Shockley Keith R, Cora Michelle C, Malarkey David E, Jackson-Humbles Daven, Vallant Molly, Collins Brad J, Mutlu Esra, Robinson Veronica G, Waidyanatha Surayma, Zmarowski Amy, Machesky Nicholas, Richey Jamie, Harbo Sam, Cheng Emily, Patton Kristin, Sparrow Barney, Dunnick June K
Biostatistics & Computational Biology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, United States.
Cellular & Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, United States.
Toxicol Lett. 2020 Oct 10;332:222-234. doi: 10.1016/j.toxlet.2020.07.016. Epub 2020 Jul 15.
The relative toxicity of three legacy and six emerging brominated flame retardants* was studied in the male Harlan Sprague Dawley rat. The hepatocellular and thyroid toxicity of each flame retardant was evaluated following five-day exposure to each of the nine flame retardants (oral gavage in corn oil) at 0.1-1000 μmol/kg body weight per day. Histopathology and transcriptomic analysis were performed on the left liver lobe. Centrilobular hypertrophy of hepatocytes and increases in liver weight were seen following exposure to two legacy (PBDE-47, HBCD) and to one emerging flame retardant (HCDBCO). Total thyroxine (TT4) concentrations were reduced to the greatest extent after PBDE-47 exposure. The PBDE-47, decaBDE, and HBCD liver transcriptomes were characterized by upregulation of liver disease-related and/or metabolic transcripts. Fewer liver disease or metabolic transcript changes were detected for the other flame retardants studied (TBB, TBPH, TBBPA-DBPE, BTBPE, DBDPE, or HCDBCO). PBDE-47 exhibited the most disruption of hepatocellular toxic endpoints, with the Nrf2 antioxidant pathway transcripts upregulated to the greatest extent, although some activation of this pathway also occurred after decaBDE, HBCD, TBB, and HCBCO exposure. These studies provide information that can be used for prioritizing the need for more in-depth brominated flame retardant toxicity studies.
在雄性哈兰·斯普拉格·道利大鼠中研究了三种传统溴化阻燃剂和六种新型溴化阻燃剂的相对毒性。在以每天0.1 - 1000 μmol/kg体重的剂量对九种阻燃剂中的每一种进行为期五天的暴露（通过玉米油口服灌胃）后，评估了每种阻燃剂对肝细胞和甲状腺的毒性。对左肝叶进行了组织病理学和转录组分析。在暴露于两种传统阻燃剂（多溴二苯醚-47、六溴环十二烷）和一种新型阻燃剂（1,2-二溴-4-(1,2-二溴乙烯基)环己烷）后，观察到肝细胞中央小叶肥大和肝脏重量增加。在暴露于多溴二苯醚-47后，总甲状腺素（TT4）浓度下降幅度最大。多溴二苯醚-47、十溴二苯醚和六溴环十二烷的肝脏转录组特征是与肝脏疾病相关和/或代谢的转录本上调。对于所研究的其他阻燃剂（四溴双酚、磷酸三(2-氯丙基)酯、双(2,3-二溴丙基)醚、双(三溴苯氧基)乙烷、1,2-二(2,4,6-三溴苯氧基)乙烷或1,2-二溴-4-(1,2-二溴乙烯基)环己烷），检测到的肝脏疾病或代谢转录本变化较少。多溴二苯醚-47对肝细胞毒性终点的干扰最大，核因子E2相关因子2（Nrf2）抗氧化途径转录本上调幅度最大，不过在十溴二苯醚、六溴环十二烷、四溴双酚和1,2-二溴-4-(1,2-二溴乙烯基)环己烷暴露后也发生了该途径的一些激活。这些研究提供了可用于确定对更深入的溴化阻燃剂毒性研究需求优先级的信息。
