2005 © Oxford University Press
Relative Susceptibilities of Male Germ Cells to Genetic Defects Induced by Cancer Chemotherapies
Author affiliations: Biosciences Directorate, Lawrence Livermore National Laboratory, University of California, Livermore (AJW, TES, FM); School of Public Health, University of California, Berkeley (TES)
Correspondence to: Andrew J. Wyrobek, PhD, Biosciences Directorate, Lawrence Livermore National Laboratory, P.O. Box 808 L- 448, Livermore, CA 94550 (e-mail: wyrobek1{at}llnl.gov).
 |
ABSTRACT |
|---|
 TopNotes Abstract IntroductionSPERMATOGENESIS AND TYPES OF...ANIMALS BREEDING TESTS FOR...MOUSE PAINT/DAPI ASSAY FOR...INFORMATION OBTAINED FROM...INFORMATION FROM MOUSE SPERM...EVIDENCE FOR SUSCEPTIBILITIES OF...References |
|---|
Some chemotherapy regimens include agents that are mutagenic or clastogenic in model systems. This raises concerns that cancer survivors who were treated before or during their reproductive years may be at increased risks for abnormal reproductive outcomes. However, the available data from offspring of cancer survivors are limited, representing diverse cancers, therapies, time to pregnancies, and reproductive outcomes. Rodent breeding data after paternal exposures to individual chemotherapeutic agents illustrate the complexity of factors that influence the risk for transmitted genetic damage including agent, dose, end point, and germ cell susceptibility profiles that vary across agents. Direct measurements of chromosomal abnormalities in sperm of mice and humans by sperm fluorescent in situ hybridization have corroborated the differences in germ cell susceptibilities. The available evidence indicates that the risk of producing chromosomally defective sperm is highest during the first few weeks after the end of chemotherapy and decays with time. Thus, sperm samples provided immediately after the initiation of cancer therapies may contain treatment-induced genetic defects that will jeopardize the genetic health of offspring.
|
INTRODUCTION |
|---|
|
TopNotesAbstractIntroductionSPERMATOGENESIS AND TYPES OF...ANIMALS BREEDING TESTS FOR...MOUSE PAINT/DAPI ASSAY FOR...INFORMATION OBTAINED FROM...INFORMATION FROM MOUSE SPERM...EVIDENCE FOR SUSCEPTIBILITIES OF...References |
|---|
The continuing search for cancer cures has produced chemotherapies that have significantly increased survival among certain cancer groups. More than 70% of individuals now survive childhood cancer and this proportion continues to increase (1). As more survivors of childhood cancers and cancers in the reproductive years regain their fertility after treatment, there are concerns that the therapy may have induced germ-line mutations that increase the risks of birth defects, genetic diseases, or cancer among the children of cancer survivors. These concerns are motivated by two major lines of evidence: doses used for human chemotherapies are in the ranges known to be mutagenic in animal models (2), and several chemotherapies have been shown to induce chromosomal abnormalities in the sperm of treated patients (3,4).
Studies evaluating genetic diseases among the offspring of cancer survivors who received chemo- or radiotherapies have found little evidence for elevated risks of chromosomal abnormalities (5) or genetic diseases (6–10) in the offspring. Although these findings are reassuring, the offspring data have major limitations (11): they include patients who received both mutagenic and nonmutagenic regimens with broad differences in drug regimens, doses, exposure duration, and so forth, with small numbers of children born to survivors of any specific treatment regimen; the end points evaluated in pregnancies and offspring have been diverse, with few data for any one end point; and most patients were treated as children so that pregnancies under investigation occurred long after treatment and do not reflect pregnancies that may result from exposure to germ cells at more sensitive time windows of gametogenesis. These variables have precluded reliable estimates of relative reproductive risks for survivors of treatment with specific chemotherapeutic agents.
