Germ cell mutagens: Risk assessment challenges in the 21st century

Abstract

Heritable mutations may result in a wide variety of detrimental outcomes, from embryonic lethality to genetic disease in the offspring. Despite this, today's commonly used test batteries do not include assays for germ cell mutation. Current challenges include a lack of practical assays and concrete evidence for human germline mutagens, and large data gaps that often impede risk assessment. Moreover, most regulatory assessments are based on the assumption that somatic cell mutation assays also protect the germline by default, which has not been adequately confirmed. The field is also faced with new challenges aimed at dramatically reducing animal testing, and attempts to rapidly classify thousands of chemicals using high throughput in vitro assays. These approaches may not adequately capture effects that may be particular to gametes, since many aspects of the germline are unique. In light of these challenges, an urgent need exists to develop new approaches to evaluate the potential of toxicants to cause germline mutation. The application of new technologies will greatly enhance our understanding of mutation in humans exposed to environmental mutagens. However, we must be poised to collect and interpret these data, and facilitate risk translation to regulators and the public. Genetic toxicologists must also become actively involved in the development of high-throughput tools to study germline mutation. Appropriate attention to these areas will result in the development of policies that prioritize the protection of the germline and future generations from DNA sequence mutations.

Sidestream tobacco smoke is a male germ cell mutagen

“…More importantly, our results show that exposure to levels of MTS and STS that induce germ-line mutations do not increase chromosomal damage in somatic cells as measured by the MN assay. These results parallel the findings that N-hydroxymethyl acrylamide induced dominant lethal mutations in male germ cells without increasing MN in peripheral blood erythrocytes in mice (26), and challenge a widely accepted tenet in genetic toxicology that somatic cell tests alone are sufficient to identify agents that induce mutations in germ cells (27).…”

“…Despite the ubiquitous presence of known mutagens and carcinogens in our day-to-day environment, extensive animal data showing induction and transmission of germ cell mutations (27), human studies showing increased genetic and chromosomal damage in sperm of older men (28) and patients receiving chemotherapy (29), and reports on increases in mutations rates in the children of parents exposed to radioactive contamination (30)(31)(32)(33), no germ cell mutagen has been identified conclusively in humans. In addition, a number of studies have failed to detect an increase in mutations among the children of Chernobyl cleanup workers (34)(35)(36)(37).…”

Declaring the existence of human germ‐cell mutagens

“…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.…”

“…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].…”

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

“…The purpose of this study was therefore to establish the long-term effects of methyl-donor deficient diet on the genome stability of treated animals and their first-generation offspring.! It is well documented that DNA damage in sperm can lead to impaired fertility or adverse effects on early embryonic development (Singer & Yauk, 2010). Any amount of DNA damage that becomes fixed as mutations in sperm DNA may well become hereditary and therefore result in a range of genetic disorders (Swayne et al, 2012b).…”