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）是环境中最具致癌性的多环芳烃（PAHs）之一，它是有机物燃烧的副产物，也存在于许多超级基金项目中。 SBRP的合作者发表了第一个在怀孕期间暴露于DBP的小鼠后代中产生T细胞淋巴瘤的动物模型，T细胞淋巴瘤是儿童和年轻人的常见癌症。T细胞淋巴瘤模型提供了一个独特的机会，以解决外推经胎盘致癌对人类的潜在风险的不确定性。可靠地预测化学品活性形式（母体化合物或代谢物）在各种接触条件下的靶组织剂量，是从实验室条件成功外推至人体的必要先决条件。 然而，目前尚无研究定量代谢活化与母体和胎仔/新生儿组织中DBP解毒和清除的其他潜在重要途径的相对贡献，这将有助于从动物模型到人体的靶组织剂量外推（胸腺中的DMA加合物）。事实上，重要的物种、组织和发育阶段在清除能力上的差异， 已知的，必须考虑的。因此，本项目的目标是开发定量的，剂量依赖性的关系，经胎盘DBP诱导的靶组织DMA加合物在小鼠中，以改善生物学基础外推致癌风险的相关人体暴露于DBP。为了实现这一目标，识别和确定小鼠和人类中激活与解毒途径的相对速率至关重要。提出了四个具体目标，包括：（1）确定DBP及其主要代谢产物和DMA加合物在小鼠经胎盘致癌性模型中的剂量依赖性药代动力学和靶组织剂量学;（2）确定代谢活化的比较速率（重点是Cyp 1b 1）和DBP在小鼠与人的原代肝细胞和胸腺细胞中的解毒作用;（3）确定DBP及其关键代谢物在人类志愿者中的体内超低剂量药代动力学;以及（4）开发DBP的第一个基于生理学的药代动力学（PBPK）模型，该模型能够识别和减少外推DBP的靶组织剂量的不确定性。 DBP的毒性代谢物从小鼠到相关的人体暴露。