C. elegans toxicant responses vary among genetically diverse individuals.
C. elegans toxicant responses vary among genetically diverse individuals.
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DOI：
10.1016/j.tox.2022.153292
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发表时间：
2022-09
期刊：
影响因子：
4.5
通讯作者：
Andersen, Erik C.
中科院分区：
文献类型：
--
作者：
Widmayer, Samuel J.;Crombie, Timothy A.;Nyaanga, Joy N.;Evans, Kathryn S.;Andersen, Erik C.
人类和哺乳动物模型中个体毒物反应的遗传变异性需要几乎无法维持的样本量来进行全面的化学危害风险评估。为了满足这一需求，易于处理的模型系统支持可重复且高效的实验工作流程，以收集暴露群体的高重复性测量结果。秀丽隐杆线虫是一种重要的毒理学模型，它彻底改变了我们对细胞对环境污染物反应的理解，并拥有强大的基因组资源和跨物种的高水平遗传变异。在这项研究中，我们使用代表全物种遗传多样性的八种线虫菌株对 23 种环境毒物进行了剂量反应分析。我们观察到不同菌株的剂量反应曲线的 EC10 估计值和斜率参数估计值存在很大差异，这表明遗传背景是不同毒物敏感性的重要驱动因素。我们还表明，在所有毒物中，至少一种秀丽隐杆线虫菌株与参考菌株 N2 (PD1074) 相比表现出显着不同的 EC10 或斜率估计，这表明菌株之间的种群范围内的差异对于了解对毒物的反应是必要的。此外，我们量化了对每种有毒物质暴露的反应的遗传性（由于个体之间的遗传差异而导致的表型差异），并观察了最接近与物种无关的 EC10 估计值的暴露与表现出最具遗传性反应的暴露之间的相关性。对每种化合物的至少一种暴露水平的敏感性差异的至少 20% 是由八种秀丽隐杆线虫菌株之间的遗传差异解释的。总而言之，这些结果提供了强有力的证据，证明遗传性遗传变异解释了一系列环境污染物的不同敏感性，并且应该利用遗传多样性的秀丽隐杆线虫菌株来帮助高通量毒理学筛查工作。
The genetic variability of toxicant responses among indisviduals in humans and mammalian models requires practically untenable sample sizes to create comprehensive chemical hazard risk evaluations. To address this need, tractable model systems enable reproducible and efficient experimental workflows to collect high-replication measurements of exposure cohorts. 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 (phenotypic variance attributable to genetic differences between individuals) to each toxicant exposure and observed a correlation between the exposure closest to the species-agnostic EC10 estimate and the exposure that exhibited the most heritable response. At least 20% of the variance in susceptibility to at least one exposure level of each compound was explained by genetic differences among the eight C. elegans strains. 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.
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影响因子：
30.8
作者：
Andersen, Erik C.;Gerke, Justin P.;Shapiro, Joshua A.;Crissman, Jonathan R.;Ghosh, Rajarshi;Bloom, Joshua S.;Felix, Marie-Anne;Kruglyak, Leonid
通讯作者：
Kruglyak, Leonid
DOI：
10.1093/g3journal/jkac114
发表时间：
2022-07-06
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
通讯作者：
--
影响因子：
9.8
作者：
McQuin C;Goodman A;Chernyshev V;Kamentsky L;Cimini BA;Karhohs KW;Doan M;Ding L;Rafelski SM;Thirstrup D;Wiegraebe W;Singh S;Becker T;Caicedo JC;Carpenter AE
通讯作者：
Carpenter AE
影响因子：
16.8
作者：
Lee D;Zdraljevic S;Stevens L;Wang Y;Tanny RE;Crombie TA;Cook DE;Webster AK;Chirakar R;Baugh LR;Sterken MG;Braendle C;Félix MA;Rockman MV;Andersen EC
通讯作者：
Andersen EC
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM