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Keywords:

  • tobacco smoke;
  • ionizing radiation;
  • air pollution;
  • chemotherapy;
  • heritable effects

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. WHY HAVE NO HUMAN GERM-CELL MUTAGENS BEEN IDENTIFIED?
  5. TECHNICAL DEVELOPMENTS AND RECENT DISCOVERIES OF DE NOVO GERM-CELL MUTATIONS IN HUMANS
  6. POSSIBLE HUMAN GERM-CELL MUTAGENS
  7. NEED FOR A DECLARATION PANEL AND IMPLICATIONS OF DECLARING AN AGENT A HUMAN GERM-CELL MUTAGEN
  8. Acknowledgements
  9. REFERENCES

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.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. WHY HAVE NO HUMAN GERM-CELL MUTAGENS BEEN IDENTIFIED?
  5. TECHNICAL DEVELOPMENTS AND RECENT DISCOVERIES OF DE NOVO GERM-CELL MUTATIONS IN HUMANS
  6. POSSIBLE HUMAN GERM-CELL MUTAGENS
  7. NEED FOR A DECLARATION PANEL AND IMPLICATIONS OF DECLARING AN AGENT A HUMAN GERM-CELL MUTAGEN
  8. Acknowledgements
  9. REFERENCES

The announcement of the discovery of the first germ-cell mutagen (X-rays) in the first mutation assay (the sex-linked recessive lethal assay in Drosophila melanogaster) was made by H.J. Muller in1927 without publishing any data to support his claim. With reference to the usefulness of his discovery, Muller [1927] noted “The time is not ripe to discuss here such possibilities with reference to the human species.” From this relatively shaky start, the 84-year search for human germ-cell mutagens has come to a similar point, with there being yet no data sufficient for any national or international organization to declare definitively that such agents exist.

2011 ALEXANDER HOLLAENDER AWARD

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The Environmental Mutagen Society conferred this award to Dr. David M. DeMarini for his outstanding contributions to environmental mutagen research and for his internationally recognized outreach and impact in the field of genetic toxicology. Dr. DeMarini's contributions are remarkably broad in scope and include characterizing the mutations recoverable by the Salmonella assay, conducting critical molecular epidemiology studies of exposed human populations, and refocusing attention on germ cell mutagenesis. His research on the mutagenicity and health risk of air and combustion emissions, drinking water disinfection byproducts, tobacco smoke, and arsenic has shaped public policy nationally and internationally. Consistent with the spirit of the Hollaender Award, his outreach to scientists in developing countries and his effort toward strengthening ties between scientists across the globe are unmatched.

As discussed below, I disagree with that view and think that sufficient data are available already to show that several agents, including ionizing radiation, chemotherapy, smoking, and air pollution, are human germ-cell mutagens. To the vindication of Muller and the legions of scientists who have followed the trail he initiated 8 decades ago, I think that the time is finally ripe to discuss in earnest the evidence for human germ-cell mutagens and to recognize that next-generation sequencing data of human families, coupled with parental exposure data, will soon provide additional, definitive proof. This Commentary is a discussion of what we need to do to prepare for this eventuality and its consequences.

WHY HAVE NO HUMAN GERM-CELL MUTAGENS BEEN IDENTIFIED?

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. WHY HAVE NO HUMAN GERM-CELL MUTAGENS BEEN IDENTIFIED?
  5. TECHNICAL DEVELOPMENTS AND RECENT DISCOVERIES OF DE NOVO GERM-CELL MUTATIONS IN HUMANS
  6. POSSIBLE HUMAN GERM-CELL MUTAGENS
  7. NEED FOR A DECLARATION PANEL AND IMPLICATIONS OF DECLARING AN AGENT A HUMAN GERM-CELL MUTAGEN
  8. Acknowledgements
  9. REFERENCES

Approximately a dozen epidemiological studies have been conducted since the1950s to investigate whether ionizing radiation, chemotherapy, or pesticides might be human germ-cell mutagens [reviewed by Shelby,1994; Dubrova,2003; Wyrobek et al.,2007; Winther et al., 2012]. All but three of these studies found no evidence of human germ-cell mutagens, including the decades-long evaluation of the survivors of the atomic bomb explosions at Hiroshima and Nagasaki in1945 [Schull et al.,1981; Kodaira et al.,1995; Fujiwara et al.,2008].