The generally negative human offspring data need to be better reconciled with the generally positive data for mouse breeding studies, as well as rodent and human sperm fluorescent in situ hybridization (FISH) assays for induced chromosomal abnormalities. The purpose of this article is to provide a brief overview of the rodent breeding data for heritable effects after paternal exposure to chemotherapeutic agents and of the human and rodent data for chemotherapy-induced chromosomal abnormalities in sperm and to identify areas for additional research and clinical recommendations regarding germ cell susceptibilities after cancer chemotherapy.
|
SPERMATOGENESIS AND TYPES OF GENETIC DAMAGE TRANSMITTED VIA SPERM |
|---|
|
TopNotesAbstractIntroductionSPERMATOGENESIS AND TYPES OF...ANIMALS BREEDING TESTS FOR...MOUSE PAINT/DAPI ASSAY FOR...INFORMATION OBTAINED FROM...INFORMATION FROM MOUSE SPERM...EVIDENCE FOR SUSCEPTIBILITIES OF...References |
|---|
Spermatogenesis is a highly regulated differentiating system, both temporally and spatially. The spermatogenic stem cells differentiate through division of spermatogonia (mitotic divisions) to form spermatocytes (meiotic cells) that undergo two meiotic divisions to give rise to spermatids (haploid postmeiotic cells) that mature into functional sperm. The kinetics of spermatogenesis are well established for men and several mammalian species (12) and are remarkably constant within species, so that the time between treatment and sampling of sperm can be used as a surrogate for sampling effects of chemotherapy on specific spermatogenic cell types. The longer the time interval between treatment and sampling, the earlier in spermatogenesis the effects are being sampled.
Physiological damage of chemotherapy to male germ cells, which has been strongly associated with fertility, is primarily monitored by parameters of semen quality. Exposure to more than 100 chemicals, individually or as mixtures and including chemotherapeutics, is known to induce detrimental effects on sperm morphology, number, and motility (13). However, we understand very little about the effects of chemotherapy on the mechanisms and frequency of sperm defects that might increase the risks of genetic or chromosomal abnormalities among offspring (Table 1) (14). Sperm defects induced by chemotherapy in model systems include whole and segmental chromosomal aneuploidies that can results in complete or partial trisomy in offspring, respectively. The molecular targets for whole chromosomal aneuploidy (e.g., centromere, microtubules, and chromosome pairing) are not thought to involve mutational mechanisms. De novo segmental aneuploidy in germ cells, however, involves double-strand DNA breaks that can arise spontaneously, especially in postmeiotic cells (15), or that can be induced by exposure to mutagens (16,17).
|
Sperm carrying defects in the imprinting profiles are theoretically important because altered expression of a paternal gene during critical stages of development might result in abnormal development or defects. Trinucleotide repeat length variation appears to be inducible in male germ cells after exposures to ionizing radiation (18) or environmental pollution (19), but there is no information on the effects of chemotherapeutic agents. More research will be needed to understand the underlying mechanisms of induction and their heritable consequences.
|
ANIMALS BREEDING TESTS FOR HERITABLE EFFECTS OF CHEMOTHERAPEUTIC AGENTS |
|---|
|
TopNotesAbstractIntroductionSPERMATOGENESIS AND TYPES OF...ANIMALS BREEDING TESTS FOR...MOUSE PAINT/DAPI ASSAY FOR...INFORMATION OBTAINED FROM...INFORMATION FROM MOUSE SPERM...EVIDENCE FOR SUSCEPTIBILITIES OF...References |
|---|
As most dramatically demonstrated in rodents, when males are treated with a mutagen and mated with unexposed females, the deleterious effects on reproduction can be profound, including infertility, lethality during development, and heritable chromosomal translocations, malformations, or cancer among offspring. Over the past 40 years, more than 30 chemicals have been tested in mice for germ cell mutagenicity, using three major tests (2,20): dominant lethal, heritable translocation, and specific locus mutation. Dominant lethal measures the induction of unstable chromosomal aberrations that lead to the embryonic death of the progeny of treated males; however, other genetic and epigenetic mechanisms cannot be excluded. The heritable translocation and specific locus mutation tests measure the induction of chromosomal reciprocal translocations and gene mutations in the offspring of treated males, respectively. Table 2 lists the chemotherapeutic agents that have been tested in at least two of these breeding tests [see (2) for an in-depth discussion of all the germ cell mutagenicity results with chemotherapeutic agents].
