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.

哈德逊河口包含超级基金网站，因为PCB，二恶英，重金属污染和多环芳烃的水平升高，在工业化和城市的网站在较低的河口沉积物。抗性是长期暴露于这些超级基金污染物对野生种群的潜在影响之一。虽然抗性在短期内对受影响的种群可能是有益的，但受影响的种群可能要付出进化的代价，污染物的营养转移可能会损害生态群落的健康。在哈德逊河和其他大西洋沿岸河口的野生鱼类种群中观察到了对细胞色素P4501 A1（CYP 1A 1）诱导的抗性，这些鱼类受到超级基金毒物的高度污染。在以前的研究中，我们已经记录了受损的诱导CYP 1A 1转录的哨兵，大西洋小鳕（小鳕）从哈德逊河，这是治疗卤代芳烃化合物（多氯联苯和2，3，7，8-TCDD），但不是与非卤代多环芳烃。本研究将重点关注我们观察到的小鳕CYP 1A 1非诱导性的机制基础。我们的工作假设是，CYP 1A 1的转录被抑制的芳香烃受体（AhR）途径在小鳕和其他脊椎动物物种的超基金污染的网站下调。由于AhR表达在不存在芳烃的情况下对正常肝脏发育和免疫监视至关重要，因此AhR的下调可能对超级基金场地修复后的人口和社区福祉产生深远影响。我们将初步确定是否受损的诱导CYP 1A 1是一种遗传适应或单代生理驯化。我们将使用我们最近开发的小鳕鱼AhR探针比较化学处理和环境暴露对小鳕鱼AhR mRNA和蛋白质表达的影响，从哈德逊河和一个更清洁的参考河流在加拿大。此外，将研究金属诱导的甲基化对小鳕CYP 1A 1表达的表观遗传效应。以前确定的小鳕鱼AhR的变种将进行表征，并与环境相关的多氯联苯和多环芳烃浓度的功能意义进行评估。最后，将评估超级基金污染物的概率响应。这些研究将为野生动物种群对超级基金化学品混合物的毒性效应的敏感性提供新的见解。