Y.E. Dubrova has suggested in Wyrobek et al. [2007] that the negative results from the bomb survivors may have been due to the size of the radiation doses, the numbers of exposed subjects available for study, and the lack of distinction between maternal and paternal exposure; he also has suggested that the negative results from one study of Chernobyl cleanup workers may have been due to fractionated exposures. Another factor could have been the 10-year difference between exposure of the father and birth of the children evaluated in the study, which would have prevented detection of short-term effects of exposure [Yauk,2004].

Negative data from studies of ionizing radiation could be due to the fact that such agents can be toxic, and toxicity to the germ cells might have resulted in dead cells (via apoptosis) rather than mutated but viable cells. Perhaps the internal dose was not sufficient in the negative studies, whereas high internal doses might have been achieved in the positive ones (described below) due to long-term consumption of food and water contaminated with radio-nuclides.

In contrast to all the negative studies, three positive studies have been reported relative to ionizing radiation that evaluated tandem repeat loci in children from (a) Chernobyl survivors (not the cleanup workers) [Dubrova et al.,2002b], (b) residents near the Semipalatinsk nuclear test site [Dubrova et al.,2002a], and (c) residents from the Techa River population [Dubrova et al.,2006], and each of these found significant increases in mutation rates in the children that were associated with paternal exposure to ionizing radiation. However, these data have not been accepted as evidence that ionizing radiation is a human germ-cell mutagen by the organizations concerned with estimating genetic risk from ionizing radiation, such as the United Nations Scientific Committee on the Effects of Atomic Radiation [UNSCEAR,2001] and the BEIR Committee of the US National Academy of Sciences [NRC,2006].

The reasons given for lack of full acceptance of the data by these organizations stem from concerns that for the initial study (a) control populations from one country are not appropriate for comparison with exposed subjects from another country, (b) potential controls within the same countries as the exposed subjects were not used, (c) there might have been unidentified environmental factors other than ionizing radiation that accounted for the observed increases in mutation rates, and (d) the use of family-based exposures is less informative than measurements based on exposures to individual subjects [UNSCEAR,2001; NRC,2006].

Considering all of the studies over the past half century that have looked for human germ-cell mutagens, I think that most may have (a) looked at the wrong populations, i.e., atomic bomb survivors or other populations with exposures that were not sufficient or suitable to induced such mutations; (b) examined the wrong loci, i.e., coding genes rather than highly variable and more mutable noncoding loci; and (c) used insensitive, i.e., pregenomic, techniques. Beyond the obvious difficulty of finding suitable parent–child cohorts to study, the greatest impediment probably has been the last reason: the absence of suitable methods for such analyses.

Even if there were generally accepted evidence for the existence of human germ-cell mutagens, there is a notable absence of an international organization broadly authorized to declare agents to be human germ-cell mutagens, such as the International Agency for Research on Cancer (IARC) does for human carcinogens. For decades, only the Atomic Bomb Casualty Commission (ABCC), which later became the Radiation Effects Research Foundation [RERF,2011], had the international stature to declare one such agent (ionizing radiation from the atomic bombs) to be a human germ-cell mutagen. More recently, other organizations now have the stature to do this for exposures to ionizing radiation from sources other than the atomic bombs [UNSCEAR,2001; NRC,2006].

TECHNICAL DEVELOPMENTS AND RECENT DISCOVERIES OF DE NOVO GERM-CELL MUTATIONS IN HUMANS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. WHY HAVE NO HUMAN GERM-CELL MUTAGENS BEEN IDENTIFIED?
  5. TECHNICAL DEVELOPMENTS AND RECENT DISCOVERIES OF DE NOVO GERM-CELL MUTATIONS IN HUMANS
  6. POSSIBLE HUMAN GERM-CELL MUTAGENS
  7. NEED FOR A DECLARATION PANEL AND IMPLICATIONS OF DECLARING AN AGENT A HUMAN GERM-CELL MUTAGEN
  8. Acknowledgements
  9. REFERENCES

The participants of a workshop (including the late James F. Crow) held in2004 under the auspices of the Environmental Mutagen Society (EMS) and funded by various organizations [U.S Department of Energy, U.S. Environmental Protection Agency, the Lawrence Livermore National Laboratory, the Oak Ridge National Laboratory, the National Institutes of Health (NIH)/National Institute of Environmental Health Sciences (NIEHS), NIH/Office of Rare Diseases, NIH/Child Health and Human Development, and The Jackson Laboratory] concluded that the absence of evidence for human germ-cell mutagens, despite the strong evidence for such mutagens in rodents, was due largely to technical reasons [Wyrobek et al.,2007]. Efforts to identify human germ-cell mutagens have never been easy. Even in mice, the classic specific-locus assay developed by W.L. Russell and used for 40 years required heroic efforts and >100,000 animals per study. However, recent technical developments, especially next-generation DNA sequencing and advanced computational techniques, have catapulted the field of germ-cell mutagenesis beyond its traditional limitations and into the realm of the possible [Sankaranarayanan and Nikjoo,2011].

