cells and the development of other histopathological features. To assess this, we evaluated 37 gonads from 19 patients with complete androgen insensitivity (ranging in age from 3 months to 18 years). Histological abnormalities were examined using hematoxylin and eosin-stained sections and sections stained for POU5F1 and KITLG, markers of early changes in Germ Cells at risk for malignant transformation. Hamartomatous nodules (HNs), Leydig Cell hyperplasia (LCH), decreased Germ Cells, tubular atrophy and stromal fibrosis were more pronounced as age increased (P<0.001). Expected residual AR activity acted as a positive predictor only for non-malignant Germ Cell survival in (post)pubertal patients (P<0.05). Immunohistochemical studies indicated that delayed maturation of Germ Cells was present in three patients, whereas intermediate changes that occurred between delayed maturation and intratubular Germ Cell neoplasia, designated pre-intratubular Germ Cell neoplasia, were identified in four cases. Intratubular Germ Cell neoplasia was observed in one patient. Neither POU5F1 nor KITLG expression was dependent on expected residual AR activity. An independent effect of inguinal versus abdominal position of the gonads was difficult to assess because inguinal gonads were present primarily in the youngest individuals. In conclusion, many histological changes occur increasingly with age. Expected residual AR activity contributes to better survival of the general Germ Cell population in (post)pubertal age; however, it did not seem to have an important role in the survival of the Germ Cells at risk for malignant transformation (defined by POU5F1 positivity and KITLG overexpression) in complete androgen insensitivity. Comparison of the high percentage of patients in our study that were carrying Germ Cells with delayed maturation or pre-intratubular Germ Cell neoplasia with previously reported cumulative risk of tumor development in adult patients indicates that not all such precursor lesions in complete androgen insensitivity will progress to invasive Germ Cell cancer.
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mutation in the type ib bone morphogenetic protein receptor alk6b impairs Germ Cell differentiation and causes Germ Cell tumors in zebrafish
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Joanie C Neumann, Leendert H. J. Looijenga, Garvin L Chandler, Vanessa Damoulis, Nicholas Fustino, Katherine Lillard, Linda R Margraf, Dinesh Rakheja, James F AmatrudaAbstract:Germ-Cell tumors (GCTs), which arise from pluripotent embryonic Germ Cells, exhibit a wide range of histologic differentiation states with varying clinical behaviors. Although testicular GCT is the most common cancer of young men, the genes controlling the development and differentiation of GCTs remain largely unknown. Through a forward genetic screen, we previously identified a zebrafish mutant line, tgct, which develops spontaneous GCTs consisting of undifferentiated Germ Cells [Neumann JC, et al. (2009) Zebrafish 6:319–327]. Using positional cloning we have identified an inactivating mutation in alk6b, a type IB bone morphogenetic protein (BMP) receptor, as the cause of the zebrafish GCT phenotype. Alk6b is expressed in spermatogonia and early oocytes, and alk6b mutant gonads display impaired BMP signal transduction, altered expression of BMP target genes, and abnormal Germ-Cell differentiation. We find a similar absence of BMP signaling in undifferentiated human GCTs, such as seminomas and embryonal carcinoma, but not in normal testis or in differentiated GCTs. These results indicate a Germ-Cell–autonomous role for BMP signal transduction in Germ-Cell differentiation, and highlight the importance of the BMP pathway in human GCTs.
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testicular Germ Cell tumours in a broader perspective
Nature Reviews Cancer, 2005Co-Authors: Wolter J Oosterhuis, Leendert H. J. LooijengaAbstract:The Germ-Cell tumours are a fascinating group of neoplasms because of their unusual biology and the spectacular therapeutic results that have been obtained in these tumours. Traditionally, this group of neoplasms is presented in an organ-oriented approach. However, recent clinical and experimental data convincingly demonstrate that these neoplasms are one disease with separate entities that can manifest themselves in different anatomical sites. We propose five entities, in which the developmental potential is determined by the maturation stage and imprinting status of the originating Germ Cell. Recent progress begins to explain the apparent unpredictable development of Germ-Cell tumours and offers a basis for understanding their exquisite sensitivity to therapy.
