Molecular Mechanisms of Endocrine Disruption in Bass

低音内分泌干扰的分子机制

• 批准号: 7940374
• 负责人: Nancy D Denslow
• 金额: $ 5.82万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 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/7940374
• 关键词: 17p; Acute; 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; Gene Proteins; 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

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.

鱼类中的短暂和永久生殖功能障碍与破坏的化学物质有关 内分泌系统，但涉及的机制尚不清楚。许多内分泌干扰化学物质（EDC） 通过充当激动剂来与性激素受体相互作用，在不适当的时期诱导基因表达 或充当防止受体正常功能的拮抗剂。其他EDC可能会间接采取行动 改变调节性类固醇合成和代谢所涉及的过程。繁殖不良 在生活在污染的生态系统中的大嘴鲈鱼中，血浆激素水平改变了 有机氯农药（OCP），包括阿波普卡湖及其周围泥浆的超级基金地点 农场，表明OCP暴露对其繁殖产生了不利影响。 在过去的研究中，我们已经确定了三个雌激素受体（a，pi和（32）的大嘴鲈鱼，这是它们，它们是 在信息和活性水平上表现出组织特异性表达和对17-P-雌二醇的反应。 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EDC可以 改变其正常表达和活性模式，可能破坏繁殖。此外，我们还有 初步证据表明，涉及EDC合成和代谢的酶的表达是 受OCP的影响。拟议的研究将测试大嘴鲈鱼暴露的中心假设 在阿波普卡湖地区发现的OCP的浓度，破坏了性别的内分泌系统功能 激素受体介导的和性激素受体独立机制。在这个建议中，我们有 设计了一组来自生物层的相互关联的实验，其中OCP的多效效应可以 可以测量可以评估特定分子机制的细胞水平。我们是 将大嘴鲈鱼暴露于甲氧基氯（及其代谢产物），p，p'dde，dieldrin和toxaphene。我们的 具体目的包括1：通过使用的生物标志物在体内开发暴露于有机氯的农药中 微阵列和新型蛋白质组学方法论； 2：确定体内OCP暴露对LME的影响 类固醇合成和代谢；和3：评估OCP对分子机制的影响 三个雌激素受体的作用。我们计划使用已知模式的化合物使用曝光 动作作为控制模式的控制模式特定基因表达模式，我们将 比较OCP诱导的基因表达变化的模式。我们将检查这些模式 针对生殖终点的变化，包括鸡蛋成熟的能力（生发囊泡分解） 和精子功能（精子运动）。鱼作为环境质量的哨兵很有用，非常完美 监测由超级基金部位污染物引起的繁殖中不良影响的模型。经过 外推鱼可以报告OCP损害人类健康的潜力。