Mechanisms of resistance of aquatic vertebrates to PAHs & metal contaminants

由于多氯联苯、二恶英和重金属污染，哈德逊河河口含有超级基金，河口下游工业化和城市地区的沉积物中多环芳烃的含量也很高。耐药性是长期暴露于这些超级基金污染物对居住野生种群的潜在影响之一。虽然耐药性可能在短期内对受影响的种群有益，但受影响的种群可能会付出进化代价，污染物的营养转移可能会损害生态群落的健康。对细胞色素P4501A1 （CYP1A1）诱导的抗性已经在哈德逊河和其他大西洋沿岸河口的野生鱼类种群中观察到，这些种群受到超级基金毒物的高度污染。在之前的研究中，我们已经记录了来自哈德逊河的哨兵大西洋小鳕（Microgadus tomcod）的CYP1A1转录诱导性受损，这些小鳕被卤化芳烃化合物（多氯联苯和2,3,7,8- tcdd）处理，而非卤化多环芳烃则没有。本研究将重点关注我们观察到的tomcod中CYP1A1不诱导的机制基础。我们的工作假设是，来自超级基金污染地点的小鳕和其他脊椎动物的芳香烃受体（AhR）通路下调抑制了CYP1A1的转录。由于AhR的表达在缺乏芳烃的情况下对正常肝脏发育和免疫监测至关重要，因此在超级基金场地修复后，AhR的下调可能对人群和社区福祉产生深远影响。我们将首先确定CYP1A1诱导性受损是遗传适应还是单代生理适应。我们将使用我们最近开发的小鳕AhR探针来比较化学处理和环境暴露对来自哈德逊河和加拿大一条更清洁的参考河的小鳕AhR mRNA和蛋白质表达的影响。此外，还将研究金属诱导甲基化对tomcod中CYP1A1表达的表观遗传影响。我们将利用多氯联苯和多环芳烃的环境相关浓度对先前发现的小鳕AhR变异进行表征，并对其功能意义进行评估。最后，将评估超级基金污染物对概率的响应。这些研究将为野生种群对超级基金化学物质混合物的毒性影响的敏感性提供新的见解。

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.