Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA.
Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA.
Environ Pollut. 2021 Oct 15;287:117637. doi: 10.1016/j.envpol.2021.117637. Epub 2021 Jun 22.
In toxicology, standard sigmoidal concentration-response curves are used to predict effects concentrations and set chemical regulations. However, current literature also establishes the existence of complex, bimodal concentration-response curves, as is the case for arsenic toxicity. This bimodal response has been observed at the molecular level, but not characterized at the whole organism level. This study investigated the effect of arsenic (sodium arsenite) on post-gastrulated zebrafish embryos and elucidated effects of bimodal concentration-responses on different phenotypic perturbations. Six hour post fertilized (hpf) zebrafish embryos were exposed to arsenic to 96 hpf. Hatching success, mortality, and morphometric endpoints were evaluated both in embryos with chorions and dechorionated embryos. Zebrafish embryos exhibited a bimodal response to arsenic exposure. Concentration-response curves for exposed embryos with intact chorions had an initial peak in mortality (88%) at 1.33 mM arsenic, followed by a decrease in toxicity (~20% mortality) at 1.75 mM, and subsequently peaked to 100% mortality at higher concentrations. To account for the bimodal response, two distinct concentration-response curves were generated with estimated LC10 values (and 95% CI) of 0.462 (0.415, 0.508) mM and 1.69 (1.58, 1.78) mM for the 'low concentration' and 'high concentration' peaks, respectively. Other phenotypic analyses, including embryo length, yolk and pericardial edema all produced similar concentration-response patterns. Tests with dechorionated embryos also resulted in a bimodal toxicity response but with lower LC10 values of 0.170 (0.120, 0.220) mM and 0.800 (0.60, 0842) mM, respectively. Similarities in bimodal concentration-responses between with-chorion and dechorionated embryos indicate that the observed effect was not caused by the chorion limiting arsenic availability, thus lending support to other studies such as those that hypothesized a conserved bimodal mechanism of arsenic interference with nuclear receptor activation.
在毒理学中，标准的 S 型浓度-反应曲线用于预测效应浓度并制定化学法规。然而，目前的文献也证实了复杂的双峰浓度-反应曲线的存在，砷毒性就是一个例子。这种双峰反应在分子水平上已经观察到，但在整个生物体水平上尚未得到描述。本研究调查了砷（亚砷酸钠）对孵化后斑马鱼胚胎的影响，并阐明了双峰浓度-反应对不同表型干扰的影响。受精后 6 小时（hpf）的斑马鱼胚胎暴露于砷至 96 hpf。在有卵壳和去卵壳的胚胎中评估孵化成功率、死亡率和形态计量终点。斑马鱼胚胎对砷暴露表现出双峰反应。有卵壳的暴露胚胎的浓度-反应曲线在 1.33 mM 砷浓度下最初出现死亡率（88%）高峰，随后毒性下降（~20%死亡率）至 1.75 mM，随后在较高浓度下达到 100%死亡率高峰。为了解释双峰反应，生成了两条具有不同 LC10 值（和 95%置信区间）的浓度-反应曲线，分别为 0.462（0.415，0.508）mM 和 1.69（1.58，1.78）mM，用于“低浓度”和“高浓度”峰值。其他表型分析，包括胚胎长度、卵黄和心包水肿，都产生了类似的浓度-反应模式。去卵壳胚胎的测试也导致双峰毒性反应，但 LC10 值较低，分别为 0.170（0.120，0.220）mM 和 0.800（0.60，0.842）mM。有卵壳和去卵壳胚胎之间双峰浓度-反应的相似性表明，观察到的效应不是由卵壳限制砷的可用性引起的，因此支持其他研究，如那些假设砷干扰核受体激活的保守双峰机制的研究。
