Transcriptomic dose-response modeling to support ecological risk assessment

生态毒理学的一个主要挑战是评估世界经济中使用的数千种化学品的环境安全性。传统的检测方法仅限于致命性等短期显性影响，不能可靠地检测出生殖和发育毒性等更微妙的长期影响。为了解决这一问题，已投入努力扩大可在毒理学测试中检测到的生物效应的广度。 最有希望的方法之一是使用基因表达技术(即转录组学)。这项技术测量了非常广泛的生物途径的影响，与长期影响相关的变化可以在接触化学物质后不久检测到。此外，最近转录组测序技术的进步使得在单个实验中包含大量剂量和时间点在经济上是可行的，从而允许先进的定量建模。现代转录剂量-反应模型(TDRM)方法可以提供对一种化学物质潜在长期毒性的估计，可用于生态风险评估。例如，我们表明，短期暴露后的TDRM分析为暴露于内分泌干扰物的鱼类提供了可靠的长期毒性估计。 在TDRM能够被常规用于生态风险评估之前，仍然存在挑战。原则上已经证明了几种应用，但需要在广泛的化学类别、各种物种和不同的模型系统中进行验证。生态毒理学特有的另一个主要挑战是，感兴趣的物种的基因组特征往往很差，这可能会限制最新和最经济的转录组技术的应用和解释。这项拟议的研究将解决限制TDRM在生态风险评估中使用的挑战。这项研究的具体目标是： 建立包括鱼类和鸟类在内的与生态有关的物种的TDRM分析 在短期测试中验证TDRM，以评估各种化学类别的长期生态毒性 开发和验证TDRM的动物替代测试应用，例如早期生命阶段胚胎模型 测试TDRM是否可以用来比较物种毒性差异 展示TDRM在现实世界生态风险评估案例研究中的实用性 这一研究计划将产生一种新的毒理基因组学方法，将直接应用于生态风险评估过程。拟议的工作为生态学家、分子生物学家、生物统计学家和风险评估员之间的合作提供了机会。这项研究将有助于在科学和政策之间建立亟需的桥梁，以确保制定强有力、有效、符合道德的方法，最重要的是，将用于支持加拿大的环境保护。

A major challenge in ecotoxicology is to assess the environmental safety of the thousands of chemicals used in the world economy. Traditional test methods are limited to short-term overt effects such as lethality and cannot reliably detect more subtle long-term effects such as reproductive and developmental toxicity. To address this issue, efforts have been invested in expanding the breadth of biological effects that can be detected in toxicological tests. One of the most promising approaches is the use of gene expression technology (i.e. transcriptomics). This technology measures effects across a very broad spectrum of biological pathways, and changes related to long-term effects can be detected shortly after chemical exposure. Furthermore, recent advances in transcriptomic sequencing technology now make it economically feasible to include large numbers of doses and time-points in a single experiment, permitting advanced quantitative modeling. Modern transcriptomic dose-response modeling (TDRM) approaches can provide estimates of a chemical's potential long-term toxicity that can be used in ecological risk assessment. For example, we showed that TDRM analysis after short-term exposures provided robust estimates long-term toxicity for fish exposed to endocrine disrupting chemicals. Challenges still remain before TDRM can be used routinely for ecological risk assessment. Several applications have been demonstrated in principle, but need to be validated across a broad suite of chemical classes, in various species and in different model systems. Another major challenge specific to ecotoxicology is that the species of interest often have very poorly characterized genomes, which can restrict the application and interpretation of latest and most economic transcriptomic technologies. This proposed research will address the challenges that restrict the use of TDRM in ecological risk assessment. The specific goals of this research are: Develop TDRM assays for ecologically relevant species including fish and birds Validate TDRM in short-term tests to estimate long-term ecotoxicity for a broad range of chemical classes Develop and validate animal-alternative testing applications of TDRM, such as early life stage embryo models Test whether TDRM can be used to compare species differences in toxicity Demonstrate the utility of TDRM in real-world ecological risk assessment case studies This research program will yield a new toxicogenomics approach that will have direct applications to ecological risk assessment process. The work proposed provides an opportunity for collaboration between ecologists, molecular biologists, biostatisticians and risk assessors. This research will help create the much-needed bridge between science and policy to ensure the development of approaches that are robust, effective, ethical, and most importantly, will be used to support environmental protection in Canada.