|
Several points can be drawn from these studies regarding differential susceptibilities of male germ cells to chemotherapeutic agents. First, mutagenic chemotherapies generally induce a wide spectrum of lesions, resulting in various chromosomal abnormalities or gene mutations. Second, most chemotherapeutic drugs induce positive results in all three tests. One notable exception is 6-mercaptopurine, which affected only preleptotene spermatocytes, inducing dominant lethal but not heritable translocation or specific locus mutation (21). Third, there are differences among the various phases of spermatogenesis in the sensitivity of induction of transmissible genetic damage. With the exception of etoposide, all treatments produced the highest response, if not the only response, in postmeiotic cells. The high sensitivity of postmeiotic cells is probably related to the reduced DNA repair capacity of late spermatids and sperm when compared with early spermatids and the other spermatogenic cell types (22). Therefore, unrepaired DNA damage induced in these late stages of spermatogenesis may be transmitted. Also, protamines—basic proteins that replace histones during postmeiosis (23)—can be preferential targets for alkylating agents. For example, acrylamide is a weak inducer of genotoxic effects in somatic (24) and female germ cells (25), but it is one of the most potent clastogens in male germ cells (26,27).
Although much has been learned from rodent breeding tests, they are very expensive, requiring thousands of animals, and they provide little information on the underlying mechanisms of action. Below, we describe two additional techniques (zygote cytogenetics and sperm FISH) as direct methods for investigating germ cell sensitivity profiles and mechanisms of action that may lead to abnormal reproductive outcomes after chemotherapy.
|
MOUSE PAINT/DAPI ASSAY FOR TRANSMITTED CHROMOSOMAL ABNORMALITIES |
|---|
|
TopNotesAbstractIntroductionSPERMATOGENESIS AND TYPES OF...ANIMALS BREEDING TESTS FOR...MOUSE PAINT/DAPI ASSAY FOR...INFORMATION OBTAINED FROM...INFORMATION FROM MOUSE SPERM...EVIDENCE FOR SUSCEPTIBILITIES OF...References |
|---|
The metaphase plate of mouse first-cleavage zygotes provides the first opportunity (28–30) for detecting cytogenetic defects in parental chromosomes after fertilization. We improved the classic cytogenetic analysis of mouse zygotes by combining 4'-6-diamidino-2-phenylindole (DAPI) staining with chromosome-specific painting probes (PAINT) for the simultaneous detection of numerical as well as stable and unstable chromosomal aberrations (31). The PAINT/DAPI procedure was recently used to demonstrate that therapeutic doses of etoposide affected primarily male meiotic germ cells, producing unstable structural aberrations and aneuploidy—effects that were transmitted to the progeny (32). This was the first report of an agent for which paternal exposure led to an increased incidence of aneuploidy in the offspring.
The PAINT/DAPI method has been used for investigating germ cell stage susceptibility, the pattern of chromosomal aberrations in the zygote, and the type of abnormal reproductive outcomes induced by various mutagens, including the chemotherapeutic agents, cyclophosphamide, etoposide, and melphalan (27). These studies have confirmed the high sensitivity of male postmeiotic germ cells to mutagens and have shown that induced chromosomal damage and premutational lesions are carried to the zygote, where they are converted into chromosomal abnormalities that are associated with specific abnormal reproductive outcomes in terms of the germ cell stage sensitivity, proportion of affected zygotes, and types of outcomes.
