Abstract
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.
Highlights
The enrichment of genes associated with the coagulation cascade, complement cascade, and cytokine-related pathways was reported in BFRs include polybrominated diphenyl ether number 47 (BDE-47)-treated mouse adipose tissue and in tetrabromobisphenol A (TBBPA)-treated human bronchial epithelial cells [19,20]
Cells were treated for 24 h with each Brominated flame retardants (BFRs) at the IC50 calculated from the MTT assay or with an equivalent volume of DMSO
This study compares the molecular mechanisms of BFR toxicity in rat and human kidney cells after acute exposure to three BFRs for the first time
Summary
Food Safety Authority (EFSA), Health Canada, and US Environmental Protection Agency (US EPA) may be inaccurate Despite their marketed purpose of protecting the public, BFRs have become famous for their toxic effects on humans and wildlife [5]. In response to the EPA’s call, a growing body of research links BFRs to toxicity in several target organs, including the kidney These studies report nephrotoxicity at doses ranging between 1.2–600 mg/kg and at time points ranging from 20 days to 2 years in rats and mice [10,11,12,13,14,15]. Analysis at time points prior to changes in cell morphology and MTT staining Data from these studies will guide future studies concerning the molecular mechanisms of BFR nephrotoxicity, as well as the use of rodents for assessing the risk of BFRs to human health
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