BaP-mediated reproductive and developmental toxicity

描述（由申请人提供）：多环芳烃（PAHs）是一种普遍存在的污染物，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。该项目的总体目标是确定苯并(a)芘（BaP）介导的CYP19A2表达抑制的分子机制及其相关的生理后果。我们的指导假设是BaP解除了对下丘脑-垂体-性腺反馈回路的类固醇激素的调节，对生殖发育和生理产生不利影响。在我们之前的研究中，我们已经成功地用异交底鱼作为模型来理解人类暴露于多环环烃的分子机制和病理后果，并建立了bap诱导的CYP19表达和活性的影响。该项目建立在我们之前的研究基础上，进一步探索与这些毒性相关的分子机制。在Aim 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Aim 2中，我们将在早期发育期间敲除CYP19A2，并测量抑制的表型和分子后果。这些目标的成功完成将使人们更深入地了解与环境有关的多环芳烃对生殖和发育产生不利影响的可能性。此外，我们将进一步了解BaP暴露可能对关键生理过程（即原始生殖细胞迁移）产生不利影响，同时验证鱼类模型，以进一步研究其他应激源对这些生理结果的影响。

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.