Mechanisms of resistance of aquatic vertebrates to PAHs & metal contaminants

水生脊椎动物对PAHs的抵抗机制

• 批准号: 6577820
• 负责人: Isaac I Wirgin
• 金额: $ 16.41万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6577820
• 关键词: aquatic organism; aromatic hydrocarbon receptor; carbopolycyclic compound; cytochrome P450; ecology; environmental contamination; environmental exposure; environmental health; environmental toxicology; evolution; fish; genetic transcription; hazardous substances; heavy metals; messenger RNA; pathologic process; receptor expression; soil pollution; water pollution

The Hudson River estuary contains Superfund sites because of PCB, dioxin, and heavy metal contamination and levels of PAHs are elevated in sediments at industrialized and urban sites in the lower estuary. Resistance is one of the potential effects of chronic exposure to these Superfund contaminants on resident feral populations. While resistance may be beneficial in the short term to impacted populations, evolutionary costs may accrue to affected populations and trophic transfer of contaminants may compromise the health of ecological communities. Resistance to cytochrome P4501A1 (CYP1A1) induction has observed in feral fish populations from the Hudson River and other Atlantic coast estuaries that are highly contaminated with Superfund toxicants. In previous studies, we have documented impaired inducibility of CYP1A1 transcription in a sentinel, Atlantic tomcod (Microgadus tomcod) from the Hudson River, that are treated with halogenated aromatic hydrocarbon compounds (PCBs and 2,3,7,8-TCDD), but not with non-halogenated PAHs. This study will focus on the mechanistic bases of non-inducibility of CYP1A1 in tomcod that we have observed. Our working hypothesis is that CYP1A1 transcription is inhibited by down-regulation of the aromatic hydrocarbon receptor (AhR) pathway in tomcod and other vertebrate species from Superfund contaminated sites. Because AhR expression is critical to normal liver development and immunosurveillance in the absence of aromatic hydrocarbons, down- regulation of AhR may have profound effects on population and community well-being after remediation of Superfund sites. We will initially determine if impaired inducibility of CYP1A1 is a genetic adaptation or a single generation physiological acclimation. We will use our recently developed tomcod AhR probes to compare the effects of chemical treatment and environmental exposure on expression of AhR mRNA and protein in tomcod from the Hudson River and a cleaner reference river in Canada. Additionally, the epigenetic effects of metals- induced methylation will be investigated on expression of CYP1A1 im tomcod. Previously identified tomcod AhR variants will be characterized and their functional significance evaluated with environmentally relevant concentrations of PCBs and PAHs. Finally, a response of probabilities to Superfund contaminants will be evaluated. These studies will provide new insights into the susceptibilities of feral populations to the toxic effects of mixtures of Superfund chemicals.

由于PCB，二恶英和重金属污染，Hudson River河口包含超级基金地点，PAH的水平在下层河口的工业化和城市地点的沉积物中升高。抗药性是慢性暴露于这些超级基金污染物对常驻野生种群的潜在影响之一。尽管在短期内抵抗可能是有益的，但进化成论可能会影响受影响的人群，而污染物的营养转移可能会损害生态群落的健康。在哈德逊河和其他被超级基金有毒物质高度污染的哈德逊河和其他大西洋海岸河口的野生鱼类种群中观察到了对细胞色素P4501A1（CYP1A1）的抗性。在先前的研究中，我们记录了来自哈德逊河的哨兵，大西洋tomcod（Microgadus tomcod）中CYP1A1转录的诱导性受损，并用卤代芳基烃化合物（PCB和2,3,7,8-TCDD）进行处理，但是没有非卤代PAH。这项研究将集中于我们观察到的CYP1A1在TomCod中不可诱导性的机械基础。我们的工作假设是，CYP1A1转录受到了Tomcod中芳香碳受体（AHR）途径的下调和超级污染部位的其他脊椎动物物种的下调。由于AHR表达对正常的肝脏发育至关重要，在没有芳香碳氢化合物的情况下，AHR的下调可能会对人群和社区福祉产生深远的影响，后者在修复超级基金地点后可能对人群和社区福祉产生深远的影响。我们最初将确定CYP1A1的诱导性受损是遗传适应还是单一生理适应。我们将使用我们最近开发的Tomcod AHR探针来比较化学处理和环境暴露对Hudson河中Tomcod中AHR mRNA和蛋白质表达的影响，以及加拿大加拿大的清洁参考河。另外，将研究金属诱导的甲基化的表观遗传作用，以对CYP1A1 IM tomcod的表达进行研究。先前确定的tomcod AHR变体将被表征，并使用与环境相关的PCB和PAH进行评估。最后，将评估概率对超级基金污染物的响应。这些研究将为野生人群对超级基金化学物质混合物的毒性作用的敏感性提供新的见解。