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Molecular Mechanisms of Endocrine Disruption in Bass

低音内分泌干扰的分子机制

基本信息

批准号：
8308091
负责人：
Nancy D Denslow
金额：
$ 1.08万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8308091
关键词：
17p Adult Adverse effects Affect Agonist Androgen Receptor Androgens Animals Aromatase Back Bass Binding Biochemical Biochemical Pathway Biological Markers CYP11A1 gene CYP19A1 gene CYP3A4 gene Cells Chemicals Cyclic AMP Data Dichlorodiphenyl Dichloroethylene Dieldrin Dose Ecosystem Electrophoretic Mobility Shift Assay Endocrine Disruptors Endocrine disruption Endocrine system Enzymes Estradiol Estrogen Receptors Exhibits Exposure to Farming environment Feedback Fishes Florida Functional disorder Gene Expression Genetic Transcription Genomics Goals Gonadal Steroid Hormones Health Hepatic Homeostasis Hormone Receptor Hormones Human Impairment In Vitro Life Link Measures Mediating Messenger RNA Metabolic Pathway Metabolism Methodology Methods Methoxychlor Micropterus Microsomes Modeling Molecular Molecular Mechanisms of Action Monitor Nomenclature Pathway interactions Pattern Pesticides Plasma Process Protein Isoforms Proteins Proteomics Protocols documentation Reaction Time Receptor Signaling Regulation Reporting Reproduction Research Research Personnel Role Sentinel Site Small Interfering RNA Sperm Motility Steroid biosynthesis Steroids Testing Testosterone Time Tissues Toxaphene Vertebrates Vesicle Work aquatic organism design egg enzyme activity field study hypothalamic pituitary gonadal axis in vivo knock-down novel organochlorine pesticide organochlorine pesticide exposure preference prevent programs promoter protein expression receptor receptor function reproductive reproductive function research study response sperm function steroid hormone receptor steroid metabolism steroidogenic acute regulatory protein superfund site transcription factor

项目摘要

Transient and permanent reproductive dysfunction in fish has been linked to chemicals that disrupt the endocrine system, but the mechanisms involved are unclear. Many endocrine-disrupting chemicals (EDCs) interact with sex hormone receptors by acting as agonists to induce gene expression at inappropriate times or act as antagonists to prevent the normal functioning of the receptors. Other EDCs may act indirectly by altering the processes involved in regulating sex steroid synthesis and metabolism. Poor reproduction and altered plasma hormone levels have been observed in largemouth bass living in ecosystems polluted with organochlorine pesticides (OCPs), including the Superfund site at Lake Apopka and its surrounding muck farms, suggesting that OCP exposure has adversely affected their reproduction. In past research, we have identified three estrogen receptors (a, pi, and (32) in largemouth bass, which exhibit tissue specific expression and respond differently to 17-p-estradiol at the message and activity level. These differences are important to control normal reproductive function. We have evidence that EDCs can alter their normal expression and activity patterns, possibly disrupting reproduction. In addition, we have preliminary evidence that expression of enzymes involved in the synthesis and metabolism of EDCs is affected by the OCPs. The proposed studies will test the central hypothesis that exposure of largemouth bass to concentrations of OCPs found in the Lake Apopka region disrupts endocrine system function by sex hormone receptor mediated and sex hormone receptor independent mechanisms. In this proposal, we have designed a set of interrelated experiments from the organismal level where pleiotropic effects of OCPs can be measured to the cellular level where specific molecular mechanisms of action can be assessed. We are exposing largemouth bass to methoxychlor (and its metabolites), p,p' DDE, dieldrin and toxaphene. Our specific aims include 1: Develop biomarkers of exposure to organochlorinated pesticides in vivo, via the use of microarrays and novel proteomics methodologies; 2: Determine the effect of in vivo OCP exposure on LME steroid synthesis and metabolism; and 3: Evaluate the effects of OCPs on the molecular mechanisms of action of the three estrogen receptors. We plan on using exposures to compounds with known modes of action as controls to determine mode of action specific gene expression patterns against which we will compare the patterns of gene expression changes induced by the OCPs. We will check these pattern changes against reproductive endpoints including the ability of eggs to mature (germinal vesicle breakdown) and sperm function (sperm motility). Fish are useful as sentinels of environmental quality and are perfect models to monitor adverse effects in reproduction caused by contaminants in superfund sites. By extrapolation fish can report on the potential of OCPs to harm human health.

