BaP-mediated reproductive and developmental toxicity

BaP 介导的生殖和发育毒性

基本信息

批准号：
8061604
负责人：
KRISTINE L WILLETT
金额：
$ 6.86万
依托单位：
UNIVERSITY OF MISSISSIPPI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-13 至 2013-03-31
项目状态：
已结题

项目摘要

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（PAHS）是无处不在的污染物，它们是人类健康的关注，因为它们与人类癌症有关，生殖和发育不足。该项目的总体目标是确定与苯并（A）pyrene（BAP）介导的CYP19A2表达抑制和相关生理后果有关的分子机制。我们的指导假设是，BAP取消了类固醇激素下丘脑 - 垂体反馈反馈环，从而不利影响生殖发育和生理学。在我们先前的研究中，我们成功地使用了FISH代表杂志作为理解人类PAH暴露的分子机制和病理后果的模型，并确定了BAP诱导的对CYP19表达和活性的影响。这项拟议的项目基于我们先前的研究，以进一步探测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，我们将在早期发育过程中敲低CYP19A2，并测量抑制作用的表型和分子后果。这些目标的成功完成将为环境相关的PAH的潜力提供更深入的分子理解，从而对繁殖和发展产生不利影响。此外，我们将获得对关键生理过程（即原始生殖细胞迁移）的更多见解，该过程可能会受到BAP暴露的不利影响，同时验证鱼类模型，以进一步研究其他压力源对这些生理结果。公共卫生相关性：环境中的多环芳族烃（PAH）浓度正在增加。这些化合物是人类健康的关注，因为它们与人类癌症以及生殖和发育缺陷有关。这项研究将为PAH暴露的分子机制和病理后果提供更多的了解。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects on specific promoter DNA methylation in zebrafish embryos and larvae following benzo[a]pyrene exposure.

DOI：
10.1016/j.cbpc.2014.02.005
发表时间：
2014-06
期刊：
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
影响因子：
3.9
作者：
Corrales, J.;Fang, X.;Thornton, C.;Mei, W.;Barbazuk, W. B.;Duke, M.;Scheffler, B. E.;Willett, K. L.
通讯作者：
Willett, K. L.

Benzo[a]pyrene effects on reproductive endpoints in Fundulus heteroclitus.