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

Autor: Papaioannou N; Environmental Engineering Laboratory, Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Balkan Center, Bldg. B, 10th Km Thessaloniki-Thermi Road, 57001, Greece., Distel E; INSERM UMR-S 1124, 45 Rue des Saints Pères, 75006, Paris, France; Université de Paris, 45 Rue des Saints Pères, 75006, Paris, France., de Oliveira E; Barcelona Science Park, Proteomics Platform, Barcelona Science Park, Barcelona, Spain., Gabriel C; Environmental Engineering Laboratory, Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Balkan Center, Bldg. B, 10th Km Thessaloniki-Thermi Road, 57001, Greece., Frydas IS; Environmental Engineering Laboratory, Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Balkan Center, Bldg. B, 10th Km Thessaloniki-Thermi Road, 57001, Greece., Anesti O; HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Balkan Center, Bldg. B, 10th Km Thessaloniki-Thermi Road, 57001, Greece; Medical School, University of Crete, Heraklion, 71003, Greece., Attignon EA; INSERM UMR-S 1124, 45 Rue des Saints Pères, 75006, Paris, France; Université de Paris, 45 Rue des Saints Pères, 75006, Paris, France., Odena A; Barcelona Science Park, Proteomics Platform, Barcelona Science Park, Barcelona, Spain., Díaz R; Barcelona Science Park, Proteomics Platform, Barcelona Science Park, Barcelona, Spain; Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Aggerbeck Μ; INSERM UMR-S 1124, 45 Rue des Saints Pères, 75006, Paris, France; Université de Paris, 45 Rue des Saints Pères, 75006, Paris, France., Horvat M; Jožef Stefan Institute, Ljubljana, Slovenia., Barouki R; INSERM UMR-S 1124, 45 Rue des Saints Pères, 75006, Paris, France; Université de Paris, 45 Rue des Saints Pères, 75006, Paris, France; Service de Biochimie Métabolomique et Protéomique, Hôpital Universitaire Necker Enfants Malades, AP-HP, 75015, Paris, France., Karakitsios S; Environmental Engineering Laboratory, Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Balkan Center, Bldg. B, 10th Km Thessaloniki-Thermi Road, 57001, Greece., Sarigiannis DA; Environmental Engineering Laboratory, Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Balkan Center, Bldg. B, 10th Km Thessaloniki-Thermi Road, 57001, Greece; School for Advanced Study (IUSS), Science, Technology and Society Department, Environmental Health Engineering, Piazza Della Vittoria 15, Pavia, 27100, Italy. Electronic address: sarigiannis@auth.gr.
Jazyk: angličtina
Zdroj: Environmental research [Environ Res] 2021 Jan; Vol. 192, pp. 110041. Date of Electronic Publication: 2020 Sep 17.
DOI: 10.1016/j.envres.2020.110041
Abstrakt: This study aimed to evaluate the response of HepaRG cells after co-exposure to phthalates and heavy metals, using a high-dimensional biology paradigm (HDB). Liver is the main metabolism site for the majority of xenobiotics. For this reason, the HepaRG cell line was used as an in vitro model, and cells were exposed to two characteristic mixtures of phthalates and heavy metals containing phthalates (DEHP, DiNP, BBzP) and metals (lead, methylmercury, total mercury) in a concentration-dependent manner. The applied chemical mixtures were selected as the most abundant pollutants in the REPRO_PL and PHIME cohorts, which were studied using the exposome-wide approach in the frame of the EU project HEALS. These studies investigated the environmental causation of neurodevelopmental disorders in neonates and across Europe. The INTEGRA computational platform was used for the calculation of the effective concentrations of the chemicals in the liver through extrapolation from human biomonitoring data and this dose (and a ten-times higher one) was applied to the hepatocyte model. Multi-omics analysis was performed to reveal the genes, proteins, and metabolites affected by the exposure to these chemical mixtures. By extension, we could detect the perturbed metabolic pathways. The generated data were analyzed using advanced bioinformatic tools following the HEALS connectivity paradigm for multi-omics pathway analysis. Co-mapped transcriptomics and proteomics data showed that co-exposure to phthalates and heavy metals leads to perturbations of the urea cycle due to differential expression levels of arginase-1 and -2, argininosuccinate synthase, carbamoyl-phosphate synthase, ornithine carbamoyltransferase, and argininosuccinate lyase. Joint pathway analysis of proteomics and metabolomics data revealed that the detected proteins and metabolites, choline phosphate cytidylyltransferase A, phospholipase D3, group XIIA secretory phospholipase A2, α-phosphatidylcholine, and the a 1,2-diacyl-sn-glycero-3-phosphocholine, are responsible for the homeostasis of the metabolic pathways phosphatidylcholine biosynthesis I, and phospholipases metabolism. The urea, phosphatidylcholine biosynthesis I and phospholipase metabolic pathways are of particular interest since they have been identified also in human samples from the REPRO_PL and PHIME cohorts using untargeted metabolomics analysis and have been associated with impaired psychomotor development in children at the age of two. In conclusion, this study provides the mechanistic evidence that co-exposure to phthalates and metals disturb biochemical processes related to mitochondrial respiration during critical developmental stages, which are clinically linked to neurodevelopmental perturbations.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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