|
INFORMATION OBTAINED FROM HUMANSPERM FISH ASSAYS |
|---|
|
TopNotesAbstractIntroductionSPERMATOGENESIS AND TYPES OF...ANIMALS BREEDING TESTS FOR...MOUSE PAINT/DAPI ASSAY FOR...INFORMATION OBTAINED FROM...INFORMATION FROM MOUSE SPERM...EVIDENCE FOR SUSCEPTIBILITIES OF...References |
|---|
During the 1990s, FISH technology was adapted for the detection of chromosomally defective sperm, and its relevance has improved with the availability of chromosome-specific DNA probes for clinically relevant aneuploid syndromes (i.e., 21, 18, 13, X, and Y) (4). Using sperm FISH, small exposure effects can be detected by studying large numbers of sperm in small number of patients. New sperm FISH methods have been recently developed for the detection of aneuploidy as well as structural aberrations (33), but essentially all of the information for chemotherapeutic effects is limited to aneuploidy outcomes (Table 3).
|
In one of the larger studies, Robbins et al. (3) used an X-Y-8 sperm-FISH assay to study eight cancer patients treated with Novantrone, Oncovin, Velban, and Prednisone (NOVP) chemotherapy and found an approximate fivefold increase in sperm with disomies and diploidies. The aneuploidy effects were transient, however, declining to pretreatment levels within about 100 days after the end of the therapy. Another analysis of NOVP patients using an X-Y-21–18 sperm FISH assay found significant, yet also transient, two- to 14-fold inductions for the most clinically relevant sperm aneuploidies, indicating that NOVP therapy increased the risk of fathering a child with any one of the major clinical aneuploidy syndromes (4). A significant increase in the frequency of diploidy and disomy for chromosomes 16, 18, and XY was induced in testicular cancer patients treated with the cisplatin, etoposide, and bleomycin (PEB) regimen (34). In a study of the effects of bleomycin, etoposide, and cisplatin (BEP) chemotherapy, sperm from eight testicular cancer patients were assessed both before and 2–13 years after treatment (35), showing no significant treatment-related increase in the frequency of chromosomal abnormalities. In a different study, sperm chromosomal abnormalities were assessed in cancer patients before, during, and after BEP therapy, using probes for chromosomes 1, 12, X, and Y (36), showing a significant increase in the frequency of XY disomic sperm with treatment. Taken together, these limited data are consistent with the statement that treatment-induced aneuploidy effects in sperm, when they occur, are transient, with no long-term effects. However, the generality of this statement is unknown, because so few treatment regimens have been evaluated for sperm aneuploidy, and essentially none have been evaluated for treatment-induced chromosomal structural aberrations in sperm.
|
INFORMATION FROM MOUSE SPERM FISH STUDIES |
|---|
|
TopNotesAbstractIntroductionSPERMATOGENESIS AND TYPES OF...ANIMALS BREEDING TESTS FOR...MOUSE PAINT/DAPI ASSAY FOR...INFORMATION OBTAINED FROM...INFORMATION FROM MOUSE SPERM...EVIDENCE FOR SUSCEPTIBILITIES OF...References |
|---|
Most chemotherapeutic regimens consist of combination of drugs. Therefore, animal models were developed to evaluate the relative risk of individual drugs for the induction of genetic and chromosomal damage in sperm. Several multicolor sperm FISH assays have been developed to detect numerical abnormalities and chromosome structural aberrations in mouse sperm (37,38). However, to date, only four chemotherapeutics have been studied with the mouse sperm-FISH assay for aneuploidy and diploidy induction. As shown in Table 4, paclitaxel (Taxol) was tested at the maximum tolerated dose, and the increase of disomic sperm was marginally significant (39), vinblastine gave inconclusive results in repeated experiments in an interlaboratory comparison (40), and etoposide and merbarone, both topoisomerase II inhibitors, showed significant increases in the frequencies of diploid and hyperhaploid sperm (41).
|
Etoposide is currently the only agent for which it is possible to compare the response to chemotherapeutic agents between rodents and humans. It induced significant increases in the frequencies of diploid and aneuploid sperm of both mice (41) and young human patients (34).
