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:
- 金额:$ 1.08万
- 依托单位:
- 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:
- 关键词:17pAdultAdverse effectsAffectAgonistAndrogen ReceptorAndrogensAnimalsAromataseBackBassBindingBiochemicalBiochemical PathwayBiological MarkersCYP11A1 geneCYP19A1 geneCYP3A4 geneCellsChemicalsCyclic AMPDataDichlorodiphenyl DichloroethyleneDieldrinDoseEcosystemElectrophoretic Mobility Shift AssayEndocrine DisruptorsEndocrine disruptionEndocrine systemEnzymesEstradiolEstrogen ReceptorsExhibitsExposure toFarming environmentFeedbackFishesFloridaFunctional disorderGene ExpressionGenetic TranscriptionGenomicsGoalsGonadal Steroid HormonesHealthHepaticHomeostasisHormone ReceptorHormonesHumanImpairmentIn VitroLifeLinkMeasuresMediatingMessenger RNAMetabolic PathwayMetabolismMethodologyMethodsMethoxychlorMicropterusMicrosomesModelingMolecularMolecular Mechanisms of ActionMonitorNomenclaturePathway interactionsPatternPesticidesPlasmaProcessProtein IsoformsProteinsProteomicsProtocols documentationReaction TimeReceptor SignalingRegulationReportingReproductionResearchResearch PersonnelRoleSentinelSiteSmall Interfering RNASperm MotilitySteroid biosynthesisSteroidsTestingTestosteroneTimeTissuesToxapheneVertebratesVesicleWorkaquatic organismdesigneggenzyme activityfield studyhypothalamic pituitary gonadal axisin vivoknock-downnovelorganochlorine pesticideorganochlorine pesticide exposurepreferencepreventprogramspromoterprotein expressionreceptorreceptor functionreproductivereproductive functionresearch studyresponsesperm functionsteroid hormone receptorsteroid metabolismsteroidogenic acute regulatory proteinsuperfund sitetranscription 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),包括阿波普卡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:
- 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:
- 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:
- 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:
- 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.
- DOI:10.1093/toxsci/kfu145
- 发表时间:2014-10
- 期刊:
- 影响因子:0
- 作者:Gustavo A. Domínguez;J. Bisesi;K. Kroll;N. Denslow;T. Sabo-Attwood
- 通讯作者:Gustavo A. Domínguez;J. Bisesi;K. Kroll;N. Denslow;T. Sabo-Attwood
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Nancy D Denslow其他文献
Nancy D Denslow的其他文献
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{{ truncateString('Nancy D Denslow', 18)}}的其他基金
In Situ Sampling Tool for Assessing Bioavailability and Toxicity of Sediments
用于评估沉积物生物利用度和毒性的原位采样工具
- 批准号:
8514608 - 财政年份:2011
- 资助金额:
$ 1.08万 - 项目类别:
In Situ Sampling Tool for Assessing Bioavailability and Toxicity of Sediments
用于评估沉积物生物利用度和毒性的原位采样工具
- 批准号:
8733971 - 财政年份:2011
- 资助金额:
$ 1.08万 - 项目类别:
In Situ Sampling Tool for Assessing Bioavailability and Toxicity of Sediments
用于评估沉积物生物利用度和毒性的原位采样工具
- 批准号:
8227888 - 财政年份:2011
- 资助金额:
$ 1.08万 - 项目类别:
In Situ Sampling Tool for Assessing Bioavailability and Toxicity of Sediments
用于评估沉积物生物利用度和毒性的原位采样工具
- 批准号:
8335411 - 财政年份:2011
- 资助金额:
$ 1.08万 - 项目类别:
Molecular Mechanisms of Endocrine Disruption in Bass
低音内分泌干扰的分子机制
- 批准号:
7916300 - 财政年份:2009
- 资助金额:
$ 1.08万 - 项目类别:
Molecular Mechanisms of Endocrine Disruption in Bass
低音内分泌干扰的分子机制
- 批准号:
7270511 - 财政年份:2006
- 资助金额:
$ 1.08万 - 项目类别:
Molecular Mechanisms of Endocrine Disruption in Bass
低音内分泌干扰的分子机制
- 批准号:
7940374 - 财政年份:2006
- 资助金额:
$ 1.08万 - 项目类别:
Molecular Mechanisms of Endocrine Disruption in Bass
低音内分泌干扰的分子机制
- 批准号:
7228682 - 财政年份:2006
- 资助金额:
$ 1.08万 - 项目类别:
Molecular Mechanisms of Endocrine Disruption in Bass
低音内分泌干扰的分子机制
- 批准号:
7407982 - 财政年份:2006
- 资助金额:
$ 1.08万 - 项目类别:
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