C. elegans toxicant responses vary among genetically diverse individuals

Abstract

Comprehensive chemical hazard risk evaluations require reproducible, efficient, and informative experimental workflows in tractable model systems that allow for high replication within exposure cohorts. Additionally, the genetic variability of toxicant responses among individuals in humans and mammalian models requires practically untenable sample sizes. Caenorhabditis elegans is a premier toxicology model that has revolutionized our understanding of cellular responses to environmental pollutants and boasts robust genomic resources and high levels of genetic variation across the species. In this study, we performed dose-response analysis across 23 environmental toxicants using eight C. elegans strains representative of species-wide genetic diversity. We observed substantial variation in EC10 estimates and slope parameter estimates of dose-response curves of different strains, demonstrating that genetic background is a significant driver of differential toxicant susceptibility. We also showed that, across all toxicants, at least one C. elegans strain exhibited a significantly different EC10 or slope estimate compared to the reference strain, N2 (PD1074), indicating that population-wide differences among strains are necessary to understand responses to toxicants. Moreover, we quantified the heritability of responses to each toxicant dose and observed a correlation between the dose closest to the species-agnostic EC10 estimate and the dose that exhibited the most heritable response. Taken together, these results provide robust evidence that heritable genetic variation explains differential susceptibility across an array of environmental pollutants and that genetically diverse C. elegans strains should be deployed to aid high-throughput toxicological screening efforts.

Variation in anthelmintic responses are driven by genetic differences among diverseC. eleganswild strains

“…The variation in strain-specific slope comparisons further supports how the incorporation of genetic diversity is necessary to identify anthelmintic responses within a species. Here, we reinforce what previous studies have shown, that C. elegans is a powerful model for assessing the impact of genetic differences on phenotypic variation [23].…”

“…The custom CellProfiler pipeline generates animal measurements by using four worm models: three worm models tailored to capture animals at the L4 larval stage, in the L2 and L3 larval stages, and the L1 larval stage, respectively, as well as a “multi-drug high dose” (MDHD) model, to capture animals with more abnormal body sizes caused by extreme anthelmintic responses. Worm model estimates and custom CellProfiler pipelines were written using the WormToolbox in the GUI-based instance of CellProfiler [23]. Next, a custom R package, easyXpress (Version 1.0), was then used to process animal measurements output from CellProfiler [17].…”

Molecular evidence of widespread benzimidazole drug resistance in Ancylostoma caninum from domestic dogs throughout the USA and discovery of a novel β-tubulin benzimidazole resistance mutation

“…A previously described high-throughput fitness assay was used for all measurements of benzimidazole responses [29][30][31]. The assay included growth measurements of 44 replicate populations comprising approximately 50 animals for each strain in each condition, with the exception of N2 in the albendazole condition (Data Available at: https://github.com/ AndersenLab/2022_BZ_Resistance_ben1_Q134H).Each strain was amplified on NGMA plates for four generations, bleach synchronized, and then approximately 50 embryos in 50 μL of K medium [56] were aliquoted into each well of a 96-well plate. The following morning, arrested L1s were given a mixture of HB101 bacterial lysate [57] at a concentration of 5 mg/mL, kanamycin at a concentration of 50 μM, and either 1% DMSO or 30 μM albendazole in 1% DMSO.…”

Variation in anthelmintic responses are driven by genetic differences among diverse C. elegans wild strains

“…Nematodes affected by anthelmintics have delayed development. Worm model estimates and custom CellProfiler pipelines were written using the WormToolbox in the GUI-based instance of CellProfiler [ 69 ]. Next, a custom R package, easyXpress (Version 1.0), was then used to process animal measurements output from CellProfiler [ 15 ].…”