Exome and whole-genome sequencing, analysis of copy-number variants, and determination of the methylome to understand epigenetic changes have revealed an abundance of de novo heritable changes in the human germline. Application of one or another of these methods to parent-child dyads has provided derived estimates of de novo mutation rates [Roach et al.,2010; Conrad et al.,2011] and has demonstrated that de novo mutations underlie many diseases such as schizophrenia, autism, epilepsy, and intellectual disability [Lupski,2010; Morrow,2010; Vissers et al.,2010; Hehir-Kwa et al.,2011]. Although current technology still has limitations, such as overly high error rates and an inability to sequence long stretches of tandem repeats [Beal et al., 2012], it nonetheless permits the identification of de novo, heritable mutations. Beyond mutation per se, there is intriguing evidence for the so-called “grandmother effect” in which epigenetic changes may be inherited trans-generationally [Juckett,2009; Guerrero-Bosagna and Skinner, 2012]. Needed next are studies to investigate the potential linkage of the de novo mutations and epigenetic changes with parental (especially paternal) exposure to environmental mutagens.

To this end, another workshop organized under the auspices of the EMS in2011 was held to forge this linkage and to consider the application of genomic methods in suitably designed human studies for the purpose of identifying environmental contributions to heritable disease [C.L. Yauk et al., in preparation]. In addition, the designs of suitable rodent studies were discussed in which genomic methods also would be applied for comparison to human studies. As 21st century, high-throughput toxicology develops, promising new methods are becoming available that permit the study of gametes in vitro [Singer and Yauk,2010], and these emerging assays should be evaluated with known rodent germ-cell mutagens. Given the timeliness of technical developments and recent discoveries, as well as the enthusiasm of the workshop attendees, it is clear that the field is poised to finally reconcile the 80-year enigma that there are agents that induce germ-cell mutations in rodents, but apparently none that do so in humans.

POSSIBLE HUMAN GERM-CELL MUTAGENS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. WHY HAVE NO HUMAN GERM-CELL MUTAGENS BEEN IDENTIFIED?
  5. TECHNICAL DEVELOPMENTS AND RECENT DISCOVERIES OF DE NOVO GERM-CELL MUTATIONS IN HUMANS
  6. POSSIBLE HUMAN GERM-CELL MUTAGENS
  7. NEED FOR A DECLARATION PANEL AND IMPLICATIONS OF DECLARING AN AGENT A HUMAN GERM-CELL MUTAGEN
  8. Acknowledgements
  9. REFERENCES

Guidance for identifying possible human germ-cell mutagens can be found from published studies on rodent germ-cell mutagens. Of 48 agents evaluated for induction of germ-cell mutations in rodents, 39 of them are positive [Shelby1996; Witt and Bishop,1996; Russell,2004; Marchetti and Wyrobek2005; Glen et al.,2008; Marchetti et al.,2011; Somers,2011]. The published rodent germ-cell mutagens include ionizing radiation; cancer chemotherapy agents; food components (acrylamide); environmental contaminants (benzo[a]pyrene); and common complex mixtures to which nearly everyone is exposed, such as main- and side-stream tobacco smoke, diesel exhaust, and the particulate fraction of air pollution [Yauk et al.,2007; Marchetti et al.,2011; Ritz et al.,2011; Somers,2011]. Table I illustrates that some of these agents are carcinogenic and somatic-cell mutagens in both humans and rodents, as well as germ-cell mutagens in rodents. What do we know about the potential of each of these agents to induce germ-cell mutations in humans?

Table I. Mutagenicity and Carcinogenicity of Potential Human Germ-Cell Mutagensa
AgentAnimalHumanRefb
MutagenicityMutagenicity
CarcinogenSomaticGermCarcinogenSomaticGerm
  • a

    Based on table from Shelby [1994].

  • b

    Ref 1: Shelby [1994]; Ref 2: DeMarini [2004], Marchetti et al. [2011], Yauk et al.2007; Ref 3: Somers and Cooper [2009], Somers [2011].

