Project 2: Cross-Species Comparison of Transplacental Dosimetry PAHs

项目 2：经胎盘剂量测定 PAH 的跨物种比较

• 批准号: 8375914
• 负责人: RICHARD A CORLEY
• 金额: $ 35.36万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8375914
• 关键词: 129 Mouse; Accounting; Address; Adolescent; Adult; Affinity; Animal Model; Aromatic Polycyclic Hydrocarbons; Binding; Biological; Biological Markers; Blood; Breeding; Burn injury; CYP1B1 gene; Chemicals; Child; DNA Adduction; DNA Adducts; Data; Development; Dose; Drug Kinetics; Drug Metabolic Detoxication; Environment; Environmental Exposure; Environmental Pollutants; Epoxide hydrolase; Equilibrium; Ethics; Etiology; Exposure to; Female; Fetus; Foundations; Gene Targeting; Genes; Genetic; Glucuronides; Glutathione; Goals; Growth; Health; Hepatocyte; High Pressure Liquid Chromatography; Human; Human Volunteers; Hydrolysis; In Vitro; Individual; Inorganic Sulfates; Label; Laboratories; Lactation; Life; Malignant Neoplasms; Mediating; Metabolic; Metabolic Activation; Metabolism; Modeling; Mothers; Mus; Neonatal; Organ; Parents; Partition Coefficient; Pathway interactions; Perinatal Exposure; Physiological; Pregnancy; Pregnant Women; Process; Production; Protein Binding; Publishing; Pyrenes; Relative (related person); Risk; Route; Staging; T-Cell Lymphoma; Thymus Gland; Time; Tissues; Transgenic Organisms; Transplacental Carcinogenesis; Uncertainty; Unspecified or Sulfate Ion Sulfates; Validation; adduct; base; calf thymus DNA; carcinogenesis; carcinogenicity; comparative; dosimetry; exposed human population; fetal; human tissue; improved; in vivo; metabolic abnormality assessment; model development; mouse model; neonate; new technology; offspring; oxidation; pharmacokinetic model; pollutant; predictive modeling; pregnant; superfund site; thymocyte; volunteer; young adult

Dibenzo[a,l]pyrene (DBP) is one of the most potent carcinogenic polycyclic aromatic hydrocarbons (PAHs) present in the environment as a by-product of the burning of organic materials and at many Superfund sites. Collaborators on this proposed SBRP published the first animal model for the production of T-cell lymphomas, a common cancer for children and young adults, in offspring of mice exposed to DBP during pregnancy. The T-cell lymphoma model provides a unique opportunity to address uncertainties in extrapolating the potential risk to humans for transplacental carcinogenesis. Reliably predicting which target tissue doses of the active form of the chemical (parent compound or metabolite) under a variety of exposure conditions is a necessary prerequisite to successful extrapolations from laboratory conditions to humans. However, no studies currently exist that quantitate the relative contribution of metabolic activation with other potentially significant pathways for detoxification and clearance of DBP in maternal and fetal/neonatal tissues that would facilitate target tissue dose extrapolations (DMA adducts in the thymus) from the animal model to humans. In fact, important species, tissue, and stage of development differences in clearance capacities are known and must be accounted for. Therefore, the goal of this project is to develop quantitative, dose-dependent relationships for transplacental DBP-induced target tissue DMA adducts in mice to improve the biological basis for extrapolating the risk of carcinogenesis to relevant human exposures to DBP. To accomplish this goal, it is critical to identify and determine the relative rates of activation vs. detoxification pathways in mice and humans. Four specific aims are proposed and include: (1) determine the dose-dependent pharmacokinetics and target tissue dosimetry of DBP and its major metabolites and DMA adducts in the mouse model for transplacental carcinogenicity (2) determine the comparative rates of metabolic activation (with an emphasis on Cyp1b1) and detoxification of DBP in primary hepatocytes and thymocytes from mice vs. humans; (3) determine the in vivo ultra low dose pharmacokinetics of DBP and its key metabolites in human volunteers; and (4) develop the first physiologically based pharmacokinetic (PBPK) model for DBP capable of identifying and reducing the uncertainties in extrapolating target tissue doses of toxic metabolites of DBP from mice to relevant human exposures.

二苯并[a，L]芘(DBP)是环境中最强的致癌多环芳烃(PAHs)之一，它是有机材料燃烧的副产物，存在于许多超级基金地点。这项提议的SBRP的合作者发表了第一个T细胞淋巴瘤的动物模型，T细胞淋巴瘤是一种儿童和年轻人常见的癌症，在怀孕期间暴露于DBP的小鼠的后代中。T细胞淋巴瘤模型提供了一个独特的机会来解决在推断人类经胎盘致癌的潜在风险方面的不确定性。可靠地预测化学物质(母体化合物或代谢物)在各种暴露条件下的活性形式的目标组织剂量是成功从实验室条件外推到人类的必要前提。然而，目前还没有研究量化代谢激活与其他潜在的重要途径在母体和胎儿/新生儿组织中的解毒和清除DBP的相对贡献，这些途径将有助于从动物模型到人类的靶组织剂量外推(胸腺中的DMA加合物)。事实上，重要的物种、组织和发育阶段的清除能力的差异是 已知且必须加以说明。因此，本项目的目标是建立经胎盘DBP诱导的小鼠靶组织DMA加合物的定量、剂量依赖关系，以改善外推相关人类暴露于DBP的致癌风险的生物学基础。为了实现这一目标，在小鼠和人类中识别和确定激活与解毒途径的相对比率至关重要。提出了四个具体目标，包括：(1)确定DBP及其主要代谢物和DMA加合物在小鼠经胎盘致癌模型中的剂量依赖药代动力学和靶组织剂量学；(2)确定DBP在小鼠和人的原代肝细胞和胸腺细胞中的代谢激活(重点是细胞色素P1B1)和解毒率的比较速率；(3)确定DBP及其关键代谢物在人体内的超低剂量药代动力学；以及(4)建立第一个能够识别和减少DBP目标组织剂量不确定性的基于生理的药代动力学(PBPK)模型。 DBP从小鼠到相关人类暴露的毒性代谢物。