Cytotoxicity, Mitochondrial Impairment, Dna Damage And Associated Mechanisms Induced By Tris(1,3-Dichloro-2-Propyl) Phosphate And Tris (2-Butoxyethyl) Phosphate In A549 Cells

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and tris(2-butoxyethyl) phosphate (TBOEP), two of the most widely applied phosphorus-containing flame retardants (PFRs), have been shown to have adverse effects in differ-ent organisms, but their underlying toxicity mechanism remains to be elucidated. In the present study, the toxico-logical effects of TDCPP and TBOEP on human lung carcinoma (A549) cells and their associated mechanisms were investigated at the cellular, organelle and transcriptional levels. Cell Counting Kit-8 assay results showed that TDCPP and TBOEP reduced cell viability in a concentration-dependent manner. High-content screening assays showed that both PFRs caused mitochondrial impairment at the organelle level, decreasing the mitochondrial mem-brane potential and increasing the mitochondrial mass, and leading to increased cell cycle arrest-associated DNA damage that decreased the ratio of cells in S phase and increased the DNA content. In addition, oxidative stress was identified as a possible initial mechanistic process underlying PFR-induced cytotoxicity and mitochondrial im-pairment, as evidenced by intracellular reactive oxygen species and mitochondrial superoxide overproduction from environmentally relevant concentrations. Furthermore, p53 activation was shown to be involved in regulating DNA damage after A549 cell exposure to TDCPP and TBOEP. Quantitative PCR analyses showed that TDCPP and TBOEP triggered p53/p21-mediated cell cycle arrest pathways, indicating that these PFRs can activate p53, and promote as-sociated functional repair. However, the p53/bax-mediated apoptosis pathway was not activated following exposure to PFRs at specific concentrations. Our results showed that TDCPP and TBOEP can cause cytotoxicity, mitochondrial impairment and cell cycle arrest-associated DNA damage in A549 cells, suggesting that oxidative stress is the initial molecular event by which these adverse outcomes are induced. (c) 2021 Elsevier B.V. All rights reserved.