Boyd Windy A, Smith Marjolein V, Co Caroll A, Pirone Jason R, Rice Julie R, Shockley Keith R, Freedman Jonathan H
Biomolecular Screening Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina, USA.
Environ Health Perspect. 2016 May;124(5):586-93. doi: 10.1289/ehp.1409645. Epub 2015 Oct 23.
Modern toxicology is shifting from an observational to a mechanistic science. As part of this shift, high-throughput toxicity assays are being developed using alternative, nonmammalian species to prioritize chemicals and develop prediction models of human toxicity.
The nematode Caenorhabditis elegans (C. elegans) was used to screen the U.S. Environmental Protection Agency's (EPA's) ToxCast™ Phase I and Phase II libraries, which contain 292 and 676 chemicals, respectively, for chemicals leading to decreased larval development and growth. Chemical toxicity was evaluated using three parameters: a biologically defined effect size threshold, half-maximal activity concentration (AC50), and lowest effective concentration (LEC).
Across both the Phase I and Phase II libraries, 62% of the chemicals were classified as active ≤ 200 μM in the C. elegans assay. Chemical activities and potencies in C. elegans were compared with those from two zebrafish embryonic development toxicity studies and developmental toxicity data for rats and rabbits. Concordance of chemical activity was higher between C. elegans and one zebrafish assay across Phase I chemicals (79%) than with a second zebrafish assay (59%). Using C. elegans or zebrafish to predict rat or rabbit developmental toxicity resulted in balanced accuracies (the average value of the sensitivity and specificity for an assay) ranging from 45% to 53%, slightly lower than the concordance between rat and rabbit (58%).
Here, we present an assay that quantitatively and reliably describes the effects of chemical toxicants on C. elegans growth and development. We found significant overlap in the activity of chemicals in the ToxCast™ libraries between C. elegans and zebrafish developmental screens. Incorporating C. elegans toxicological assays as part of a battery of in vitro and in vivo assays provides additional information for the development of models to predict a chemical's potential toxicity to humans.
Boyd WA, Smith MV, Co CA, Pirone JR, Rice JR, Shockley KR, Freedman JH. 2016. Developmental effects of the ToxCast™ Phase I and II chemicals in Caenorhabditis elegans and corresponding responses in zebrafish, rats, and rabbits. Environ Health Perspect 124:586-593; http://dx.doi.org/10.1289/ehp.1409645.
现代毒理学正从一门观察性科学向机制性科学转变。作为这一转变的一部分，正在利用替代的非哺乳动物物种开发高通量毒性检测方法，以便对化学物质进行优先级排序并建立人类毒性预测模型。
使用线虫秀丽隐杆线虫（C. elegans）对美国环境保护局（EPA）的ToxCast™一期和二期文库进行筛选，这两个文库分别包含292种和676种化学物质，以寻找导致幼虫发育和生长减缓的化学物质。使用三个参数评估化学毒性：生物学定义的效应大小阈值、半数最大活性浓度（AC50）和最低有效浓度（LEC）。
在一期和二期文库中，62%的化学物质在秀丽隐杆线虫检测中被归类为活性≤200μM。将秀丽隐杆线虫中的化学活性和效力与两项斑马鱼胚胎发育毒性研究以及大鼠和兔子的发育毒性数据进行了比较。在一期化学物质中，秀丽隐杆线虫与一项斑马鱼检测之间的化学活性一致性（79%）高于与另一项斑马鱼检测（59%）。使用秀丽隐杆线虫或斑马鱼预测大鼠或兔子的发育毒性，平衡准确率（一项检测的敏感性和特异性的平均值）在45%至53%之间，略低于大鼠和兔子之间的一致性（58%）。
在此，我们展示了一种能够定量且可靠地描述化学毒物对秀丽隐杆线虫生长和发育影响的检测方法。我们发现，秀丽隐杆线虫和斑马鱼发育筛选中，ToxCast™文库中的化学物质活性存在显著重叠。将秀丽隐杆线虫毒理学检测纳入一系列体外和体内检测中，可为建立预测化学物质对人类潜在毒性的模型提供更多信息。
Boyd WA, Smith MV, Co CA, Pirone JR, Rice JR, Shockley KR, Freedman JH. 2016. Developmental effects of the ToxCast™ Phase I and II chemicals in Caenorhabditis elegans and corresponding responses in zebrafish, rats, and rabbits. Environ Health Perspect 124:586 - 593; http://dx.doi.org/10.1289/ehp.1409645.
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