Mechanistic Study on Oxidative DNA Damage and Modifications by Haloquinoid Carcinogenic Intermediates and Disinfection Byproducts

Abstract

Haloquinones (XQs) are a group of carcinogenic intermediates of the haloaromatic environmental pollutants and newly identified chlorination disinfection byproducts (DBPs) in drinking water. The highly reactive hydroxyl radicals/alkoxyl radicals and quinone enoxy/ketoxy radicals were found to arise in XQs and H2O2 or organic hydroperoxides system, independent of transition-metal ions. However, it was not clear whether these haloquinoid carcinogens and hydroperoxides can cause oxidative DNA damage and modifications, and if so, what are the underlying molecular mechanisms. We found that 8-oxodeoxyguanosine (8-oxodG), DNA strand breaks, and three methyl oxidation products could arise when DNA was treated with tetrachloro-1,4-benzoquinone and H2O2 via a metal-independent and intercalation-enhanced oxidation mechanism. Similar effects were observed with other XQs, which are generally more efficient than the typical Fenton system. We further extended our studies from isolated DNA to genomic DNA in living cells. We also found that potent oxidation of DNA to the more mutagenic imidazolone dIz could be induced by XQs and organic hydroperoxides such as t-butylhydroperoxide or the physiologically relevant hydroperoxide 13S-hydroperoxy-9Z,11E-octadecadienoic acid via an unprecedented quinone-enoxy radical-mediated mechanism. These findings should provide new perspectives to explain the potential genotoxicity, mutagenesis, and carcinogenicity for the ubiquitous haloquinoid carcinogenic intermediates and DBPs.

Theoretical Study on the Reaction between Carcinogenic 2,5-Dichloro-1,4-benzoquinone and tert-Butyl Hydroperoxide: Self-Catalysis and Water Catalysis

“…These radicals can cause breaks or mutations of DNA strands and result in cellular aging and cancer. 15,16 This type of radical In this study, our initial theoretical calculations suggested that the reaction of DCBQ and t-BuOOH encounters a high energy barrier and is energetically infeasible. An analogous high barrier has also been reported for the reaction between tetrachloro-1,4-benzoquinone (TCBQ) and neutral hydrogen peroxide (H 2 O 2 ).…”

“…CBQ-O • then isomerizes to form quinone ketoxy radical • CBQO (see Scheme ). These radicals can cause breaks or mutations of DNA strands and result in cellular aging and cancer. , This type of radical generation mechanism may partly explain the carcinogenicity of halogenated aromatic compounds. Until now, the experimentally speculated reaction mechanism of DCBQ and t -BuOOH has not yet been confirmed by theoretical calculations.…”

Elimination and Redistribution of Intracellular and Extracellular Antibiotic Resistance Genes in Water and Wastewater Disinfection Processes: A Review

“…In addition to disinfectants, the formed halogenated DBPs such as HAAs and haloacetonitriles could also select bacteria harboring iARGs. − The ARGs encoding multidrug resistance in Pseudomonas aeruginosa increased by 1.49- to 2.92-fold after exposing to dibromoacetic acid . It was reported that the disinfectants and halogenated DBPs at both subminimum inhibitory concentrations (MICs) and above-MICs could select bacteria harboring iARGs with different mechanisms. , Sub-MIC levels of disinfectants or halogenated DBPs induce selection via enhanced horizontal gene transfer and cumulative mutations, which is associated with the generation of intracellular ROS. − Above-MIC disinfectants or halogenated DBPs cause mutations and/or simultaneously enrich the pre-existing antibiotic resistance mutations with washing out of the susceptible species, which is ascribed to the similar resistance mechanisms (e.g., efflux pump) toward antibiotics and disinfectants or DBPs. − …”