Costa Lucio G, Pellacani Claudia, Dao Khoi, Kavanagh Terrance J, Roque Pamela J
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Department Neuroscience, University of Parma, Parma, Italy.
Department Neuroscience, University of Parma, Parma, Italy.
Neurotoxicology. 2015 May;48:68-76. doi: 10.1016/j.neuro.2015.03.008. Epub 2015 Mar 19.
Polybrominated diphenyl ethers (PBDEs), used for decades as flame retardants, have become widespread environmental contaminants. Exposure is believed to occur primarily through diet and dust, and infants and toddlers have the highest body burden, raising concern for potential developmental neurotoxicity. The exact mechanisms of PBDE neurotoxicity have not been elucidated, but two relevant modes of action relate to impairment of thyroid hormone homeostasis and to direct effects on brain cells causing alterations in signal transduction, oxidative stress and apoptotic cell death. The present study shows that BDE-47 (2,2',4,4'-tetrabromodiphenyl ether) induces oxidative stress and ensuing apoptotic cell death in mouse cerebellar granule neurons in vitro. Similarly, in vivo administration of BDE-47, according to an exposure protocol shown to induce behavioral and biochemical alterations (10mg/kg, per os on post-natal day 10), induces oxidative stress and apoptosis, without altering serum levels of thyroid hormones. The effects of BDE-47 both in vitro and in vivo were more pronounced in a mouse model lacking the modifier subunit of glutamate cysteine ligase (GCLM) which results in reduced anti-oxidant capability due to low levels of GSH. Concentrations of BDE-47 in brain were in the mid-nanomolar range. These findings indicate that effects observed with BDE-47 in vitro are also present after in vivo administration, suggesting that in addition to potential endocrine effects, which were not seen here, direct interactions with brain cells should be considered as a potential mechanism of BDE-47 neurotoxicity.
多溴二苯醚（PBDEs）作为阻燃剂已使用数十年，现已成为广泛存在的环境污染物。据信，接触主要通过饮食和灰尘发生，婴幼儿的体内负担最高，这引发了对潜在发育神经毒性的担忧。PBDE神经毒性的确切机制尚未阐明，但两种相关的作用模式与甲状腺激素稳态受损以及对脑细胞的直接影响有关，后者会导致信号转导、氧化应激和凋亡性细胞死亡发生改变。本研究表明，BDE - 47（2,2',4,4'-四溴二苯醚）在体外可诱导小鼠小脑颗粒神经元发生氧化应激及随后的凋亡性细胞死亡。同样，根据一项已证明可诱导行为和生化改变的暴露方案（出生后第10天经口给予10mg/kg）对小鼠进行体内给予BDE - 47，可诱导氧化应激和凋亡，而不会改变血清甲状腺激素水平。在缺乏谷氨酸半胱氨酸连接酶（GCLM）调节亚基的小鼠模型中，BDE - 47的体外和体内效应更为明显，由于谷胱甘肽（GSH）水平低，该模型的抗氧化能力降低。脑内BDE - 47的浓度处于中纳摩尔范围。这些发现表明，BDE - 47在体外观察到的效应在体内给药后也存在，这表明除了此处未观察到的潜在内分泌效应外，与脑细胞的直接相互作用应被视为BDE - 47神经毒性的一种潜在机制。
