Environmental and Fisheries Science Division, Northwest Fisheries Science Center, National Marine Fisheries Service, NOAA Fisheries, Seattle, WA, USA.
Environmental and Fisheries Science Division, Northwest Fisheries Science Center, National Marine Fisheries Service, NOAA Fisheries, Seattle, WA, USA.
Sci Total Environ. 2024 Mar 25;918:170544. doi: 10.1016/j.scitotenv.2024.170544. Epub 2024 Feb 1.
Multiple lines of evidence at whole animal, cellular and molecular levels implicate polycyclic aromatic compounds (PACs) with three rings as drivers of crude oil toxicity to developing fish. Phenanthrene (P0) and its alkylated homologs (C1- through C4-phenanthrenes) comprise the most prominent subfraction of tricyclic PACs in crude oils. Among this family, P0 has been studied intensively, with more limited detail available for the C4-phenanthrene 1-methyl-7-isopropyl-phenanthrene (1-M,7-IP, or retene). While both compounds are cardiotoxic, P0 impacts embryonic cardiac function and development through direct blockade of K and Ca currents that regulate cardiomyocyte contractions. In contrast, 1-M,7-IP dysregulates aryl hydrocarbon receptor (AHR) activation in developing ventricular cardiomyocytes. Although no other compounds have been assessed in detail across the larger family of alkylated phenanthrenes, increasing alkylation might be expected to shift phenanthrene family member activity from K/Ca ion current blockade to AHR activation. Using embryos of two distantly related fish species, zebrafish and Atlantic haddock, we tested 14 alkyl-phenanthrenes in both acute and latent developmental cardiotoxicity assays. All compounds were cardiotoxic, and effects were resolved into impacts on multiple, highly specific aspects of heart development or function. Craniofacial defects were clearly linked to developmental cardiotoxicity. Based on these findings, we suggest a novel framework to delineate the developmental toxicity of petrogenic PAC mixtures in fish, which incorporates multi-mechanistic pathways that produce interactive synergism at the organ level. In addition, relationships among measured embryo tissue concentrations, cytochrome P4501A mRNA induction, and cardiotoxic responses suggest a two-compartment toxicokinetic model that independently predicts high potency of PAC mixtures through classical metabolic synergism. These two modes of synergism, specific to the sub-fraction of phenanthrenes, are sufficient to explain the high embryotoxic potency of crude oils, independent of as-yet unmeasured compounds in these complex environmental mixtures.
多方面的证据表明，三环多环芳烃（PACs）化合物中的蒽及其烷基化同系物（C1-至 C4-蒽）是导致原油对鱼类发育毒性的主要成分。在这一族中，蒽已被广泛研究，而对于 C4-蒽 1-甲基-7-异丙基-蒽（1-M,7-IP，或屈）的研究则较为有限。虽然这两种化合物都具有心脏毒性，但蒽通过直接阻断调节心肌细胞收缩的 K 和 Ca 电流来影响胚胎心脏功能和发育。相比之下，1-M,7-IP 会使发育中的心室心肌细胞中的芳烃受体（AHR）激活失调。虽然尚未对更大的烷基化蒽族化合物进行详细评估，但可以预期烷基化程度的增加会使蒽族化合物的活性从 K/Ca 离子电流阻断转变为 AHR 激活。我们使用两种亲缘关系较远的鱼类，斑马鱼和大西洋鳕鱼的胚胎，在急性和潜伏性发育性心脏毒性试验中测试了 14 种烷基化蒽。所有化合物都具有心脏毒性，其作用可以归结为对心脏发育或功能的多个特定方面产生影响。颅面缺陷与发育性心脏毒性明显相关。基于这些发现，我们提出了一个新的框架，用于描绘鱼类中生源多环芳烃混合物的发育毒性，该框架纳入了多机制途径，这些途径在器官水平上产生了相互作用的协同作用。此外，测量的胚胎组织浓度、细胞色素 P4501A mRNA 诱导和心脏毒性反应之间的关系表明，存在一种双室毒代动力学模型，该模型可通过经典代谢协同作用独立预测 PAC 混合物的高效力。这两种协同作用模式，是蒽族化合物特有的，足以解释原油的高胚胎毒性效力，而无需考虑这些复杂环境混合物中尚未测量到的化合物。
