Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA.
Department of Environmental and Global Health and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611, USA.
Int J Mol Sci. 2021 Sep 17;22(18):10044. doi: 10.3390/ijms221810044.
Brominated flame retardants (BFRs) are environmentally persistent, are detected in humans, and some have been banned due to their potential toxicity. BFRs are developmental neurotoxicants and endocrine disruptors; however, few studies have explored their potential nephrotoxicity. We addressed this gap in the literature by determining the toxicity of three different BFRs (tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCD), and tetrabromodiphenyl ether (BDE-47)) in rat (NRK 52E) and human (HK-2 and RPTEC) tubular epithelial cells. All compounds induced time- and concentration-dependent toxicity based on decreases in MTT staining and changes in cell and nuclear morphology. The toxicity of BFRs was chemical- and cell-dependent, and human cells were more susceptible to all three BFRs based on ICs after 48 h exposure. BFRs also had chemical- and cell-dependent effects on apoptosis as measured by increases in annexin V and PI staining. The molecular mechanisms mediating this toxicity were investigated using RNA sequencing. Principal components analysis supported the hypothesis that BFRs induce different transcriptional changes in rat and human cells. Furthermore, BFRs only shared nine differentially expressed genes in rat cells and five in human cells. Gene set enrichment analysis demonstrated chemical- and cell-dependent effects; however, some commonalities were also observed. Namely, gene sets associated with extracellular matrix turnover, the coagulation cascade, and the SNS-related adrenal cortex response were enriched across all cell lines and BFR treatments. Taken together, these data support the hypothesis that BFRs induce differential toxicity in rat and human renal cell lines that is mediated by differential changes in gene expression.
溴化阻燃剂（BFRs）在环境中具有持久性，在人类体内被检测到，并且由于其潜在的毒性，其中一些已经被禁止使用。BFRs 是发育神经毒物和内分泌干扰物；然而，很少有研究探讨其潜在的肾毒性。我们通过确定三种不同的 BFR（四溴双酚 A（TBBPA）、六溴环十二烷（HBCD）和四溴二苯醚（BDE-47））在大鼠（NRK 52E）和人（HK-2 和 RPTEC）肾小管上皮细胞中的毒性，填补了这一文献空白。所有化合物均基于 MTT 染色减少和细胞及核形态变化，诱导出时间和浓度依赖性毒性。BFR 的毒性具有化学和细胞依赖性，并且基于 48 小时暴露后的 IC，人细胞对所有三种 BFR 更为敏感。BFRs 还对细胞凋亡产生化学和细胞依赖性影响，如 Annexin V 和 PI 染色增加所测。使用 RNA 测序研究了介导这种毒性的分子机制。主成分分析支持 BFRs 在大鼠和人细胞中诱导不同转录变化的假设。此外，BFRs 在大鼠细胞中仅共享 9 个差异表达基因，在人细胞中共享 5 个差异表达基因。基因集富集分析表明，化学和细胞依赖性影响；然而，也观察到一些共同之处。即，与细胞外基质周转、凝血级联和 SNS 相关的肾上腺皮质反应相关的基因集在所有细胞系和 BFR 处理中均得到富集。总之，这些数据支持 BFRs 在大鼠和人肾细胞系中诱导不同毒性的假设，这是由基因表达的差异变化介导的。
