Related Experiment Videos
Human mutagens: evidence from paternal exposure?
S A Narod1, G R Douglas, E R Nestmann
1Department of Community Medicine and Epidemiology, University of Ottawa, Ontario, Canada.
Abstract:
The importance of inherited mutations as a cause of human disease has been established clearly through examples of well-defined genetic anomalies, such as Down syndrome and retinoblastoma. Furthermore, it is suspected that environmental contaminants induce mutations resulting in increased risk for such defects in subsequent generations of persons exposed. The present lack of direct evidence for induced inherited genetic disorders in human beings hampers the development of risk estimation techniques for extrapolation from animal models. The most extensive prospective epidemiologic studies of inherited genetic effects have involved survivors of atomic bomb detonations and patients treated with cancer chemotherapy. In neither case has a significant elevation in inherited genetic effects or cancer been detected in the offspring of exposed individuals. Epidemiologic studies of subjects receiving chronic exposure may be confounded by the effect of maternal exposure during pregnancy. Consideration of only paternal exposure can minimize the confounding influence of teratogenicity, enhancing the resolving power of studies for inherited effects. Using this approach, retrospective (case-control) studies of childhood cancer patients have provided limited but suggestive evidence for inheritance of induced effects. Endpoints, such as congenital malformations and spontaneous abortion following paternal exposure, can also be considered as indicators of heritable mutagenic effects. For example, there is limited evidence suggesting that paternal exposure to anaesthetic gases may cause miscarriage and congenital abnormalities as a result of induced male germ cell mutations. By comparing male-exposure endpoints for which there are human data, as described above, with parallel or similar animal endpoints, such as dominant lethal, inherited cancer and "male teratogenic" effects, it is possible that suitable models for extrapolating to human risk can be developed. In order to establish a clearer relationship between induced mutation and genetic disease, the current surveillance systems should be expanded to include endpoints relevant to genetic study. The relaxation of regulations regarding access to census data could improve the chances of documenting such an association.
Insights
Environmental contaminants may induce inherited mutations, increasing disease risk in offspring. Limited human data and animal models suggest a link, necessitating expanded surveillance for genetic effects.
Area of Science:
- Genetics
- Environmental Health
- Epidemiology
Background:
- Inherited mutations cause human diseases like Down syndrome.
- Environmental contaminants are suspected to induce mutations, increasing genetic defect risks in exposed populations.
- Lack of direct evidence for induced inherited genetic disorders in humans hinders risk assessment.
Purpose of the Study:
- To review evidence for induced inherited genetic effects in humans.
- To explore methods for developing risk estimation techniques by comparing human and animal data.
- To identify endpoints and improve surveillance for documenting associations between induced mutations and genetic disease.
Main Methods:
- Reviewed prospective epidemiologic studies (atomic bomb survivors, chemotherapy patients).
- Analyzed retrospective (case-control) studies focusing on paternal exposure to minimize confounding.
- Considered endpoints like congenital malformations and spontaneous abortion.
Main Results:
- No significant elevation in inherited genetic effects detected in offspring of atomic bomb survivors or chemotherapy patients.
- Retrospective studies with paternal exposure focus show limited, suggestive evidence for induced inherited effects.
- Limited evidence suggests anesthetic gas exposure may induce male germ cell mutations, leading to miscarriage and congenital abnormalities.
Conclusions:
- Paternal exposure studies offer better resolution for detecting inherited effects.
- Comparing human male-exposure endpoints with animal models (e.g., dominant lethal, inherited cancer) can aid risk extrapolation.
- Expanding surveillance systems and improving data access are crucial for establishing relationships between induced mutations and genetic disease.