Chlorinated organophosphorus flame retardants-induced mitochondrial abnormalities and the correlation with progesterone production in mLTC-1 cells

Environmental monitoring data have indicated that three chlorinated organophosphorus flame retardants (Cl-OPFRs), including tris(2-chloroethyl)-phosphate (TCEP), tris(2-chloropropyl)-phosphate (TCPP), and tris(1,3-dichloro-2-propyl)-phosphate (TDCPP) are the predominant chemicals in various environmental matrices and exhibit reproductive endocrine disrupting activities. Currently, mitochondrial abnormality is a new paradigm for evaluating chemical-mediated cell dysfunction. However, a comprehensive correlation between these two aspects of Cl-OPFRs remains unclear. In this research, the effects of TCEP, TCPP, and TDCPP on progesterone production and mitochondrial impairment were investigated by using mouse Leydig tumor cells (mLTC-1). The half maximal inhibitory concentration (IC50) values at 48 h exposure indicated that the rank order of anti-androgenic activity was TDCPP > TCPP. Whereas, TCEP exhibited elevation of progesterone production. At concentrations close to IC50 of progesterone production by TCPP and TDCPP, the elevation of intracellular reactive oxygen species (ROS), depletion of mitochondrial membrane potential (MMP), reduction of cellular adenosine triphosphate (ATP) content, and alteration of mitochondrial structures was observed. In addition, the expression of main genes related to progesterone synthesis was dramatically down-regulated by TCPP and TDCPP treatments. These results imply that the inhibition effect of TCPP and TDCPP on progesterone production might be related to mitochondrial damage and down-regulated steroidogenic genes.