鱼类的暂时性和永久性生殖功能障碍与化学物质有关，内分泌系统，但涉及的机制尚不清楚。许多内分泌干扰物（EDCs）与性激素受体相互作用，作为激动剂在不适当的时间诱导基因表达或作为拮抗剂阻止受体的正常功能。其他EDCs可能通过以下方式间接起作用：改变参与调节性类固醇合成和代谢的过程。繁殖能力差，在生活在被污染的生态系统中的大口黑鲈中观察到了血浆激素水平的改变，有机氯农药（OCPs），包括Apopka湖的超级基金场地及其周围的淤泥农场，这表明OCP暴露对它们的繁殖产生了不利影响。在过去的研究中，我们已经确定了三种雌激素受体（A，PI和（32）在大口黑鲈，表现出组织特异性表达，并在信息和活性水平上对17-β-雌二醇有不同的反应。这些差异对于控制正常的生殖功能很重要。我们有证据表明内分泌干扰物改变它们的正常表达和活动模式，可能干扰生殖。另外我们有初步证据表明，参与内分泌干扰物合成和代谢的酶的表达，受到OCP的影响。拟议的研究将测试中心假设，即暴露于大口黑鲈在Apopka湖地区发现的OCPs浓度会破坏内分泌系统功能激素受体介导和性激素受体非依赖机制。在本提案中，我们有从生物体水平设计了一系列相互关联的实验，其中OCP的多效性作用可以可以测量到细胞水平，其中可以评估特定的分子作用机制。我们将大口黑鲈暴露于甲氧滴滴涕（及其代谢物）、p，p' DDE、狄氏剂和毒杀芬。我们具体目标包括：1.通过使用生物标志物，微阵列和新的蛋白质组学方法; 2：确定体内OCP暴露对LME的影响类固醇的合成和代谢; 3：评价OCP对三种雌激素受体的作用。我们计划使用暴露于已知模式的化合物，作为对照，以确定作用模式特异性基因表达模式，我们将比较OCP诱导的基因表达变化模式。我们将检查这些模式生殖终点的变化，包括卵子成熟的能力（生殖囊泡破裂）和精子功能（精子活力）。鱼类作为环境质量的哨兵是有用的，超级基金场址污染物对生殖造成不利影响的监测模式。通过外推鱼类可以报告有机氯农药对人类健康的潜在危害。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Applications for next-generation sequencing in fish ecotoxicogenomics.

DOI：
10.3389/fgene.2012.00062
发表时间：
2012
期刊：
Frontiers in genetics
影响因子：
3.7
作者：
Mehinto AC;Martyniuk CJ;Spade DJ;Denslow ND
通讯作者：
Denslow ND

Ecotoxico-lipidomics: An emerging concept to understand chemical-metabolic relationships in comparative fish models.

DOI：
10.1016/j.cbd.2020.100742
发表时间：
2020-12
期刊：
Comparative biochemistry and physiology. Part D, Genomics & proteomics
影响因子：
0
作者：
Dreier DA;Bowden JA;Aristizabal-Henao JJ;Denslow ND;Martyniuk CJ
通讯作者：
Martyniuk CJ

Exploring androgen-regulated pathways in teleost fish using transcriptomics and proteomics.

利用转录组学和蛋白质组学探索硬骨鱼中雄激素调节途径。

DOI：
10.1093/icb/ics072
发表时间：
2012
期刊：
Integrative and comparative biology
影响因子：
2.6
作者：
Martyniuk,ChristopherJ;Denslow,NancyD
通讯作者：
Denslow,NancyD

Sexually dimorphic transcriptomic responses in the teleostean hypothalamus: a case study with the organochlorine pesticide dieldrin.

在静脉下下丘脑中的性二态转录组反应：用有机氯农药dieldrin的案例研究。

DOI：
10.1016/j.neuro.2012.09.012
发表时间：
2013-01
期刊：
NEUROTOXICOLOGY
影响因子：
3.4
作者：
Martyniuk, Christopher J.;Doperalski, Nicholas J.;Kroll, Kevin J.;Barber, David S.;Denslow, Nancy D.
通讯作者：
Denslow, Nancy D.

Control of transcriptional repression of the vitellogenin receptor gene in largemouth bass (Micropterus salmoides) by select estrogen receptors isotypes.