A multi-level approach to study the metabolic effects of chronic exposure to Aldrin in prostate cancer cells

Abstract Despite numerous studies support a dose-effect relation between Endocrine disruptors (EDs) and tumor progression and malignancy, the effects of chronic exposure to non-lethal concentrations of EDs in cancer remains unknown. Previous studies demonstrated induction of the malignant phenotype in DU145 prostate cancer (PCa) cells after chronic exposure to Aldrin (an ED). However, the mechanisms underlying this process remain limited. Here, two complementary computational approaches to investigate the molecular processes involved in the observed malignancy acquisition in Pca are applied. Firstly, the metabolic reprogramming associated to the chronic exposure to Aldrin in DU145 cells was studied by integrating transcriptomics and metabolomics via constraint-based metabolic modeling. Secondly, Gene Set Enrichment Analysis was applied to determine: i) altered regulatory pathways and ii) correlation of changes in the transcriptomic profile between the DU145 Aldrin-exposed cells and tumor progression in different tumor types.The experimentally validated predictions unveiled a dis-regulation in metabolic and regulatory pathways, modifying the triacylglyceride/cholesterol ratio in Aldrin-exposed cells, which is associated with the malignant phenotype reported in Aldrin-exposed cells.This approach can be applied to study the molecular mechanisms triggered by the chronic exposure to sub-lethal concentration of other pollutants ina variety of diseases with potential clinical and environmental applications.