|
EVIDENCE FOR SUSCEPTIBILITIES OF DIFFERENTIATING MALE GERM CELLS TO CHEMOTHERAPIES AND CLINICAL IMPLICATIONS |
|---|
|
TopNotesAbstractIntroductionSPERMATOGENESIS AND TYPES OF...ANIMALS BREEDING TESTS FOR...MOUSE PAINT/DAPI ASSAY FOR...INFORMATION OBTAINED FROM...INFORMATION FROM MOUSE SPERM...EVIDENCE FOR SUSCEPTIBILITIES OF...References |
|---|
The evidence from sperm, zygote, and breeding studies demonstrates that chemotherapy can induce significant increases in the frequencies of sperm with chromosomal abnormalities (aneuploidies, structural abnormalities, and prelesions) that can lead to abnormal reproductive outcomes, and that male germ cells differ in their susceptibility to damage. For aneuploidies, induced increases in ejaculated sperm diminish with increasing time after exposure, indicating that cancer patients have only a transient risk for producing abnormal offspring after chemotherapy. However, very few chemotherapeutic agents have been evaluated for chromosomal aberrations and gene mutations in sperm, and further studies are needed for both these sperm end points and others listed in Table 1.
Our knowledge of the mechanisms underlying the susceptibility differences among types of male germ cells is very limited. There is evidence indicating that the nature of gene mutations is more dependent on the germ cell stage than on the chemical itself (42). The time-dependent risks for specific types of abnormal reproductive outcomes may differ depending on the type of chemotherapeutic agents employed and time from the end of therapy.
We do not know how many cancer drugs produce transient chromosomal abnormalities in male meiotic and postmeiotic germ cell stages and persistent gene mutations in spermatogonial stem cells. Using the cumbersome animal breeding tests, only a few chemicals have been found to cause mutations in spermatogonial stem cells (2). The animal breeding tests show that most mutagens are effective in differentiating germ cells (Table 2); namely, spermatocytes and spermatids (43). Genetic damage to spermatids is a special case, because genetically damaged spermatids are known to develop into mature sperm that are fully capable of fertilizing eggs despite the presence of DNA damage (2,32). Taken together, the available data from animal breeding and human sperm studies indicate that it may be ill advised to cryopreserve sperm within the first few weeks after the start of chemotherapy, even though sperm counts and motility are still high. Postponing fertilization for at least 3 months and up to a year following chemotherapy is likely to reduce the risk of fathering an abnormal reproductive outcome (44) for those agents that do not produce stem cell mutations. Better methods are needed to assess the risk of chemotherapy exposures on mutations in stem cells, because these mutations, if they occur, may persist throughout the reproductive life of the cancer survivor. Modern molecular assays for specific gene mutations in sperm, such as those recently applied to age effects in men (45,46), may provide a new approach to assess susceptibility and persistence in sperm from treated cancer patients.
Although the primary responsibility of the physician is to try to achieve remission and cure, the increasing effectiveness of modern anticancer treatments increases the importance of understanding whether drug regimens can induce elevated frequencies of sperm with gene mutations or chromosomal abnormalities. Furthermore, young cancer survivors and their parents deserve counseling regarding the possibility that chemotherapy may have detrimental effects on the future ability to father healthy progeny, especially for samples obtained within the first few weeks after receiving treatment, when highly susceptible meiotic and postmeiotic cells have progressed to the ejaculate.
|
NOTES |
|---|
This work was performed under the auspices of the U.S. Department of Energy by the University of California, Lawrence Livermore National Laboratory, under contract W-7405-Eng-48, with funding support from National Institute of Environmental Health Sciences Superfund P4ZES04705, NIH ES 09117–03, and NIEHS IAG Y1 ES 8016–5.
