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No evidence of increased mutations in the germline of a group of British nuclear test veterans.

ABSTRACT: The potential germline effects of radiation exposure to military veterans present at British nuclear tests in Australia and the South Pacific is of considerable interest. We analyzed germline mutations in 60 families of UK military personnel comprising 30 control and 30 nuclear test veterans (NTV). Using whole-genome sequencing we studied the frequency and spectra of de novo mutations to investigate the transgenerational effect of veterans' (potential) exposure to radiation at nuclear bomb test sites. We find no elevation in total de novo single nucleotide variants, small insertion-deletions, structural variants or clustered mutations among the offspring of nuclear test veterans compared to those of control personnel. We did observe an elevated occurrence of single base substitution mutations within mutation signature SBS16, due to a subset of NTV offspring. The relevance of this elevation to potential exposure of veteran fathers and, future health risks, require further investigation. Overall, we find no evidence of increased mutations in the germline of a group of British nuclear test veterans. ISRCTN Registry 17461668.

SUBMITTER: Moorhouse AJ

PROVIDER: S-EPMC9256629 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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No evidence of increased mutations in the germline of a group of British nuclear test veterans.

Moorhouse Alexander J AJ Scholze Martin M Sylvius Nicolas N Gillham Clare C Rake Christine C Peto Julian J Anderson Rhona R Dubrova Yuri E YE

Scientific reports 20220705 1

The potential germline effects of radiation exposure to military veterans present at British nuclear tests in Australia and the South Pacific is of considerable interest. We analyzed germline mutations in 60 families of UK military personnel comprising 30 control and 30 nuclear test veterans (NTV). Using whole-genome sequencing we studied the frequency and spectra of de novo mutations to investigate the transgenerational effect of veterans' (potential) exposure to radiation at nuclear bomb test ...[more]

PMID: 35790751

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Project description:BackgroundAutism spectrum disorder (ASD) has a strong genetic etiology. Germline mutation in the tumor suppressor gene PTEN is one of the best described monogenic risk cases for ASD. Animal modeling of cell-specific Pten loss or mutation has provided insight into how disruptions to the function of PTEN affect neurodevelopment, neurobiology, and social behavior. As such, there is a growing need to understand more about how various aspects of PTEN activity and cell-compartment-specific functions, contribute to certain neurological or behavior phenotypes.MethodsTo understand more about the relationship between Pten localization and downstream effects on neurophenotypes, we generated the nuclear-predominant PtenY68H/+ mouse, which is identical to the genotype of some PTEN-ASD individuals. We subjected the PtenY68H/+ mouse to morphological and behavioral phenotyping, including the three-chamber sociability, open field, rotarod, and marble burying tests. We subsequently performed in vivo and in vitro cellular phenotyping and concluded the work with a transcriptomic survey of the PtenY68H/+ cortex, which profiled gene expression.ResultsWe observe a significant increase in P-Akt downstream of canonical Pten signaling, macrocephaly, decreased sociability, decreased preference for novel social stimuli, increased repetitive behavior, and increased thigmotaxis in PtenY68H/+ six-week-old (P40) mice. In addition, we found significant microglial activation with increased expression of complement and neuroinflammatory proteins in vivo and in vitro accompanied by enhanced phagocytosis. These observations were subsequently validated with RNA-seq and qRT-PCR, which revealed overexpression of many genes involved in neuroinflammation and neuronal function, including oxytocin. Oxytocin transcript was fivefold overexpressed (P = 0.0018), and oxytocin protein was strongly overexpressed in the PtenY68H/+ hypothalamus.ConclusionsThe nuclear-predominant PtenY68H/+ model has clarified that Pten dysfunction links to microglial pathology and this associates with increased Akt signaling. We also demonstrate that Pten dysfunction associates with changes in the oxytocin system, an important connection between a prominent ASD risk gene and a potent neuroendocrine regulator of social behavior. These cellular and molecular pathologies may related to the observed changes in social behavior. Ultimately, the findings from this work may reveal important biomarkers and/or novel therapeutic modalities that could be explored in individuals with germline mutations in PTEN with ASD.

Project description:The malign contribution of northern industrial cities to the stagnation of national life expectancy over the period 1820-1870 forms part of one of the most long-running debates in English economic history, regarding the impact of early industrialisation on living standards. The deteriorating quality of urban water supplies often features in these arguments as the key driver of worsening mortality in this period. Here we use mortality reported from cholera in the epidemic years 1831-1832 and 1848-1849 as an indicator of the extent of sewage contamination of water in English and Welsh towns in this period. Surprisingly, the geography of reported mortality did not indicate that northern manufacturing and industrial towns were especially deficient in this respect. However, logistic regression analyses identified a number of risk factors for high cholera mortality, including location on coal-bearing strata, which was a feature of many industrial towns. Notably, however, textile-manufacturing towns, although often located in coal-rich districts, were associated with low levels of cholera mortality, and high population growth rates did not influence the risk of cholera. Reductions in cholera mortality after 1849 raise the possibility of widespread improvements in water quality after mid-century, rather earlier than is often assumed. However, in contrast to cholera, infant and diarrhoeal mortality remained high especially in northern towns until at least 1900. Several lines of evidence suggest that infants were relatively protected from waterborne diseases such as cholera and typhoid, and therefore did not benefit greatly from improvements in water quality. We conclude (1) that any worsening of water quality in urban areas c.1800-1850 was not confined to new͛ or rapidly growing industrial or manufacturing towns; and (2) infants probably rarely drank untreated water, so high infant or diarrhoeal mortality rates should not be read as indicators of poor water quality, in the English context.

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No evidence of increased mutations in the germline of a group of British nuclear test veterans.

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No evidence of increased mutations in the germline of a group of British nuclear test veterans.

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