Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Xian Nong Tan Street, Beijing 100050, China.
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Xian Nong Tan Street, Beijing 100050, China.
Environ Toxicol Pharmacol. 2017 Dec;56:340-349. doi: 10.1016/j.etap.2017.10.010. Epub 2017 Oct 31.
Cadmium (Cd) and lead (Pb) are naturally existing heavy metals that pose significant health risks. The present study aims to identify sensitive biomarkers for differentiating the toxicities induced by Cd and Pb and for providing clues for the early prediction of toxicity and environmental risk assessment. Indicators related to oxidative stress and inflammatory responses in zebrafish treated with Cd and Pb over time (from 24hpf to 96hpf) were compared. Furthermore, endpoints such as embryo lethality and teratogenicity were detected. Then, several related genes involved in oxidative stress and inflammatory responses characterizing both Cd and Pb exposure, along with key molecules in the MAPKs pathway, were compared at the mRNA level, allowing the selection of the most sensitive and informative biomarkers. Significant increases in reactive oxygen species (ROS) production were observed in zebrafish exposed to Cd and Pb. Cd and Pb exposure induced developmental toxicity, influencing survival rate, hatching rate, larval growth, and heart rate and causing abnormal embryonic development. Similar trends in SOD1 and SOD2 gene expression were induced by Cd and Pb, while nuclear factor erythroid-2 related factor 2 (Nrf2) gene expression responded differently to each metal. In addition, Cd and Pb induced a delayed activation of the CAT and HO-1 genes, with no apparent change in the 24hpf and 48hpf groups. Genes related to immunotoxicity were activated significantly in a time-dependent manner, and these genes exhibited different sensitivities to Cd and Pb. MAPKs pathway genes were also activated in a time-dependent manner, and the expression of these genes showed different effects under Cd and Pb treatment. In summary, the present works have identified some potential sensitive biomarkers. The Nrf2 gene is a potential biomarker to differentiate Pb-induced toxicity from that of Cd, and the IFN-γ gene may be used as a sensitive biomarker for evaluating the risk of Pb contamination. We found that the timeline of MAPKs pathway activation helped to differentiate these two metals toxicities. Furthermore, Pb induced the early activation of ERK2/3 and JNK1, while p38 MAPKs showed delayed activation with no apparent change in the 24hpf group. Cd induced an early activation of ERK2 and a delayed activation of p38a, p38b, ERK3 and JNK1, indicating that the JNK1 pathway is sensitive to Pb exposure, while the p38 pathway may be susceptible to Cd. This work contributes to sensitive biomarker identification and early environmental risk evaluation for chemicals as well as toxicity prediction.
镉（Cd）和铅（Pb）是两种天然存在的重金属，它们对健康构成严重威胁。本研究旨在寻找能够区分 Cd 和 Pb 诱导毒性的敏感生物标志物，并为毒性早期预测和环境风险评估提供线索。比较了斑马鱼在 Cd 和 Pb 暴露下随时间（从 24hpf 到 96hpf）产生的氧化应激和炎症反应相关指标。此外，还检测了胚胎致死率和致畸率等终点。然后，在 mRNA 水平上比较了与 Cd 和 Pb 暴露相关的几个涉及氧化应激和炎症反应的相关基因，以及 MAPKs 途径中的关键分子，从而选择最敏感和最有信息的生物标志物。结果表明，暴露于 Cd 和 Pb 的斑马鱼体内活性氧（ROS）的产生显著增加。Cd 和 Pb 暴露导致发育毒性，影响存活率、孵化率、幼虫生长和心率，并导致胚胎发育异常。SOD1 和 SOD2 基因表达也呈现出相似的 Cd 和 Pb 诱导趋势，而核因子红细胞 2 相关因子 2（Nrf2）基因表达对每种金属的反应不同。此外，Cd 和 Pb 诱导 CAT 和 HO-1 基因的延迟激活，在 24hpf 和 48hpf 组中没有明显变化。免疫毒性相关基因呈时间依赖性显著激活，且对 Cd 和 Pb 的敏感性不同。MAPKs 途径基因也呈时间依赖性激活，Cd 和 Pb 处理下这些基因的表达呈现不同的效应。综上所述，本研究确定了一些潜在的敏感生物标志物。Nrf2 基因可能是区分 Pb 诱导毒性和 Cd 诱导毒性的潜在生物标志物，IFN-γ 基因可作为评估 Pb 污染风险的敏感生物标志物。我们发现，MAPKs 途径激活的时间线有助于区分这两种金属的毒性。此外，Pb 诱导 ERK2/3 和 JNK1 的早期激活，而 p38 MAPKs 则表现出延迟激活，在 24hpf 组中没有明显变化。Cd 诱导 ERK2 的早期激活和 p38a、p38b、ERK3 和 JNK1 的延迟激活，表明 JNK1 途径对 Pb 暴露敏感，而 p38 途径可能对 Cd 敏感。本研究有助于识别敏感生物标志物，早期评估环境化学物质风险，并预测毒性。
