Organophosphate flame retardants induce oxidative stress and Chop/Caspase 3-related apoptosis via Sod1/p53/Map3k6/Fkbp5 in NCI-1975 cells

Organophosphate flame retardants (OPFRs) have been ubiquitously detected in dust and air which could cause damage to human health through inhalation. Currently the understanding of their adverse effects and potential mechanisms on the lung are still limited. In this study, human non-small cell lung cancer cell line NCI-H1975 was used to investigate the cytotoxicity, oxidative stress, cellular apoptosis of 9 typical OPFRs with concentrations varied from 0 to 200 μM, and their toxic mechanism associated with molecular structure was compared. After 72 h, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) displayed the highest cytotoxicity, followed by 2-ethylhexyl diphenyl phosphate (EHDPP), tris(2-butoxyethyl) phosphate (TBOEP) and tris(2-chloroisopropyl) phosphate (TCIPP), while tris(2-chloroethyl) phosphate (TCEP) and tris(2-ethylhexyl) phosphate (TEHP) exhibited the least suppression on cell viability. These results indicated that the variation of cytotoxicity on OPFRs could only be partially explained by their ester linkage. Moreover, the overexpression of intracellular reactive oxygen species (ROS), free Ca2+ and cellular apoptosis suggested that exposure to OPFRs can lead to apoptosis related to oxidative stress. Six genes associated with oxidative stress and apoptosis were upregulated dramatically compared with the control, demonstrating OPFRs induced Chop/Caspase 3-related apoptosis by activating Sod1/p53/Map3k6/Fkbp5 expression in NCI-H1975 cells. This is the first study to investigate cytotoxicity and related mechanism on commonly-used OPFRs in NCI-H1975 cells.