Document Type
Article
Publication Date
4-1-2024
Original Citation
O'Connor C,
Keele G,
Martin W,
Stodola T,
Gatti D,
Hoffmann B,
Korstanje R,
Churchill G,
Reinholdt L.
Unraveling the genetics of arsenic toxicity with cellular morphology QTL. PLoS Genet. 2024;20(4):e1011248.
Keywords
JMG, SS1, Quantitative Trait Loci, Animals, Mice, Arsenic, Oxidative Stress, Humans, Fibroblasts, Cell Line, NF-E2-Related Factor 2, Gene-Environment Interaction, Arsenic Poisoning, Chromosome Mapping
JAX Source
PLoS Genet. 2024;20(4):e1011248.
ISSN
1553-7404
PMID
38662777
DOI
https://doi.org/10.1371/journal.pgen.1011248
Grant
This work was funded by the National Institutes of Health, National Institute of Environmental Health Sciences, R01ES029916 (L. G.R., G.C., and R.K.) and by the NIH Office of Research Infrastructure Programs, Division of Comparative Medicine, P40 OD011102 and U42 OD010921, Mouse Mutant Resource and Research Center at The Jackson Laboratory (L.G.R.). The mass spectrometry-based proteomics was performed at The Jackson Laboratory utilizing a Thermo Eclipse Tribrid Orbitrap mass spectrometer obtained through NIH S10 award (S10 OD026816). The Scientific Services at The Jackson Laboratory are supported by The Jackson Laboratory Cancer Center grant NIH/NCI P30CA034196
Abstract
The health risks that arise from environmental exposures vary widely within and across human populations, and these differences are largely determined by genetic variation and gene-by-environment (gene-environment) interactions. However, risk assessment in laboratory mice typically involves isogenic strains and therefore, does not account for these known genetic effects. In this context, genetically heterogenous cell lines from laboratory mice are promising tools for population-based screening because they provide a way to introduce genetic variation in risk assessment without increasing animal use. Cell lines from genetic reference populations of laboratory mice offer genetic diversity, power for genetic mapping, and potentially, predictive value for in vivo experimentation in genetically matched individuals. To explore this further, we derived a panel of fibroblast lines from a genetic reference population of laboratory mice (the Diversity Outbred, DO). We then used high-content imaging to capture hundreds of cell morphology traits in cells exposed to the oxidative stress-inducing arsenic metabolite monomethylarsonous acid (MMAIII). We employed dose-response modeling to capture latent parameters of response and we then used these parameters to identify several hundred cell morphology quantitative trait loci (cmQTL). Response cmQTL encompass genes with established associations with cellular responses to arsenic exposure, including Abcc4 and Txnrd1, as well as novel gene candidates like Xrcc2. Moreover, baseline trait cmQTL highlight the influence of natural variation on fundamental aspects of nuclear morphology. We show that the natural variants influencing response include both coding and non-coding variation, and that cmQTL haplotypes can be used to predict response in orthogonal cell lines. Our study sheds light on the major molecular initiating events of oxidative stress that are under genetic regulation, including the NRF2-mediated antioxidant response, cellular detoxification pathways, DNA damage repair response, and cell death trajectories.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.