Limited evidence for transgenerational chromosomal instability in families with elevated mutation pattern SBS16 in the germline

Abstract

Purpose: The transgenerational effects of preconception parental radiation exposure in humans remain unclear. We assessed genomic integrity in adult children of British nuclear test (NT) veterans—a community that has expressed long-standing concerns about adverse health effects, including in their offspring—to investigate for any constitutional chromosomal abnormalities and/or cytogenetic indicators of genomic instability that might be associated with paternal participation at NT sites.

Materials and Methods: Peripheral blood samples were obtained from 86 adult children (45 from nuclear test (NT) and 41 control), all born to veterans from the British Army, Royal Air Force, or Royal Navy.

Results: G-banded karyotyping revealed no constitutional chromosomal abnormalities in any NT sample, including those from families reporting adverse health outcomes. We next assessed for unstable aberrations using conventional Giemsa staining and found some evidence of instability. Specifically, a small subset of NT children (N = 4) showed elevated chromatid aberration frequencies (7.81 ± 4.01 per 100 cells) compared with controls (4.36 ± 0.62; N = 26). To investigate further, we analyzed matched veteran father–child pairs observing a weak association between fathers’ unstable aberration burden and chromatid aberrations in their children, suggesting a potential transgenerational effect. This positive trend was most pronounced in the small group of families (N = 8; 2 control and 6 NT) previously identified as being enriched for mutation signature SBS16 in the germline.

Conclusions: Although based on a small sample size, this observation warrants further investigation to understand the significance of SBS16, if any, including whether it may serve as a potential transgenerational mutational signature of radiation exposure. Overall, and in the context of health concerns raised by NT families, none of the self-reported health-related variables showed any association with unstable aberration burden in either the veteran fathers or their adult children.