Kehkooi Kee - One of the best experts on this subject based on the ideXlab platform.
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human dazl daz and boule genes modulate primordial Germ Cell and haploid gamete formation
Nature, 2009Co-Authors: Kehkooi Kee, Vanessa T Angeles, Martha Flores, Ha Nam Nguyen, Renee Reijo A PeraAbstract:Defects in Germ-Cell (oocyte and sperm) development are a leading cause of infertility in men and women. Several studies have shown that Germ Cells can be differentiated from mouse and human embryonic stem Cells, but human Germ Cells produced in this way generally fail to develop beyond the earliest stages and do not enter meiosis. Now a team from Stanford's Institute for Stem Cell Biology and Regenerative Medicine has developed a system in which primordial Germ Cells can be derived from both male and female human embryonic stem Cells. By silencing and overexpressing Germ-Cell-specific genes, human Germ-Cell formation and developmental progression can be modulated. Specifically, the human DAZL gene, which is implicated in infertility, is shown to function in primordial Germ-Cell formation, whereas closely related family members, DAZ and BOULE, modulate later stages of meiosis and development of haploid male gametes. This system can be used to study Germ-Cell defects and the potential to correct them therapeutically. Defects in human Germ-Cell (oocyte and sperm) development are the leading cause of infertility in men and women. A Germ-Cell reporter is now used to quantify and isolate primordial Germ Cells derived from both male and female human embryonic stem Cells. Human DAZL is observed to function in primordial Germ-Cell formation, whereas the closely related genes DAZ and BOULE promote later stages of meiosis and development of gametes. The leading cause of infertility in men and women is quantitative and qualitative defects in human Germ-Cell (oocyte and sperm) development. Yet, it has not been possible to examine the unique developmental genetics of human Germ-Cell formation and differentiation owing to inaccessibility of Germ Cells during fetal development. Although several studies have shown that Germ Cells can be differentiated from mouse and human embryonic stem Cells, human Germ Cells differentiated in these studies generally did not develop beyond the earliest stages1,2,3,4,5,6,7,8. Here we used a Germ-Cell reporter to quantify and isolate primordial Germ Cells derived from both male and female human embryonic stem Cells. By silencing and overexpressing genes that encode Germ-Cell-specific cytoplasmic RNA-binding proteins (not transcription factors), we modulated human Germ-Cell formation and developmental progression. We observed that human DAZL (deleted in azoospermia-like) functions in primordial Germ-Cell formation, whereas closely related genes DAZ and BOULE (also called BOLL) promote later stages of meiosis and development of haploid gametes. These results are significant to the generation of gametes for future basic science and potential clinical applications.
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human dazl daz and boule genes modulate primordial Germ Cell and haploid gamete formation
Nature, 2009Co-Authors: Kehkooi Kee, Vanessa T Angeles, Martha Flores, Ha Nam Nguyen, Renee Reijo A PeraAbstract:The leading cause of infertility in men and women is quantitative and qualitative defects in human Germ-Cell (oocyte and sperm) development. Yet, it has not been possible to examine the unique developmental genetics of human Germ-Cell formation and differentiation owing to inaccessibility of Germ Cells during fetal development. Although several studies have shown that Germ Cells can be differentiated from mouse and human embryonic stem Cells, human Germ Cells differentiated in these studies generally did not develop beyond the earliest stages. Here we used a Germ-Cell reporter to quantify and isolate primordial Germ Cells derived from both male and female human embryonic stem Cells. By silencing and overexpressing genes that encode Germ-Cell-specific cytoplasmic RNA-binding proteins (not transcription factors), we modulated human Germ-Cell formation and developmental progression. We observed that human DAZL (deleted in azoospermia-like) functions in primordial Germ-Cell formation, whereas closely related genes DAZ and BOULE (also called BOLL) promote later stages of meiosis and development of haploid gametes. These results are significant to the generation of gametes for future basic science and potential clinical applications.
