Multi-omics analysis reveals that co-exposure to phthalates and metals disturbs urea cycle and choline metabolism

This study aimed to evaluate the response of HepaRG cells after co-exposure phthalates and heavy metals, using a high-dimensional biology paradigm (HDB). Liver is main metabolism site for majority xenobiotics. For this reason, cell line was used as an in vitro model, were exposed two characteristic mixtures metals containing (DEHP, DiNP, BBzP) (lead, methylmercury, total mercury) concentration-dependent manner. The applied chemical selected most abundant pollutants REPRO_PL PHIME cohorts, which studied exposome-wide approach frame EU project HEALS. These studies investigated environmental causation neurodevelopmental disorders neonates across Europe. INTEGRA computational platform calculation effective concentrations chemicals liver through extrapolation from human biomonitoring data dose (and ten-times higher one) hepatocyte model. Multi-omics analysis performed reveal genes, proteins, metabolites affected by exposure these mixtures. By extension, we could detect perturbed metabolic pathways. generated analyzed advanced bioinformatic tools following HEALS connectivity multi-omics pathway analysis. Co-mapped transcriptomics proteomics showed that leads perturbations urea cycle due differential expression levels arginase-1 -2, argininosuccinate synthase, carbamoyl-phosphate ornithine carbamoyltransferase, lyase. Joint metabolomics revealed detected proteins metabolites, choline phosphate cytidylyltransferase A, phospholipase D3, group XIIA secretory A2, ?-phosphatidylcholine, 1,2-diacyl-sn-glycero-3-phosphocholine, are responsible homeostasis pathways phosphatidylcholine biosynthesis I, phospholipases metabolism. urea, I particular interest since they have been identified also samples cohorts untargeted associated with impaired psychomotor development children at age two. In conclusion, provides mechanistic evidence disturb biochemical processes related mitochondrial respiration during critical developmental stages, clinically linked perturbations.