BaP-mediated reproductive and developmental toxicity

BaP 介导的生殖和发育毒性

• 批准号: 7870863
• 负责人: KRISTINE L WILLETT
• 金额: $ 6.93万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-13 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870863
• 关键词: Affect; Animal Model; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; Biological Monitoring; CYP19A1 gene; Cancer Model; Chorion; DNA Adducts; Development; Embryo; Endocrine disruption; Environment; Feedback; Fishes; Fundulus heteroclitus; Germ Cells; Goals; Gonadal structure; Health; Human; Hypothalamic structure; Investigation; Malignant Neoplasms; Measures; Mediating; Modeling; Molecular; Molecular Probes; Morphology; Outcome; Physiological; Physiological Processes; Physiology; Pituitary Gland; Predisposition; Production; Reproduction; Research; Steroids; Structure of primordial sex cell; Testing; Toxic effect; Toxicology; Vertebrates; Zebrafish; cell motility; in vivo; insight; pollutant; public health relevance; reproductive; reproductive development; reproductive success; steroid hormone; stressor; tumor

DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants that are a human health concern because they are implicated in human cancers and reproductive and developmental deficits. The overall goal of this project is to determine the molecular mechanisms involved with benzo (a)pyrene (BaP)-mediated inhibition of CYP19A2 expression and the related physiological consequences. Our guiding hypothesis is that BaP deregulates the steroid hormone hypothalamus-pituitary-gonad feedback loop adversely affecting reproductive development and physiology. In our previous research, we have successfully used the fish Fundulus heteroclitus as a model for understanding the molecular mechanisms and pathological consequences of PAH exposure in humans and established BaP-induced effects on CYP19 expression and activity. This proposed project builds on our prior research to further probe the molecular mechanisms associated with these toxicities. In Aim 1 we will further establish BaP-mediated toxicological endpoints including phenotypic (gonad morphology) and molecular consequences (steroid concentrations, LH and FSH expression, and primordial germ cell migration). In Aim 2 we will knockdown CYP19A2 during early development and measure phenotypic and molecular consequences of the inhibition. Successful completion of these aims will provide a greater molecular understanding of the potential for environmentally relevant PAHs to adversely impact reproduction and development. In addition, we will gain additional insights into a critical physiological process (i.e. primordial germ cell migration) that could be adversely affected by BaP exposure while validating the fish model for further investigation of other stressors on these physiological outcomes. PUBLIC HEALTH RELEVANCE: Polycyclic aromatic hydrocarbon (PAH) concentrations in the environment are increasing. These compounds are a human health concern because they are implicated in human cancers and reproductive and developmental deficits. This research will provide a greater understanding of the molecular mechanisms and pathological consequences of PAH exposure.

描述（由申请人提供）：多环芳烃 (PAH) 是一种普遍存在的污染物，由于与人类癌症以及生殖和发育缺陷有关，因此会引起人类健康问题。该项目的总体目标是确定苯并 (a) 芘 (BaP) 介导的 CYP19A2 表达抑制作用的分子机制以及相关的生理后果。我们的指导性假设是，BaP 会解除类固醇激素下丘脑-垂体-性腺反馈回路的调节，从而对生殖发育和生理机能产生不利影响。在我们之前的研究中，我们成功地使用鱼眼底异斜鱼作为模型来了解人类 PAH 暴露的分子机制和病理后果，并建立了 BaP 诱导的对 CYP19 表达和活性的影响。该拟议项目建立在我们之前的研究基础上，以进一步探讨与这些毒性相关的分子机制。在目标 1 中，我们将进一步建立 BaP 介导的毒理学终点，包括表型（性腺形态）和分子后果（类固醇浓度、LH 和 FSH 表达以及原始生殖细胞迁移）。在目标 2 中，我们将在早期发育过程中敲低 CYP19A2，并测量抑制的表型和分子后果。成功完成这些目标将使人们对环境相关多环芳烃对生殖和发育产生不利影响的潜力有更深入的分子了解。此外，我们还将进一步了解可能受到 BaP 暴露不利影响的关键生理过程（即原始生殖细胞迁移），同时验证鱼类模型，以进一步研究对这些生理结果的其他压力源。 公共卫生相关性：环境中的多环芳烃 (PAH) 浓度正在增加。这些化合物是人类健康问题，因为它们与人类癌症以及生殖和发育缺陷有关。这项研究将使人们更好地了解多环芳烃暴露的分子机制和病理后果。