Biotransformation and oxidative stress responses in rat hepatic cell-line (H4IIE) exposed to organophosphate esters (OPEs)

Organophosphate esters (OPEs) are frequently used as replacements for the banned polybrominated diphenyl ether (PBDEs). Since OPEs are structurally similar to organophosphate pesticides, exposure and toxicity of these compounds is of significant societal and scientific interest. Cytotoxicity (MTT), biotransformation (cyp1a1) and oxidative stress responses (gpx1, gr, gsta2, cat) were investigated in H4IIE cells exposed for 48 h to four different OPEs (tributyl phosphate (TBP), tris(2-butoxyethyl) phosphate (TBOEP), tris-(2-chloroethyl) phosphate (TCEP) and triphenyl phosphate (TPP)). MTT assay revealed a dose-dependent decrease of cell viability following exposure to TBP, TBOEP, TCEP and TPP. Cells treated with TBP and TBOEP exhibited significant increase of cyp1a1 at the highest tested concentration, at transcriptional and enzymatic (MROD) levels. Significant increases of oxidative stress markers were observed after exposure to TBP and TBOEP. On the other hand, cells treated with TCEP and TPP showed opposite trends between cyp1a1 mRNA and enzymatic activities. Furthermore, exposure to TCEP increased gst and cat especially at the highest concentration tested, whereas TPP produced significant changes only for gr and cat at the highest concentration. In conclusion, OPEs produced compound and concentration-specific effects on biotransformation and oxidative stress processes. Overall, our results suggest the participation of multiple mechanisms of detoxification in defense of OPEs exposure with different modes of action depending on their chemical structure.