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

描述（由申请人提供）：多溴联苯醚（PBDEs）是一类重要的阻燃剂，已广泛应用于各种消费品中。随着多溴二苯醚渗入环境，它们已成为持久性有机污染物，在人类血液和母乳中也被检测到。多溴二苯醚在北美的人体负担远高于世界其他地区，在婴儿（因为通过母乳接触）和幼儿（因为通过室内灰尘和饮食接触）中是最高的。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/或产后暴露于多溴二苯醚会导致长期的行为异常，特别是在运动活动和认知领域。有限的证据也提示多溴二苯醚暴露可能对人类发育产生不利影响。多溴二苯醚的发育神经毒性机制尚不明确，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。大多数多溴二苯醚的机理研究都使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。对低的、与环境有关的多溴二苯醚浓度的生物效应的调查是拟议研究的重点。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，但会以一种激效（预处理）的方式起作用。由BDE-47引起的低水平氧化应激会刺激细胞中的防御机制，从而保护细胞免受高暴露的毒性。然而，基因与环境的相互作用可能在这种致敏反应中起作用。事实上，我们假设在模拟人类Gclm（谷氨酸半胱氨酸连接酶修饰子亚基）多态性的小鼠（即Gclm+/-和Gclm-/-小鼠）的细胞中，这种致热反应将会丢失。第二种假设是，体外培养的神经元暴露于低水平的BDE-47会导致表观遗传变化，在DNA甲基化和miRNA稳态水平上，这可能与大脑发育有关，并可能导致基因表达的特异性变化。总之，R21提案的结果将为进一步开展低剂量多溴二苯醚的体内研究提供基础。

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.