|
REFERENCES |
|---|
|
TopNotesAbstractIntroductionSPERMATOGENESIS AND TYPES OF...ANIMALS BREEDING TESTS FOR...MOUSE PAINT/DAPI ASSAY FOR...INFORMATION OBTAINED FROM...INFORMATION FROM MOUSE SPERM...EVIDENCE FOR SUSCEPTIBILITIES OF...References |
|---|
(1) Thomson AB, Campbell AJ, Irvine DC, Anderson RA, Kelnar CJ, Wallace WH. Semen quality and spermatozoal DNA integrity in survivors of childhood cancer: a case-control study. Lancet 2002;360:361–7.[CrossRef][ISI][Medline]
(2) Witt KL, Bishop JB. Mutagenicity of anticancer drugs in mammalian germ cells. Mutat Res 1996;355:209–34.[ISI][Medline]
(3) Robbins WA, Meistrich ML, Moore D, Hagemeister FB, Weier HU, Cassel MJ, et al. Chemotherapy induces transient sex chromosomal and autosomal aneuploidy in human sperm. Nat Genet 1997;16:74–78.[CrossRef][ISI][Medline]
(4) Frias S, Van Hummelen P, Meistrich ML, Lowe XR, Hagemeister FB, Shelby MD, et al. NOVP chemotherapy for Hodgkin's disease transiently induces sperm aneuploidies associated with the major clinical aneuploidy syndromes involving chromosomes X, Y, 18, and 21. Cancer Res 2003;63:44–51.
(5) Winther JF, Boice JD, Jr., Mulvihill JJ, Stovall M, Frederiksen K, Tawn EJ, et al. Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: a population-based study. Am J Hum Genet 2004;74:1282–5.[CrossRef][ISI][Medline]
(6) Byrne J, Rasmussen SA, Steinhorn SC, Connelly RR, Myers MH, Lynch CF, et al. Genetic disease in offspring of long-term survivors of childhood and adolescent cancer. Am J Hum Genet 1998;62:45–52.[CrossRef][ISI][Medline]
(7) Kenney LB, Nicholson HS, Brasseux C, Mills JL, Robison LL, Zeltzer LK, et al. Birth defects in offspring of adult survivors of childhood acute lymphoblastic leukemia. A Childrens Cancer Group/National Institutes of Health Report. Cancer 1996;78:169–76.[CrossRef][ISI][Medline]
(8) Meistrich ML, Byrne J. Genetic disease in offspring of long-term survivors of childhood and adolescent cancer treated with potentially mutagenic therapies. Am J Hum Genet 2002;70:1069–71.[CrossRef][ISI][Medline]
(9) Blatt J. Pregnancy outcome in long-term survivors of childhood cancer. Med Pediatr Oncol 1999;33:29–33.[CrossRef][ISI][Medline]
(10) Green DM, Whitton JA, Stovall M, Mertens AC, Donaldson SS, Ruymann FB, et al. Pregnancy outcome of partners of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2003;21:716–21.
(11) Boice JD, Jr., Tawn EJ, Winther JF, Donaldson SS, Green DM, Mertens AC, et al. Genetic effects of radiotherapy for childhood cancer. Health Phys 2003;85:65–80.[CrossRef][ISI][Medline]
(12) Adler ID. Comparison of the duration of spermatogenesis between male rodents and humans. Mutat Res 1996;352:169–172.[CrossRef][ISI][Medline]
(13) Wyrobek AJ, Gordon LA, Burkhart JG, Francis MW, Kapp RW Jr, Letz G, et al. An evaluation of human sperm as indicators of chemically induced alterations of spermatogenic function. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat Res 1983;115:73–148.[CrossRef][ISI][Medline]
(14) Wyrobek AJ. Methods and concepts in detecting abnormal reproductive outcomes of paternal origin. Reprod Toxicol 1993;7:3–16.
(15) Morris ID. Sperm DNA damage and cancer treatment. Int J Androl 2002; 25:255–61.[CrossRef][ISI][Medline]
(16) Caron N, Veilleux S, Boissonneault G. Stimulation of DNA repair by the spermatidal TP1 protein. Mol Reprod Dev 2001;58:437–43.[CrossRef][ISI][Medline]
(17) Robbins W. Cytogenetic damage measured in human sperm following cancer chemotherapy. Mutat Res 1996;355:235–52.[CrossRef][ISI][Medline]
(18) Dubrova YE, Plumb M, Gutierrez B, Boulton E, Jeffreys AJ. Transgenerational mutation by radiation. Nature 2000;405:37.[CrossRef][Medline]
(19) Somers CM, McCarry BE, Malek F, Quinn JS. Reduction of particulate air pollution lowers the risk of heritable mutations in mice. Science 2004;304:1008–10.
