BaP-mediated reproductive and developmental toxicity

描述（由申请人提供）：多环芳烃（PAH）是普遍存在的污染物，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。本项目的总体目标是确定苯并（a）芘（BaP）介导的CYP 19 A2表达抑制及其相关生理后果的分子机制。我们的指导性假设是BaP失调类固醇激素下丘脑-垂体-性腺反馈回路，对生殖发育和生理产生不利影响。在我们以前的研究中，我们已经成功地使用了鱼类底heteroclitus作为模型，了解分子机制和病理后果的PAH暴露在人类和建立BaP诱导的影响CYP 19的表达和活性。该项目建立在我们先前的研究基础上，进一步探索与这些毒性相关的分子机制。在目标1中，我们将进一步确定BaP介导的毒理学终点，包括表型（性腺形态学）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CYP 19 A2，并测量抑制的表型和分子后果。这些目标的成功完成将提供一个更大的分子了解的潜在环境相关的多环芳烃产生不利影响的生殖和发展。此外，我们将获得额外的见解到一个关键的生理过程（即原始生殖细胞迁移），可能会受到苯并（a）芘暴露的不利影响，同时验证鱼模型，以进一步研究其他压力对这些生理结果的影响。 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和生殖发育缺陷有关。这项研究将提供一个更好的了解的分子机制和病理后果的多环芳烃暴露。

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.