Metabolic pathway analysis in HepG2 cells exposed to organoclorines using null diffusion-based enrichment

Abstract

Introduction: organochlorines are a group of organic pesticides developed to control insect plagues, but with a relevant impact for human health. Intoxication caused by organochlorines can cause serious health compromises that can lead to death. However, the organochlorines molecular mechanism remains unclear. Therefore, researching about this topic is necessary to propose new therapeutic strategies. This study presents a bioinformatics approach to elucidate the metabolic pathways involved in organochlorines exposure using strategies based in support vector machines with recursive feature elimination (SVM—RFE) followed by an enrichment pathway analysis with null-diffusion. Methods: five groups of HepG2 cells were exposed to aldrin, DDT, endosulfan, lindane, and a mixture of them. A control group with dimethyl sulfoxide was included. A metabolomic analysis was done using GC/MS-TOF, followed by SVM-RFE and a pathway analysis using FELLA in order to identify relevant metabolites and metabolic pathways affected. Genes reported by FELLA were introduced in gene ontology platform (GO) to estimate cellular components where reactions associated to organochlorines occur. Results: 153 metabolites were identified in metabolomic analysis. SVM-RFE was trained with the datasets and the top ten metabolites for each organochlorine were determined. Pentose phosphate and the central carbon metabolism in cancer were identified by FELLA as common pathways for all organochlorines. Alanine, aspartate, and glutamate metabolism pathways were suggested for aldrin, DDT, and endosulfan. Taurine and hypotaurine metabolism for lindane, and citrate cycle for the organochlorine’s mixture. GO analysis proposed to cytosol and exosomes as the cellular components where the pathways take place. Conclusions: the pathway analysis with FELLA suggests an impact in energy production and some amino acid synthesis pathways occasioned by the organochlorines exposure.