(20) Shelby MD. Selecting chemicals and assays for assessing mammalian germ cell mutagenicity. Mutat Res 1996;352:159–67.[CrossRef][ISI][Medline]
(21) Generoso WM, Preston RJ, Brewen JG. 6-mercaptopurine, an inducer of cytogenetic and dominant-lethal effects in premeiotic and early meiotic germ cells of male mice. Mutat Res 1975;28:437–47.[CrossRef][ISI][Medline]
(22) Sotomayor RE, Sega GA. Unscheduled DNA synthesis assay in mammalian spermatogenic cells: an update. Environ Mol Mutagen 2000;36:255–65.[CrossRef][ISI][Medline]
(23) Meistrich ML, Brock WA, Grimes SR, Platz RD, Hnilica LS. Nucleoprotein transitions during spermatogenesis. Federation Proceedings 1978;37:2522–5.[ISI][Medline]
(24) Adler ID, Ingwersen I, Kliesch U, El Tarras A. Clastogenic effects of acrylamide in mouse bone marrow cells. Mutat Res 1988;206:379–85.[CrossRef][ISI][Medline]
(25) Tyl RW, Friedman MA. Effects of acrylamide on rodent reproductive performance. Reprod Toxicol 2003;17:1–13.[CrossRef][ISI][Medline]
(26) Pacchierotti F, Tiveron C, D'Archivio M, Bassani B, Cordelli E, Leter G, et al. Acrylamide-induced chromosomal damage in male mouse germ cells detected by cytogenetic analysis of one-cell zygotes. Mutat Res 1994;309:273–84.[CrossRef][ISI][Medline]
(27) Marchetti F, Bishop JB, Cosentino L, Moore D II, Wyrobek AJ. Paternally transmitted chromosomal aberrations in mouse zygotes determine their embryonic fate. Biol Reprod 2004;70:616–24.
(28) Mailhes JB, Marchetti F. Chemically-induced aneuploidy in mammalian oocytes. Mutat Res 1994;320:87–111.[CrossRef][ISI][Medline]
(29) Albanese R. The use of fertilized mouse eggs in detecting potential clastogens. Mutat Res 1982;97:315–326.[CrossRef][ISI][Medline]
(30) Matsuda Y, Tobari I. Repair capacity of fertilized mouse eggs for X-ray damage induced in sperm and mature oocytes. Mutat Res 1989;210:35–47.[CrossRef][ISI][Medline]
(31) Marchetti F, Lowe X, Moore DH 2nd, Bishop J, Wyrobek AJ. Paternally inherited chromosomal structural aberrations detected in mouse first-cleavage zygote metaphases by multicolour fluorescence in situ hybridization painting. Chromosome Res 1996;4:604–13.[CrossRef][ISI][Medline]
(32) Marchetti F, Bishop JB, Lowe X, Generoso WM, Hozier J, Wyrobek AJ. Etoposide induces heritable chromosomal aberrations and aneuploidy during male meiosis in the mouse. Proc Natl Acad Sci USA 2001;98:3952–7.
(33) Sloter ED, Lowe X, Moore ID, Nath J, Wyrobek AJ. Multicolor FISH analysis of chromosomal breaks, duplications, deletions, and numerical abnormalities in the sperm of healthy men. Am J Hum Genet 2000;67:862–72.[CrossRef][ISI][Medline]
(34) De Mas P, Daudin M, Vincent MC, Bourrouillou G, Calvas P, Mieusset R, et al. Increased aneuploidy in spermatozoa from testicular tumor patients after chemotherapy with cisplatin, etoposide and bleomycin. Hum Reprod 2001;16:1204–8.
