The effects of combined low-dose cadmium and deltamethrin on mitochondrial bioenergetics and metabolism in human lung fibroblasts

Cadmium (Cd) is a pervasive environmental metal that bioaccumulates in humans and causes lung disease. Deltamethrin (DM) is a pyrethroid insecticide that is used widely in agriculture, commercial, and residential areas. Both Cd and DM impair mitochondrial function, but responses to combined DM plus Cd have not been studied. The purpose of this study was to test DM and Cd effects on mitochondrial metabolism, bioenergetic activities, and reactive oxidant production in human lung fibroblasts. Metabolomics analyses with liquid chromatography-high resolution mass spectrometry were used to analyze mitochondrial metabolic effects. Extracellular flux analyses were used to measure mitochondrial bioenergetics. Fluorescence cytochemistry was used to measure mitochondrial oxidant production. The results show that mitochondrial metabolic perturbations were greatest with DM plus Cd, with significant effects on the citric acid cycle, along with increased collagen amino acids, proline, and hydroxyproline, indicators of fibrotic activity. Mitochondria bioenergetics, including basal, maximal, and ATP-linked respiration, were inhibited by Cd, with greater effects due to DM and Cd plus DM. Mitochondrial superoxide production was greatest with Cd plus DM. Taken together, this study shows that low environmental levels of DM and Cd cause changes in mitochondrial bioenergetics and metabolism in human lung fibroblasts consistent with adverse effects in lung disease.