Fatty acid oxidation makes the difference: Lineage-selective disturbance by DEHP via ROS in myeloid hematopoiesis

Endocrine disrupting compounds (EDC) are found ubiquitous in the human environment, displaying a highly relevant research topic. Here, the impact of EDC on the differentiation of primitive cells, e.g. hematopoiesis, is of particular interest. We therefore assessed the impact of di-2-ethylhexyl phthalate (DEHP) on erythroid, dendritic and neutrophil differentiation and found profound inhibitory effects of DEHP on erythropoiesis and dendropoiesis, mediated via ROS generation. ROS leads to a shift from glycolysis to pentose phosphate pathway and diminishes ATP generation from glycolysis, ultimately resulting in apoptosis in both cell lines. In neutrophils, however, ATP generation is held constant by active fatty acid oxidation (FAO), rendering these cells highly resistant against ROS. As we could verify this relationship also in other tissues and, furthermore, with other compounds, we propose this to be a general mechanism. Therefore, future toxicological studies should also consider FAO activity to be involved in ROS quenching capability.