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Genotoxic risk assessment and mechanism of DNA damage induced by phthalates and their metabolites in human peripheral blood mononuclear cells.

ABSTRACT: The human genome is persistently exposed to damage caused by xenobiotics, therefore the assessment of genotoxicity of substances having a direct contact with humans is of importance. Phthalates are commonly used in industrial applications. Widespread exposure to phthalates has been evidenced by their presence in human body fluids. We have assessed the genotoxic potential of selected phthalates and mechanism of their action in human peripheral blood mononuclear cells (PBMCs). Studied cells were incubated with di-n-butyl phthalate (DBP), butylbenzyl phthalate (BBP) and their metabolites: mono-n-butylphthalate (MBP), mono-benzylphthalate (MBzP) in the concentrations range of 0.1-10 µg/mL for 24 h. Analyzed compounds induced DNA single and double strand-breaks (DBP and BBP???0.5 µg/mL, MBP and MBzP???1 µg/mL) and more strongly oxidized purines than pyrimidines. None of the compounds examined was capable of creating adducts with DNA. All studied phthalates caused an increase of total ROS level, while hydroxyl radical was generated mostly by DBP and BBP. PBMCs exposed to DBP and BBP could not completely repair DNA strand-breaks during 120 min of postincubation, in opposite to damage caused by their metabolites, MBP and MBzP. We have concluded that parent phthalates: DBP and BBP caused more pronounced DNA damage compared to their metabolites.

SUBMITTER: Sicinska P

PROVIDER: S-EPMC7814068 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Genotoxic risk assessment and mechanism of DNA damage induced by phthalates and their metabolites in human peripheral blood mononuclear cells.

Sicińska Paulina P Mokra Katarzyna K Wozniak Katarzyna K Michałowicz Jaromir J Bukowska Bożena B

Scientific reports 20210118 1

The human genome is persistently exposed to damage caused by xenobiotics, therefore the assessment of genotoxicity of substances having a direct contact with humans is of importance. Phthalates are commonly used in industrial applications. Widespread exposure to phthalates has been evidenced by their presence in human body fluids. We have assessed the genotoxic potential of selected phthalates and mechanism of their action in human peripheral blood mononuclear cells (PBMCs). Studied cells were i ...[more]

PMID: 33462290

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Project description:OBJECTIVES:Metabolic derangements in sepsis stem from mitochondrial injury and contribute significantly to organ failure and mortality; however, little is known about mitochondrial recovery in human sepsis. We sought to test markers of mitochondrial injury and recovery (mitochondrial biogenesis) noninvasively in peripheral blood mononuclear cells from patients with sepsis and correlate serial measurements with clinical outcomes. DESIGN:Prospective case-control study. SETTING:Academic Medical Center and Veterans Affairs Hospital. PATIENTS:Uninfected control patients (n = 20) and septic ICU patients (n = 37). INTERVENTIONS:Blood samples were collected once from control patients and serially with clinical data on days 1, 3, and 5 from septic patients. Gene products for HMOX1, NRF1, PPARGC1A, and TFAM, and mitochondrial DNA ND1 and D-loop were measured by quantitative reverse transcriptase-polymerase chain reaction. Proinflammatory cytokines were measured in plasma and neutrophil lysates. MEASUREMENTS AND MAIN RESULTS:Median (interquartile range) Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 21 (8) and 10 (4), respectively, and 90-day mortality was 19%. Transcript levels of all four genes in peripheral blood mononuclear cells were significantly reduced in septic patients on day 1 (p < 0.05), whereas mitochondrial DNA copy number fell and plasma D-loop increased (both p < 0.05), indicative of mitochondrial damage. D-loop content was directly proportional to tumor necrosis factor-α and high-mobility group protein B1 cytokine expression. By day 5, we observed transcriptional activation of mitochondrial biogenesis and restoration of mitochondrial DNA copy number (p < 0.05). Patients with early activation of mitochondrial biogenesis were ICU-free by 1 week. CONCLUSIONS:Our findings support data that sepsis-induced mitochondrial damage is reversed by activation of mitochondrial biogenesis and that gene transcripts measured noninvasively in peripheral blood mononuclear cells can serve as novel biomarkers of sepsis recovery.

Dataset Information

Genotoxic risk assessment and mechanism of DNA damage induced by phthalates and their metabolites in human peripheral blood mononuclear cells.

Publications

Genotoxic risk assessment and mechanism of DNA damage induced by phthalates and their metabolites in human peripheral blood mononuclear cells.

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