Tris(2-chloroisopropyl) phosphate (TCPP) decreases CYP1A1, CYP1A2, and CYP1B1/CYP2B expression and activities through potential interactions between AhR and NRF2 pathways in the HepG2 cell line

Tris(2-chloropropyl) phosphate (TCPP) is a flame retardant used in various products. Since it is not chemically bound to polymers, it easily migrates into the environment and has been detected in water, soil, and air. Additionally, TCPP can bioaccumulate in living organisms. Although suspected to be a carcinogen and endocrine disruptor, its cytotoxic properties and potential carcinogenic mechanisms remain largely unknown. This study aimed to elucidate the effects of TCPP on the HepG2 cell line, particularly its impact on CYP enzyme expression and activity. Cells were exposed to increasing TCPP concentrations (1 nM-100 μM) for 24 and 48 h. Our results show that TCPP, at any tested concentration, did not affect lactate dehydrogenase release or resazurin reduction. However, at 50 and 100 μM, it increased reactive oxygen species production. Moreover, after 48 h, TCPP (100 nM-100 μM) enhanced caspase-3 activity. This is the first study suggesting that, despite probable aryl hydrocarbon receptor (AhR) pathway activation, TCPP (1-10 μM) decreases CYP1A1, CYP1A2, and CYP1B1/CYP2B expression and activity in HepG2 cells after 48 h. Given the crucial role of CYP enzymes in detoxification, their inhibition may have serious health implications. AhR, PPARγ, and CYP enzymes regulate fatty acid, steroid hormone, vitamin, and melatonin synthesis. Our findings also indicate that TCPP increases lipid accumulation in HepG2 cells, likely due to CYP disruption. Therefore, TCPP may function as an endocrine disruptor.