Project 3: Toxicology of Petrogenic PAH in the Gulf Oil Spill

墨西哥湾漏油事件中石油成因多环芳烃的毒理学。据信，由于通过食物链、皮肤接触和可能受污染的水的长期暴露，石油多环芳烃（PAH）是与海湾石油泄漏有关的主要长期人类健康危害。GC-HARMS联盟的总体主题是了解和传达暴露于潜在危险的食源性产岩PAH的人类健康风险。目前我们对PAH的毒理学认识大多来自于对PAH的代表性化合物苯并[a]芘（B [a] P）的研究，苯并[a]芘是一种多器官、多物种的致癌物，也是已知的人类致癌物。因此，美国环保署将B [a] P列为其在食物链中监测的16种优先PAH污染物之一。然而，B [a] P和其他优先PAH污染物不是原油的主要成分。事实上，原油中的多环芳烃成分很复杂，含有多环芳烃混合物，我们对这些混合物的毒理学数据知之甚少。因此，在缺乏进一步信息的情况下，无法根据B [a] P毒性当量商数（TEO）进行风险评估。两 岩石成因的PAH种类丰富，它们是广泛烷基化的PAH和与原油风化有关的氧化PAH。我们假设烷基化PAH将在其烷烃侧链上羟基化，然后通过硫酸化活化。我们还假设，含氧多环芳烃可能介导其影响，通过广泛的氧化还原循环，导致活性氧（ROS）的产生。 我们的目标是表征岩源PAH物种的代谢和毒性。我们的实验室在使用最先进的技术研究PAH代谢、PAH毒性和氧化PAH方面拥有丰富的经验。 方法论。我们的具体目标如下。目标1将使用基于细胞的暴露和效应生物标志物（Elferink）确定选定的烷基化和氧化的岩源性PAH和PAH提取物的相对效力。目的2将阐明代表性的烷基化和氧化的岩石成因PAH（潘宁）的代谢。目的3旨在确定氧化的成岩PAH是否引起氧化应激损伤（Penning），目的4将确定烷基化和氧化的成岩PAH的致突变性。 PAH（Penning）。

Toxicology of Petrogenic PAH in the Gulf Oil Spill. Petrogenic Polycyclic Aromatic Hydrocarbons (PAH) are believed to be the major long-term human health hazard associated with the gulf-oil spill due to chronic exposure through the food chain, dermal contact and possibly contaminated water. The overall theme of the GC-HARMS consortium is to understand and communicate the human health risks of exposure to potentially hazardous food-borne petrogenic PAH. Most of what we currently know about the toxicology of PAH has been learned from studying the representative PAH, benzo[a]pyrene (B[a]P) which is a multi-organ and multi-species carcinogen and known human carcinogen. As a result, US-EPA includes B[a]P as one of its 16 priority PAH pollutants that it monitors in the food chain. However, B[a]P and the other priority PAH pollutants are not major components of crude-oil. In fact, the PAH composition of crude oil is complex and contains PAH mixtures for which we have little to know toxicological data. Thus risk assessment based on the B[a]P toxicity equivalency quotient (TEO) cannot be performed in the absence of further information. Two classes of petrogenic PAH are abundant and these are the extensively alkylated PAH and the oxygenated PAH associated with crude oil weathering. We hypothesize that alkylated PAH will be hydroxylated on their alkane side chains, followed by activation via sulfation. We also hypothesize that the oxygenated PAH may mediate their effects via extensive redox-cycling leading to the generation of reactive oxygen species (ROS). Our goal is to characterize the metabolism and toxicity of the petrogenic PAH species. Our laboratories have extensive experience in studying PAH-metabolism, PAH-toxicity, and oxygenated PAH using state-of-the art methodologies. Our specific aims are as follows. Aim 1 will determine the relative potency of selected alkylated and oxygenated petrogenic PAH and PAH extracts using cell-based exposure and effect biomarkers (Elferink). Aim 2 will elucidate the metabolism of representative alkylated and oxygenated petrogenic PAH (Penning). Aim 3 seeks to determine whether oxygenated petrogenic PAH causes oxidative stress injury (Penning), and Aim 4 will determine the mutagenicity of alkylated and oxygenated petrogenic PAH (Penning).