Human mutagens: Evidence from paternal exposure?

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.

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

“…Although this is not evidence of a causative relationship, it should not be completely dismissed. Narod et al [1988] examined in retrospective (case-control) studies of childhood cancer patients, incidences of paternal, but not maternal, exposure to minimize the confounding influence of teratogenicity. Their review provided suggestive evidence that paternal exposure to anesthetic gases may cause miscarriage and congenital abnormalities as a result of male germ cell mutations following occupational exposures.…”

Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders

“…It is thus important to identify potential environmental factors that contribute to the increased rate of de novo mutations and/or epigenetic modifications in the parents (Kinney et al, 2010). We assume that excessive alcohol consumption may be associated with an increased rate of de novo mutations in germ cells (sperms or eggs), because previous studies showed that exposures to alcohol could lead to increased rates of mutations in germ cells (Narod et al, 1988; Yamauchi et al, 2012). It is thus necessary to examine whether the risks of autism and ADHD are increased among individuals with a family history of alcohol use disorders (AUDs).…”

Paternal occupational exposures and the risk of congenital malformations — A case-control study

“…With increasing concern about male reproductive function raised in the past decade, epidemiological studies are being published taking into account the role of paternal exposures by evaluating paternal occupations and risk of birth defects [8]. It is suspected that environmental and occupational contaminants induce mutations resulting in increased risk for such defects in subsequent generations of the persons exposed [13]. Paternal occupational exposures are likely to affect congenital malformations through the spermatogenesis cycle.…”