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Progress in Chemistry 2022, Vol. 34 Issue (1): 227-236 DOI: 10.7536/PC210443 Previous Articles   

• Review •

Mechanism Investigation on DNA Damage Induced by Carcinogenic Haloquinoid Disinfection Byproducts

Benzhan Zhu1,2(), Jing Zhang1,2, Miao Tang1,2, Chunhua Huang1,3, Jie Shao1,2()   

  1. 1 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085,China
    2 University of Chinese Academy of Sciences, Beijing 100049, China
  • Received: Revised: Online: Published:
  • Contact: Benzhan Zhu, Jie Shao
  • Supported by:
    Strategic Priority Research Program Chinese Academy Sciences(XDB14030100); from "0" to "1" Original Innovation Project of the Basic Frontier Science Research Program of the Chinese Academy of Sciences(ZDBS-LY-SLH027); Natianal Natural Science Foundation of China(21976200); Natianal Natural Science Foundation of China(21207150); Natianal Natural Science Foundation of China(21836005); Natianal Natural Science Foundation of China(21621064); Natianal Natural Science Foundation of China(21321004); Young Scientist Foundation of Research Center for Eco-Environmental Sciences(RCEES-QN-20130052F)
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Halobenzoquinones (HBQs) are a class of toxic intermediates of the haloaromatic persistent organic pollutants and newly identified chlorination disinfection byproducts in drinking water and swimming pool water. The highly reactive hydroxyl/alkoxyl radicals and quinone enoxy/ketoxy radicals were found to be produced by HBQs with H2O2 or organic hydroperoxides metal-independently. However, it remains unknown whether HBQs and hydroperoxides can induce DNA damage, 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 be generated from DNA oxidation by tetrachloro-1,4-benzoquinone (TCBQ) and H2O2 via an intercalation-enhanced oxidation mechanism. Analogous effects were observed with other HBQs, which are generally more effective than the classic iron-mediated Fenton system. Further investigations were extended from isolated DNA to genomic DNA in living cells. Potent oxidation of DNA to the more mutagenic imidazolone dIz was also found to be induced by HBQs and organic hydroperoxides such as the physiologically-relevant hydroperoxide 13S-hydroperoxy-9Z,11E-octadecadienoic acid (13-HPODE) via a unique quinone-enoxy radical-mediated mechanism. These findings should provide new perspectives to explain the potential genotoxicity, mutagenesis, and carcinogenicity for the ubiquitously-present haloaromatic persistent organic pollutants.

Contents

1 Introduction

2 Potent oxidative DNA damage by HBQs and H2O2 via an intercalation-enhanced oxidation mechanism

3 Detection of HQ-induced DNA damage by photoelectrochemical DNA sensor

4 Genotoxicity and mutagenesis induced by TCHQ in mammalian cells

5 Potent methyl oxidation of 5-methyl-2'-deoxycytidine (5mCyt) by HBQs and H2O2

6 Genome-wide DNA methylation alterations induced by HBQs and other redox-active quinones at cellular level

7 Potent oxidation of DNA by HBQs/organic hydroperoxides to the more mutagenic imidazolone dIz via the reactive haloquinone-enoxy radicals

8 Conclusion

Key words: halobenzoquinones, hydroperoxides, free radicals, DNA damage, genotoxicity
Fig.1 TCBQ and TCHQ are two major genotoxic and carcinogenic quinoid metabolites of PCP
Fig. 2 Mechanism of enhancement by HBQs of the decomposition of hydroperoxides and formation of alkoxyl/hydroxyl radicals and quinone ketoxy/enoxy radicals metal-independently via nucleophilic substitution followed by homolytical decompositionreaction.
Fig. 3 The chemical structures of HQs in this study
Fig. 4 Proposed mechanism for the formation of 5mCyt oxidation products by TCBQ and H2O2 via a metal-independent pathway (modified according to Ref 63). First, ·OH produced by TCBQ/H2O2 may abstract hydrogen atom from the methyl group of 5mC, leading to the formation of 5-(2'-deoxycytidylyl)methyl radical, which then combines with O2 to form its corresponding peroxyl radical. The unstable peroxyl radical can transform into 5HpmC. 5HmC and 5fC were produced via dismutation of 5-CH2O· formed through a nucleophilic substitution followed homolytical decomposition reaction.
Fig. 5 Proposed mechanism for the formation of Gua oxidation products by TCBQ and t-BuOOH via quinone enoxy radical intermediates in a metal-independent pathway (modified according to Ref 79). First, the quinone enoxy radical produced by TCBQ/t-BuOOH may abstract one electron from Gua to generate Gua·+, which deprotonates at physiological pH to produce Gua(-H)·. Gua(-H)· combines with O2 and then transforms into the corresponding hydroperoxide 5-HOO-Gua(-H). The decarboxylation of 5-HOO-Gua(-H) and further rearrangement lead to the formation of the imidazolone lesion. In a similar way, the initially produced 8-oxoG would result in the formation of Iz after one-electron oxidation and rearrangement. The imidazolone lesion could further hydrolyze to form the oxazolone (Oz) lesion.
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