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Connections between the mixture containing bis(2- ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bisphenol A (BPA) and liver injury were explored through in silico investigation and 2 in vivo models. Comparative Toxicogenomics Database (CTD), ShinyGO, ToppCluster and Cytoscape were used for bioinformatic analysis. In vivo subacute study was performed on rats - five groups (n = 6): (1) Control: corn oil, (2) DEHP: 50 mg/kg b.w./day, (3) DBP: 50 mg/kg b.w./day, (4) BPA: 25 mg/kg b.w./day, (5) MIX: DEHP + DBP + BPA. Zebrafish embryos were exposed to the investigated substances in different doses, singularly and combined (binary and ternary mixtures). Liver injury was linked to 75 DEHP, DBP, and BPA genes, mostly connected to inflammation/oxidative stress. In rats, significant alterations in redox status/bioelements and pathohistology were most notable or exclusively present in MIX (probable additive effects). BPA decreased liver area (LA) index in dose-dependent manner. DEHP (< 2 µg/mL) and DBP (≤ 5 µg/mL) reduced LA values, while their higher doses increased LA index. The effect of DBP in binary mixtures led to a lethal outcome at the two highest concentrations, while the hepatotoxicity of DEHP/DBP/BPA mixture was dictated by BPA (confirmed by the benchmark dose analysis). [Display omitted] • Oxidative stress and inflammation – the most important mechanisms. • Changes in rat liver – most prominent/present only in the MIX group. • Redox status and bioelements changes – most prominent/present only in the MIX group. • Zebrafish: DBP in binary mixtures – lethal outcome at two highest concentrations. • Zebrafish: hepatotoxicity of DEHP/DBP/BPA mixture dictated by BPA. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the mechanisms of bis(2- ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bisphenol A (BPA) mixture-induced asthma development and test probiotic as a potential positive intervention. Comparative Toxicogenomics Database (CTD) and ToppGene Suite were used as the main tools for in silico analysis. In vivo 28-day experiment was conducted on rats - seven groups (n = 6): (1) Control: corn oil, (2) P: probiotic (8.78 * 108 CFU/kg/day); (3) DEHP: 50 mg/kg b.w./day, (4) DBP: 50 mg/kg b.w./day, (5) BPA: 25 mg/kg b.w./day; (6) MIX: DEHP + DBP + BPA; (7) MIX + P. Lungs, thymus and kidneys were extracted and prepared for redox status and essential metals analysis. By conducting additional in vitro experiment, probiotic phthalate and BPA binding ability was explored. There were 24 DEHP, DBP and BPA asthma-related genes, indicating the three most probable mechanisms - apoptosis, inflammation and oxidative stress. In vivo experiment confirmed that significant changes in redox status/essential metal parameters were either prominent, or only present in the MIX group, indicating possible additive effects. In vitro experiment confirmed the ability of the multy-strain probiotic to bind DEHP/DBP/BPA mixture, while probiotic administration ameliorated mixture-induced changes in rat tissue. [Display omitted] • MIX (DEHP + DBP + BPA): 24 mutual genes connected with asthma development. • Apoptosis, inflammation and oxidative stress – the most probable mechanisms. • Redox status and bioelements changes – most prominent/present only in the MIX group. • Multi-strain probiotic bound 29.25, 29.04 and 41.75% for DEHP, DBP and BPA. • Probiotic mitigated MIX-induced changes in rat lung, thymus and kidney tissue. [ABSTRACT FROM AUTHOR]

Linkage between bis(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and bisphenol A (BPA) co-exposure and type 2 diabetes mellitus (T2DM), as well as ability of multi-strained probiotic to reduce DEHP, DBP and BPA mixture-induced oxidative damage in rat pancreas were investigated. The Comparative Toxicogenomics Database, Cytoscape software and ToppGene Suite were used for data-mining. Animals were sorted into seven groups (n = 6): (1) Control group: corn oil, (2) P: probiotic: Saccharomyces boulardii + Lactobacillus rhamnosus + Lactobacillus plantarum LP 6595 + Lactobacillus plantarum HEAL9; (3) DEHP: 50 mg/kg b.w./day, (4) DBP: 50 mg/kg b.w./day, (5) BPA: 25 mg/kg b.w./day, and (6) MIX: 50 mg/kg b.w./day DEHP + 50 mg/kg b.w/day DBP + 25 mg/kg b.w./day BPA; (7) MIX + P. Rats were sacrificed after 28 days of oral exposure. In silico investigation highlighted 44 DEHP, DBP and BPA mutual genes linked to the T2DM, while apoptosis and oxidative stress were highlighted as the main mechanisms of DEHP, DBP and BPA mixture-linked T2DM. In vivo experiment confirmed the presence of significant changes in redox status parameters (TOS, SOD and SH groups) only in the MIX group, indicating possible additive effects, while probiotic ameliorated mixture-induced redox status changes in rat pancreatic tissue. [Display omitted] • MIX (DEHP, DBP and BPA): 44 mutual genes linked to T2DM. • Apoptosis and oxidative stress – the most probable mechanisms of MIX-linked T2DM. • Significant redox status parameters changes (TOS, SOD and SH) only in the MIX group. • Polybiotic ameliorated MIX-induced redox status changes in rat pancreatic tissue. [ABSTRACT FROM AUTHOR]