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

说明书(申请人提供)：多溴二苯醚(PBDEs)是一类重要的阻燃剂，已广泛应用于各种消费品中。随着它们渗出到环境中，多溴二苯醚已成为持久性有机污染物，在人类血液和母乳中也检测到了这些污染物。北美人类的多溴二苯醚的身体负担比世界其他地区高得多，婴儿(因为通过母乳接触)和蹒跚学步的儿童(由于通过室内灰尘和饮食接触)的负担最高。这引起了人们对多溴二苯醚潜在的发育毒性和神经毒性的关注，因为动物研究表明，在产前和/或出生后暴露会导致长期的行为异常，特别是在运动活动和认知领域。有限的证据也表明，接触多溴二苯醚可能会对人类的发育产生不利影响。多溴联苯醚的发育神经毒性机制尚不清楚，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。大多数关于多溴二苯醚的机理研究都利用了这些化合物的微摩尔浓度，尽管美国成年人的多溴二苯醚水平在纳摩尔范围内。对低浓度、与环境相关的多溴二苯醚的生物效应的调查是拟议研究的重点。第一种假设是，小鼠神经元在体外长期暴露于低浓度的BDE-47(被选为模型同系物)不会对细胞造成任何明显的毒性，但会起到刺激(预适应)的作用。由BDE-47引起的低水平的氧化应激将刺激细胞中的防御机制，这将保护它们免受更高暴露的毒性。然而，基因-环境的相互作用将在这种兴奋反应中发挥作用。事实上，我们假设，来自模仿人类GCLM(谷氨酸半胱氨酸连接酶修饰亚单位)多态的小鼠的细胞将失去兴奋反应，即GCLM/-和GCLM-/-小鼠)。第二个假设是，体外培养的神经元暴露于低水平的BDE-47会导致DNA甲基化和miRNA动态平衡水平的表观遗传学变化，这可能与大脑发育有关，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多溴二苯醚进行体内研究提供基础。

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.