Brominated flame retardants (BFRs) are added to household products to reduce their flammability. BFRs are persistent in the environment and in humans, and consequently, 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 IC50s after 48 hour exposure. BFRs also had chemical- and cell-dependent effects on apoptosis as measured by increases in annexin V and PI (propidium iodide) 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 9 differentially expressed genes in rat cells and 5 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. By highlighting potentially translational mechanisms between rat and human renal cells, this study motivates future in vivo studies on the mechanisms of BFR nephrotoxicity. It also motivates future studies that explore how distinct chemical structures produce distinct mechanisms of nephrotoxicity. Such studies will advance our knowledge of BFR nephrotoxicity and hasten the development of safer BFRs.
