Low level exposure to PBDEs: testing the hormetic and epigenetic hypotheses

低水平接触多溴联苯醚：检验毒物兴奋和表观遗传假设

基本信息

批准号：
8473620
负责人：
LUCIO G COSTA
金额：
$ 19.31万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8473620
关键词：
Accounting Address Adult Adverse effects Affect Animals Apoptotic Behavioral Biological Blood Body Burden Brain Cell Death Cells Chronic Cognition DNA DNA Methylation Defense Mechanisms Development Developmental Process Diet Dose Environment Environmental Pollutants Epigenetic Process Exposure to Flame Retardants Gene Expression Genetic Genetic Polymorphism Homeostasis House Dust Human Human Milk Immunoprecipitation In Vitro Individual Infant Investigation Mediating Messenger RNA Methylation MicroRNAs Modeling Motor Activity Mus Neurons North America Oxidative Stress Pattern Play Regulation Reporting Rest Risk Risk Assessment Role Scientist Signal Transduction Testing Thyroid Hormones Toddler Toxic effect Wild Type Mouse base brain cell conditioning consumer product developmental neurotoxicity gene environment interaction human GCLM protein human tissue in vivo innovation neurotoxicity novel phenyl ether pollutant postnatal prenatal public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Polybrominated diphenyl ethers (PBDEs) are an important group of flame retardants, which have been widely used in a variety of consumer products. As they leach out into the environment, PBDEs have become persistent organic pollutants, and have also been detected in human blood and breast milk. Body burden of PBDEs in humans in North America is much higher than in the rest of the world, and it is highest in infants (because of exposure through breast milk) and in toddlers (because of exposure through house dust and the diet). This has raised concerns for the potential developmental toxicity and neurotoxicity of PBDEs, as animal studies have shown that exposure during the prenatal and/or postnatal periods causes long-lasting behavioral abnormalities, particularly in the domains of motor activity and cognition. Limited evidence is also suggestive of possible developmental adverse effects in humans from PBDE exposure. The mechanisms of PBDE developmental neurotoxicity are still elusive, but include potential effects on thyroid hormone homeostasis and direct effects on brain cells, particularly oxidative stress- mediated toxicity. Most mechanistic studies with PBDEs have utilized micromolar concentrations of these compounds, though levels of PBDEs in adults in the USA are in the nanomolar range. Investigations of the biological effects of low, environmentally relevant, concentrations of PBDEs, are the focus of proposed studies. The first hypothesis is that chronic exposure of mouse neurons in vitro to low concentrations of BDE-47 (chosen as a model congener) would not cause any overt toxicity in cells, but would act in a hormetic (pre-conditioning) fashion. A lo level of oxidative stress caused by BDE-47 would stimulate defense mechanisms in the cell, which would protect them from the toxicity of higher exposures. However, gene-environment interactions would play a role in such hormetic response. Indeed, we hypothesize that the hormetic response would be lost in cells from mice mimicking human polymorphisms of Gclm (glutamate cysteine ligase modifier subunit) i.e. Gclm+/- and Gclm-/- mice). The second hypothesis is that exposure of neurons in vitro to low levels of BDE-47 would result in epigenetic changes, at the level of DNA methylation and of miRNA homeostasis, which may be relevant for brain development and may result in specific changes in gene expression. Altogether, results from this R21 proposal will provide the basis for further in vivo studies to be carried out with lo doses PBDEs.

描述（由申请人提供）：多溴二苯醚（PBDE）是一类重要的阻燃剂，已广泛应用于各种消费品中。当多溴二苯醚渗入环境中时，它们已成为持久性有机污染物，并且也在人类血液和母乳中检测到。北美人类体内的多溴联苯醚负担远高于世界其他地区，其中婴儿（因为通过母乳接触）和幼儿（因为通过室内灰尘和饮食接触）最高。这引起了人们对多溴联苯醚潜在发育毒性和神经毒性的担忧，因为动物研究表明，产前和/或产后期间的接触会导致长期行为异常，特别是在运动活动和认知领域。有限的证据还表明，接触多溴联苯醚可能对人类发育产生不利影响。 PBDE 发育神经毒性的机制仍不清楚，但包括对甲状腺激素稳态的潜在影响和对脑细胞的直接影响，特别是氧化应激介导的毒性。尽管美国成年人体内的 PBDE 水平处于纳摩尔范围内，但大多数 PBDE 的机理研究都使用了这些化合物的微摩尔浓度。研究低浓度、与环境相关的多溴二苯醚的生物效应是拟议研究的重点。第一个假设是，小鼠神经元在体外长期暴露于低浓度的 BDE-47（选择作为模型同系物）不会对细胞造成任何明显的毒性，但会以毒物兴奋（预调节）方式发挥作用。 BDE-47 引起的低水平氧化应激会刺激细胞中的防御机制，从而保护它们免受较高暴露的毒性。然而，基因-环境相互作用将在这种激效反应中发挥作用。事实上，我们假设模拟人类 Gclm（谷氨酸半胱氨酸连接酶修饰剂亚基）多态性的小鼠细胞（即 Gclm+/- 和 Gclm-/- 小鼠）的细胞中会丢失毒物兴奋反应。第二个假设是，神经元在体外暴露于低水平的 BDE-47 会导致 DNA 甲基化和 miRNA 稳态水平的表观遗传变化，这可能与大脑发育相关，并可能导致基因表达的特定变化。总而言之，R21 提案的结果将为进一步使用低剂量 PBDE 进行体内研究提供基础。