In utero Exposure to Genotoxicants Leading to Genetic Mosaicism: An Overlooked Window of Susceptibility in Genetic Toxicology Testing?

Abstract

In utero development represents a sensitive window for the induction of mutations. These mutations may subsequently expand clonally to populate entire organs or anatomical structures. Although not all adverse mutations will affect tissue structure or function, there is growing evidence that clonally expanded genetic mosaics contribute to various monogenic and complex diseases, including cancer. We posit that genetic mosaicism is an underestimated potential health problem that is not fully addressed in the current regulatory genotoxicity testing paradigm. Genotoxicity testing focuses exclusively on adult exposures and thus may not capture the complexity of genetic mosaicisms that contribute to human disease. Numerous studies have shown that conversion of genetic damage into mutations during early developmental exposures can result in much higher mutation burdens than equivalent exposures in adults in certain tissues. Therefore, we assert that analysis of genetic effects caused by in utero exposures should be considered in the current regulatory testing paradigm, which is possible by harmonization with current reproductive/developmental toxicology testing strategies. This is particularly important given the recent proposed paradigm change from simple hazard identification to quantitative mutagenicity assessment. Recent developments in sequencing technologies offer practical tools to detect mutations in any tissue or species. In addition to mutation frequency and spectrum, these technologies offer the opportunity to characterize the extent of genetic mosaicism following exposure to mutagens. Such integration of new methods with existing toxicology guideline studies offers the genetic toxicology community a way to modernize their testing paradigm and to improve risk assessment for vulnerable populations. Environ. Mol. Mutagen. 61:55–65, 2020. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

Genetic analysis and multimodal imaging identify novel mtDNA 12148T>C leading to multisystem dysfunction with tissue-specific heteroplasmy

“…However, the m.12148T>C variant was not investigated beyond this clinical case report, thus has not yet been designated as a confirmed pathogenic mutation. This variant is in the D arm stem loop of the mt-tRNA for histidine presenting as a single nucleotide modification from the reference mtDNA genome and is presumed to disrupt base pairing of the stem loop structure and thus a potential alteration in aminoacyl-tRNA synthetase activity 30,31 but had yet to be proven as a mitochondrial function disrupting event. We provide expanded data on this novel mutation and present a parent and offspring carrying the m.12148T>C mutation, with optic, aural, renal and neurologic symptoms, along with evidence of functional impacts of this mutation in relevant patient-specific cell types and in biochemical assays.…”

“…For example, dermal fibroblast-derived cells have a mixture of heterogenous cell types which move between states of rapid migration/growth 27,28 , possibly lending a wide distribution of heteroplasmy states as seen in our results 7,29 . It is also possible that exposures to environmental factors in utero or post-natally may increase or decrease heteroplasmy in an individual, explaining drastic differences in heteroplasmy and disease manifestation across and within generations 30 . In our cohort, the parent had a low level of heteroplasmy, yet her first daughter (proband) subsequently propagated an elevated level of heteroplasmy resulting in significant symptoms.…”

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

“…Heterotopias in the HD brain appear to be due to altered migration of cortical precursors through somatic mutations of migratory genes ( Hickman et al, 2021 ). A mutation in HTT not only leads to a disruption of protein synthesis and progressive neurodegeneration, but these latent events are preceded by neurodevelopment changes during fetal brain development that disrupt the cell cycle, which can also be experimentally reproduced in utero by treatment of animals with genotoxic chemicals ( Modgil et al, 2014 ; Koufaris and Sismani, 2015 ; Godschalk et al, 2020 ). As described above, cycad genotoxins are considered etiological agents of the prototypical progressive neurodegenerative disorder Western Pacific ALS/PDC ( Spencer et al, 2020a ).…”

Transferring Mosaic Embryos during ART Cycles: Increasing the Load of Genetic Diseases in Human Generations—A Critical Analysis

“…6 During an embryonic stage, some mutations are proven fatal during initial developmental periods, especially during the period of organogenesis, increasing the probability of clonal expansion and the detrimental effect on phenotype. 7 In genetic mosaicism, mutations can affect a single base to large DNA rearrangements, which can involve a few or thousands of bases to the whole of the chromosome. A nondisjunction event during an early embryonic division can lead to an aneuploidy mosaicism, though with a milder phenotype because of the absence of mutations in all cells.…”