Transcriptomic Analysis of the Differential Nephrotoxicity of Diverse Brominated Flame Retardants in Rat and Human Renal Cells.

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 IC50s 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.

Cellular and Molecular Mechanisms of Kidney Toxicity.

Toxicant-induced acute kidney injury is responsible for millions of deaths each year. An underlying cause of toxicant-induced acute kidney injury is renal cell death. As such, understanding the mechanisms by which toxicants cause renal cell death can aid the development of targeted therapies for the prevention and treatment of kidney disease. Accordingly, this article focuses on cellular and molecular mechanisms of nephrotoxicity. This article describes specific factors that make the kidney vulnerable to toxicants. Selective transporters and enzymes that are involved in toxicant uptake and metabolism in kidney cells, respectively, are highlighted. The role of reactive oxygen species in nephrotoxicity is discussed, followed by a review of the types of cell death pathways induced in renal cells after toxicant exposure, with a particular emphasis on the role of signaling pathways. Roles for the mitochondria, endoplasmic reticulum, and nucleus in renal cell death signaling pathways are discussed, and current challenges in the field are reviewed.