(35) Martin RH, Ernst S, Rademaker A, Barclay L, Ko E, Summers N. Analysis of human sperm karyotypes in testicular cancer patients before and after chemotherapy. Cytogenet Cell Genet 1997;78:120–3.[ISI][Medline]
(36) Martin R, Ernst S, Rademaker A, Barclay L, Ko E, Summers N. Analysis of sperm chromosome complements before, during, and after chemotherapy. Cancer Genet Cytogenet 1999;108:133–6.[CrossRef][ISI][Medline]
(36a) Martin RH, Rademaker AW, Leonard NJ. Analysis of chromosomal abnormalities in human sperm after chemotherapy by karyotyping and fluorescence in situ hybridization (FISH). Cancer Genet Cytogenet 1995;80:29–32.[CrossRef][ISI][Medline]
(37) Lowe X, O'Hogan S, Moore DN, Bishop J, Wyrobek A. Aneuploid epididymal sperm detected in chromosomally normal and Robertsonian translocation-bearing mice using a new three-chromosome FISH method. Chromosoma 1996;105:204–10.[CrossRef][ISI][Medline]
(38) Hill FS, Marchetti F, Liechty M, Bishop J, Hozier J, Wyrobek AJ. A new FISH assay to simultaneously detect structural and numerical chromosomal abnormalities in mouse sperm. Mol Reprod Dev 2003;66:172–80.[CrossRef][ISI][Medline]
(39) Adler ID, Schmid TE, Baumgartner A. Induction of aneuploidy in male mouse germ cells detected by the sperm-FISH assay: a review of the present data base. Mutat Res 2002;504:173–82.[ISI][Medline]
(40) Schmid TE, Lowe X, Marchetti F, Bishop J, Haseman J, Wyrobek AJ. Evaluation of inter-scorer and inter-laboratory reliability of the mouse epididymal sperm aneuploidy (m-ESA) assay. Mutagenesis 2001;16:189–95.
(41) Attia SM, Schmid TE, Badary OA, Hamada FM, Adler ID. Molecular cytogenetic analysis in mouse sperm of chemically induced aneuploidy: studies with topoisomerase II inhibitors. Mutat Res 2002;520:1–13.[ISI][Medline]
(42) Russell L. Effects of spermatogenic cell type on quantity and quality of mutations. In: Olsham A, Mattison D, editors. Male-mediated developmental toxicity. New York: Plenum; 1994. p. 37–48.
(43) Russell LB. Factors that affect the molecular nature of germ-line mutations recovered in the mouse specific-locus test. Environ Mol Mutagen 1991;18:298–302.[ISI][Medline]
(44) Meistrich ML. Effects of chemotherapy and radiotherapy on spermatogenesis. Eur Urol 1993;23:136–41.[ISI][Medline]
(45) Tiemann-Boege I, Navidi W, Grewal R, Cohn D, Eskenazi B, Wyrobek AJ, et al. The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect. Proc Natl Acad Sci USA 2002;99:14952–7.
(46) Glaser RL, Broman KW, Schulman RL, Eskenazi B, Wyrobek AJ, Jabs EW. The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am J Hum Genet 2003;73:939–4.[CrossRef][ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S.S. Young, B. Eskenazi, F.M. Marchetti, G. Block, and A.J. Wyrobek The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men Hum. Reprod., March 19, 2008; (2008) den036v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.G. Tempest, E. Ko, P. Chan, B. Robaire, A. Rademaker, and R.H. Martin Sperm aneuploidy frequencies analysed before and after chemotherapy in testicular cancer and Hodgkin's lymphoma patients Hum. Reprod., February 1, 2008; 23(2): 251 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.E. Schmid, B. Eskenazi, A. Baumgartner, F. Marchetti, S. Young, R. Weldon, D. Anderson, and A.J. Wyrobek The effects of male age on sperm DNA damage in healthy non-smokers Hum. Reprod., January 1, 2007; 22(1): 180 - 187. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||