Ionizing radiation+++++?1
Chemotherapy+++++?1
Smoking+++++?2
Air pollution+++++?3

The similarity of germ-cell biology [Wyrobek et al.,2007] and germ-cell mutational response to ionizing radiation [Neel and Lewis,1990; Dubrova,2005] between humans and rodents leads to the conclusion that at least some rodent germ-cell mutagens are likely human germ-cell mutagens. For ionizing radiation, I have already mentioned the evidence from studies using repeat loci that show that under certain exposure conditions, this agent is a human germ-cell mutagen [Dubrova et al.,2002a,b,2006]. Despite their shortcomings [UNSCEAR,2001; NRC,2006], these studies provide the clearest evidence thus far that ionizing radiation is a human germ-cell mutagen. A recent study also has found trans-generational genomic instability in somatic cells, and increased morbidity, of nonirradiated children born from fathers who were exposed to low doses of ionizing radiation while working as clean-up workers (liquidators) at the Chernobyl site [Aghajanyan et al.,2011].

Many cancer chemotherapeutic agents are both somatic- and germ-cell mutagens in rodents and somatic-cell mutagens in humans [Shelby,1994,2006; Witt and Bishop,1996]. Despite the negative epidemiology studies [Winther et al., 2012], I think it unlikely that cancer chemotherapeutic agents are not germ-cell mutagens in humans. Genomic technologies should provide more definitive insight into this conundrum [Sankaranarayanan and Nikjoo,2011; C.L. Yauk et al., in preparation].

For cigarette smoke, many studies have shown that smoking (a) is a somatic-cell mutagen, (b) results in genotoxic fluids and genotoxicity in reproductive tissues in children of smoking mothers, (c) is genotoxic to oocytes and sperm of smokers, and (d) causes increased risk for cancer in children of smoking fathers [DeMarini,2004; IARC,2012]. In addition, side-stream cigarette smoke is a germ-cell mutagen in rodents but is negative for cytogenetic damage in mouse bone marrow [Marchetti et al.,2011], indicating that an agent can be negative for cytogenetic damage in somatic cells in vivo but still be a germ-cell mutagen. The mutagenicity of smoking, especially the genotoxic effects of smoking on egg and sperm in humans, makes smoking a likely human germ-cell mutagen [DeMarini,2004].

As reviewed by Somers and Cooper [2009], the particulate fraction of urban air is a germ-cell mutagen in rodents and birds, and studies in humans have also found that exposure to highly polluted air induces DNA damage and aneuploidy in sperm and genotoxic effects in somatic cells [Rubes et al.,2005; Somers,2011]. These studies and reviews make a compelling argument that urban air is highly likely a germ-cell mutagen in humans.

Although some have argued that assessments of agents for their ability to induce somatic-cell mutation are sufficient to detect germ-cell mutagens, this argument is based largely on a biased data base in which nearly all of the 48 agents ever tested for rodent germ-cell mutation were already known to induce somatic-cell mutation [Shelby,1996; Singer and Yauk,2010]. As noted above, side-stream cigarette smoke is a notable exception. Both the genetic and epigenetic effects of agents on germ cells, especially those agents that are not somatic-cell mutagens in mouse bone marrow, need to be determined before this conclusion can be drawn.

NEED FOR A DECLARATION PANEL AND IMPLICATIONS OF DECLARING AN AGENT A HUMAN GERM-CELL MUTAGEN

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. WHY HAVE NO HUMAN GERM-CELL MUTAGENS BEEN IDENTIFIED?
  5. TECHNICAL DEVELOPMENTS AND RECENT DISCOVERIES OF DE NOVO GERM-CELL MUTATIONS IN HUMANS
  6. POSSIBLE HUMAN GERM-CELL MUTAGENS
  7. NEED FOR A DECLARATION PANEL AND IMPLICATIONS OF DECLARING AN AGENT A HUMAN GERM-CELL MUTAGEN
  8. Acknowledgements
  9. REFERENCES

Because of the developments noted above, I think that there will likely soon be genomic evidence of human germ-cell mutagens, and it is incumbent upon us to think about that eventuality and its implications. Indeed, many people have been thinking about this for decades, as evidenced by the genetic toxicity testing guidelines of countries throughout the world in which assays for the detection of germ-cell mutation have been incorporated [Cimino,2006], as well as that of the International Programme on Chemical Safety (IPCS) Harmonized Scheme for Mutagenicity Testing, which is part of the World Health Organization (WHO) [Eastmond et al.,2009]. In addition, various regulatory agencies in the U.S., Canada, the U.K., and the European Union consider heritable mutation a regulatory endpoint per se, regardless of the ability of the agent to induce somatic-cell mutation or cancer [Cimino,2006].

