Cantón Rocío F, Peijnenburg Ad A C M, Hoogenboom Ron L A P, Piersma Aldert H, van der Ven Leo T M, van den Berg Martin, Heneweer Marjoke
Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, NL-3508 TD, Utrecht, The Netherlands.
Toxicol Appl Pharmacol. 2008 Sep 1;231(2):267-72. doi: 10.1016/j.taap.2008.04.013. Epub 2008 Apr 27.
Hexabromoyclododecane (HBCD), used as flame retardant (FR) mainly in textile industry and in polystyrene foam manufacture, has been identified as a contaminant at levels comparable to other brominated FRs (BFRs). HBCD levels in biota are increasing slowly and seem to reflect the local market demand. The toxicological database of HBCD is too limited to perform at present a solid risk assessment, combining data from exposure and effect studies. In order to fill in some gaps, a 28-day HBCD repeated dose study (OECD407) was done in Wistar rats. In the present work liver tissues from these animals were used for gene expression profile analysis. Results show clear gender specificity with females having a higher number of regulated genes and therefore being more sensitive to HBCD than males. Several specific pathways were found to be affected by HBCD exposure, like PPAR-mediated regulation of lipid metabolism, triacylglycerol metabolism, cholesterol biosynthesis, and phase I and II pathways. These results were corroborated with quantitative RT-PCR analysis. Cholesterol biosynthesis and lipid metabolism were especially down-regulated in females. Genes involved in phase I and II metabolism were up-regulated predominantly in males, which could explain the observed lower HBCD hepatic disposition in male rats in this 28-day study. These sex-specific differences in gene expression profiles could also underlie sex-specific differences in toxicity (e.g. decreased thyroid hormone or increased serum cholesterol levels). To our knowledge, this is the fist study that describes the changes in rat hepatic gene profiles caused by this commonly used flame retardant.
六溴环十二烷（HBCD）主要用作纺织工业和聚苯乙烯泡沫塑料制造中的阻燃剂，已被确定为一种污染物，其含量与其他溴化阻燃剂（BFRs）相当。生物群中的HBCD含量正在缓慢增加，似乎反映了当地市场需求。HBCD的毒理学数据库目前过于有限，无法结合暴露和效应研究的数据进行可靠的风险评估。为了填补一些空白，在Wistar大鼠中进行了一项为期28天的HBCD重复剂量研究（OECD407）。在本研究中，使用这些动物的肝脏组织进行基因表达谱分析。结果显示出明显的性别特异性，雌性动物中受调控的基因数量更多，因此比雄性动物对HBCD更敏感。发现几条特定的途径受到HBCD暴露的影响，如PPAR介导的脂质代谢调控、三酰甘油代谢、胆固醇生物合成以及I相和II相途径。这些结果通过定量RT-PCR分析得到了证实。胆固醇生物合成和脂质代谢在雌性动物中尤其下调。参与I相和II相代谢的基因在雄性动物中主要上调，这可以解释在这项为期28天的研究中观察到的雄性大鼠肝脏中HBCD处置较低的现象。基因表达谱中的这些性别特异性差异也可能是毒性性别特异性差异的基础（如甲状腺激素降低或血清胆固醇水平升高）。据我们所知，这是第一项描述这种常用阻燃剂引起大鼠肝脏基因谱变化的研究。
