Active fatty acid oxidation defines the cellular response towards reactive oxygen species

Abstract

Endocrine disrupting compounds (EDC) are ubiquitous in the human environment, displaying a highly relevant research topic. The impact of EDC on the differentiation of primitive cells, e.g. in hematopoiesis, is of particular interest. We found profound inhibitory effects of di-2-ethylhexyl phthalate (DEHP) on erythropoiesis and dendropoiesis, mediated via reactive oxygen species (ROS) generation. Neutrophil differentiation, however, was not affected by DEHP. ROS leads to a shift from glycolysis to the pentose phosphate pathway and diminishes ATP generation from glycolysis, ultimately resulting in apoptosis in both cell types. In neutrophils, ATP generation is held constant by active fatty acid oxidation (FAO), rendering these cells highly resistant against ROS. This relationship also holds true in HUVEC and HepG2 cells, also in combination with other organic peroxides. We, therefore, uncover a key mechanism for ROS quenching which further explains the distinct ROS quenching ability of different tissues.