Various regulatory agencies have also considered how to classify germ-cell mutagens in terms of risk to humans, such as known, probable, or possible human germ-cell mutagens [Health Canada,1994; GHS,2003; Cimino,2006; MAK,2009]. Most of these schemes are modeled closely on the IARC classification scheme for carcinogens [IARC,2006], as is a proposed classification scheme for human reproductive toxicants [Shelby,2005].

Using an IARC-type of evaluation, sufficient evidence in animals (mammalian) for a germ-cell mutagen would require positive data in at least two species and/or repeated positive results in one. Table II shows that this criterion is achieved by the four agents considered here. In the absence of human epidemiology (i.e., not considering the Y.E. Dubrova data on ionizing radiation), an evaluation of these four agents as Group 1 human germ-cell mutagens would also require human biomarker data that were strongly relevant to mechanistic data in animals. At a minimum, the observed DNA damage induced by these agents in sperm of rodents and humans (Table II) is, in my view, sufficient to fulfill this criterion, leading to a proposed evaluation of all four agents as Group 1 human germ-cell mutagens. The addition of positive genomic data in humans would provide confirmatory molecular epidemiology; however, in my opinion, these data are not necessary for a Group 1 evaluation, which can be concluded with the data currently available.

Table II. Proposed Evaluation of Agents as Potential Human Germ-Cell Mutagens
AgentAnimalaHuman
MouseRatBirdEvidenceMechanismcEvaluationd
  • a

    Based on references in Table I.

  • b

    There are two studies, both in mice [Yauk et al.,2007; Marchetti et al.,2011].

  • c

    These agents induce similar biomarker effects in humans as they do in animals, such as DNA damage in sperm, as reviewed for ionizing radiation and chemotherapy [Kamiguchi and Tateno,2002], smoking [DeMarini,2004], and air pollution [Somers,2011]. Thus, there is sufficiently strong mechanistic evidence for how these agents affect animals and humans.

  • d

    All agents could be proposed as Group 1 (known) human germ-cell mutagens because (a) three of them induce germ-cell mutations in at least two species, and there are two studies for smoking in one species; thus, there is sufficient evidence for all four agents for their ability to induce germ-cell mutations in animals, and (b) the relevance of the human biomarker data to mechanisms by which the agents induce germ-cell mutations in animals is strong and sufficient.

Ionizing radiation++ SufficientSufficientGroup 1
Chemotherapy++ SufficientSufficientGroup 1
Smoking +b  SufficientSufficientGroup 1
Air pollution+ +SufficientSufficientGroup 1

As noted, testing strategies, classification schemes, and regulatory authority are already in place in many countries to identify an agent as a human germ-cell mutagen. The identification of a bona fide human germ-cell mutagen based on genomic data could trigger regulatory consideration by a number of agencies within the developed world. Such a regulatory effort for something other than ionizing radiation would be unprecedented in that it would consider the potential health effects of an agent not to the exposed person but to his/her unexposed offspring. Although the paucity of human data has prevented such regulatory action, calculations have been made with available data to estimate the risk for germ-cell mutation in humans exposed to ethylene oxide [Rhomberg et al.,1990], acrylamide [Dearfield et al.,1995], and ionizing radiation based on mouse data to predict increases in the frequency of genetic diseases relative to a baseline frequency in a population [USNSCEAR,2001]. The regulatory challenges associated with a human germ-cell risk assessment have been discussed by Singer and Yauk [2010].

Assuming that the “genomic data gap” will soon be filled, the need for an IARC-type panel to assess the data and make a declaration, perhaps using one of the classification schemes already proposed, seems essential. I suggest that when genomic data become available indicating that an agent might be a human germ-cell mutagen, then WHO should assemble a suitable panel to evaluate the agent as a human germ-cell mutagen. The panel might be constructed like IARC within WHO so that it would have broad-based participation and international acceptance. Scientists from various disciplines could be organized into sub-groups dealing with exposure assessment, molecular and clinical genetics, rodent and human germ-cell biology, and epidemiology in order to consider all available data. Most importantly, scientists with expert technical knowledge of genomic methods, especially bioinformatics and computational methods, would be needed to provide a sound assessment of the data quality. Support from various national and international organizations would be important.

