Increased mitochondrial content and function by resveratrol and select flavonoids protects against benzo[a]pyrene-induced bioenergetic dysfunction and ROS generation in a cell model of neoplastic transformation

Dietary polyphenols act in cancer prevention and may inhibit carcinogenesis. A possible mitochondrial me- chanism for carcinogen -induced neoplastic transformation and chemoprevention by polyphenols, however, is largely unexplored. Using the Bhas 42 cell model of carcinogen -induced neoplastic transformation, we in- vestigated benzo[a]pyrene (B[a]P) along with different polyphenols for their effects on mitochondrial content and function, and on mitochondrial and intracellular ROS generation. Bhas 42 cells were either co -treated with 5 ?M polyphenol starting 2 h before exposure to 4 ?M B[a]P for 24 or 72 h, or pre-treated with polyphenol for 24 h and removed prior to B[a]P exposure. Exposure to B[a]P decreased mitochondrial content (by 46% after 24 h and 30% after 72 h), decreased mitochondrial membrane potential and cellular ATP, and increased gen- eration of mitochondrial superoxide and intracellular ROS. Polyphenol co -treatments protected against the decreased mitochondrial content, with resveratrol being the most effective (increasing the mitochondrial content after 72 h by 75%). Measurements after 24 h of mRNA for mitochondria -related proteins and of SIRT1 enzyme activity suggested an involvement of increased mitochondrial biogenesis in the polyphenol effects. The poly - phenol co -treatments also ameliorated B[a]P-induced deficits in mitochondrial function (most strongly resver- atrol), and increases in generation of mitochondrial superoxide and intracellular ROS. Notably, 24 h pre - treatments with polyphenols strongly suppressed subsequent B[a]P-induced increases, after 24 and 72 h, in mitochondrial superoxide and intracellular ROS generation, with resveratrol being the most effective. In con- clusion, the results support a mechanism for B[a]P carcinogenesis involving impaired mitochondrial function and increased mitochondria -derived ROS, that can be ameliorated by dietary polyphenols. The evidence sup- ports an increase in mitochondrial biogenesis behind the strong chemoprevention by resveratrol, and a mi- tochondrial antioxidant effect in chemoprevention by quercetin.