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human Germ Cell lineage differentiation from embryonic stem Cells
CSH Protocols, 2008Co-Authors: Kehkooi Kee, Renee Reijo A PeraAbstract:INTRODUCTIONBiological and ethical constraints hinder studies of human Germ Cell development despite its importance to reproductive health, including fertility and tumorigenesis. Thus, most of what we know of human Germ Cell development has been extrapolated from studies in model organisms. Human embryonic stem Cells (hESCs) may provide an ideal system for probing the developmental genetics of Germ Cell formation and differentiation in vitro. The growth factors BMP (bone morphogenetic protein) 4, BMP7, and BMP8b are required for development of primordial Germ Cells (PGCs) in mice. It has been shown that these BMPs significantly increase Germ Cell differentiation from hESCs in vitro. This protocol describes a method to induce Germ Cell differentiation from hESCs by the addition of BMPs to hESC differentiation medium. The protocol can be used to study the basic mechanism of Germ Cell development in human Cells.
Yaotseng Chen - One of the best experts on this subject based on the ideXlab platform.
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cancer testis antigen expression in testicular Germ Cell tumors and in intratubular Germ Cell neoplasia
Modern Pathology, 2015Co-Authors: Yaotseng ChenAbstract:Cancer testis antigen expression in testicular Germ Cell tumors and in intratubular Germ Cell neoplasia
David M Demarini - One of the best experts on this subject based on the ideXlab platform.
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approaches for identifying Germ Cell mutagens report of the 2013 iwgt workshop on Germ Cell assays
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Carole L Yauk, David M Demarini, Marilyn J Aardema, Ja Van Benthem, Jack Ishop, Kerry L Dearfield, Masamitsu Honma, James R Lupski, Francesco MarchettiAbstract: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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Approaches for identifying Germ Cell mutagens: Report of the 2013 IWGT workshop on Germ Cell assays(☆)
2015Co-Authors: Carole L Yauk, David M Demarini, Marilyn J Aardema, Kerry L Dearfield, Masamitsu Honma, James R Lupski, J. V. Benthem, J. B. Bishop, Francesco MarchettiAbstract: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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declaring the existence of human Germ Cell mutagens
Environmental and Molecular Mutagenesis, 2012Co-Authors: David M DemariniAbstract:After more than 80 years of searching for human Germ-Cell mutagens, I think that sufficient evidence already exists for a number of agents to be so considered, and definitive confirmation seems imminent due to the application of recently developed genomic techniques. In preparation for this, an assessment panel of internationally recognized experts in Germ-Cell biology and genomics is required to consider either the current evidence now, or impending genomic evidence later, to declare whether an agent is a human Germ-Cell mutagen. I propose that such a panel be organized under the aegis of the World Health Organization and constructed similarly to the working groups assembled by the International Agency for Research on Cancer for the evaluation of human carcinogens. Support from prominent national and international organizations would be important. Many regulatory agencies already have procedures in place for assessing potential human Germ-Cell mutagens, and the time is approaching when definitive genomic data in humans will obligate such evaluations. In my view, application of an IARC-type of assessment using available evidence leads to the conclusion that ionizing radiation, cancer chemotherapy, cigarette smoking, and air pollution are “Group 1” human Germ-Cell mutagens. Consideration of the potential adverse health effects to the unexposed offspring of an exposed parent will usher in an entirely new realm of environmental health assessment. I suggest that the long search for human Germ-Cell mutagens is about to end, and a demonstration of the much-anticipated linkage between heritable disease and environmental factors is poised to begin. Environ. Mol. Mutagen. 2012. © 2012 Wiley Periodicals, Inc.