The widely held view that there might be a few or no human germ-cell mutagens in our environment (other than, perhaps, ionizing radiation [UNSCEAR]), has likely persisted because of the absence of definitive proof in humans that such agents exist and the relatively few published studies showing that such agents exist even for rodents, rather than a true lack of germ-cell mutagens in our environment. As my colleagues and I have noted and reviewed [Claxton et al.,2010], there was almost no knowledge of the prevalence of somatic-cell mutagens in our environment prior to the introduction by B.N. Ames of the Salmonella mutagenicity assay in1971. However, by1978, the first studies were reported using this assay showing that chlorinated water, urban air, and grilled fish were mutagenic; even something as noxious as cigarette smoke went unrecognized as a mutagen until it was tested in the Salmonella mutagenicity assay in1974. Furthermore, a series of key experiments in this assay culminated in1973 in the first clear linkage between mutagenesis and carcinogenesis [Claxton et al.,2010]. Thus, the paradigm shifts linking mutagenicity with carcinogenicity, as well as showing the ubiquitous presence of environmental mutagens, did not occur until the application of a new technology, the Salmonella mutagenicity assay [Claxton et al.,2010].

Likewise, we should be prepared for a similar shift from the current paradigm that there are few if any human germ-cell mutagens in our environment. Indeed, many people have considered and anticipated such a possibility [Wyrobek et al.,2007; Sankaranarayanan and Nikjoo,2011; Yauk et al.,2012]. The technical breakthrough represented by next-generation sequencing, especially third-generation sequencing, which will permit characterization of large stretches of repeated sequences, coupled with epigenomic analyses, will dispel our sense of complacency regarding germ-cell mutagens in our environment.

Our ignorant state seems about to end, mandating our preparation for the inevitable—the genomic evidence for the first of potentially many environmental, human germ-cell mutagens. How important to human disease these agents may be is unknown, but our knowledge of them may shed light on the currently unknown cause of 20% of infant deaths in the US that are due to birth defects [Heron et al.,2009]. Identifying these environmental agents might also help explain the origin of some of the de novo mutations associated with various neurological diseases [Lupski,2010], as well as the “missing heritability” for cancer, aging, diabetes, and other chronic diseases.

Although 50–80% of miscarriages in the first trimester are due to “sporadic” chromosomal mutation [Simpson,2007], application of genomic methods might show that gene mutation and copy-number variation also play an important role; and epidemiology studies involving genomic analyses might show that these genetic events are less “sporadic” and actually associated with environmental exposures. We may soon be able to determine the potential harm from an agent not just to those who are exposed to that agent, but to their unexposed descendents. After more than 80 years, this is a consideration whose time is finally “ripe…with reference to the human species” [Muller,1927].

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. WHY HAVE NO HUMAN GERM-CELL MUTAGENS BEEN IDENTIFIED?
  5. TECHNICAL DEVELOPMENTS AND RECENT DISCOVERIES OF DE NOVO GERM-CELL MUTATIONS IN HUMANS
  6. POSSIBLE HUMAN GERM-CELL MUTAGENS
  7. NEED FOR A DECLARATION PANEL AND IMPLICATIONS OF DECLARING AN AGENT A HUMAN GERM-CELL MUTAGEN
  8. Acknowledgements
  9. REFERENCES

The author thanks Barbara Parsons and other nominators, as well as the Awards and Honors Committee of the Environmental Mutagen Society for selecting him to receive the 2011 Alexander Hollaender Award. The author also thanks Francesco Marchetti, the Editor-in-Chief of Environmental and Molecular Mutagenesis, for inviting him to write this Commentary. He thanks Jack Bishop, George Douglas, Andrew Kligerman, Heinrich Malling, Francesco Marchetti, R. Julian Preston, Daniel Shaughnessy, Michael Shelby, Kristine Witt, and Carole Yauk for their helpful comments and encouragement. This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. WHY HAVE NO HUMAN GERM-CELL MUTAGENS BEEN IDENTIFIED?
  5. TECHNICAL DEVELOPMENTS AND RECENT DISCOVERIES OF DE NOVO GERM-CELL MUTATIONS IN HUMANS
  6. POSSIBLE HUMAN GERM-CELL MUTAGENS
  7. NEED FOR A DECLARATION PANEL AND IMPLICATIONS OF DECLARING AN AGENT A HUMAN GERM-CELL MUTAGEN
  8. Acknowledgements
  9. REFERENCES
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