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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：
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
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/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

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.

鱼类的短暂和永久性生殖功能障碍与化学物质有关