Journal
JOURNAL OF HAZARDOUS MATERIALS
Volume 423, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jhazmat.2021.127194
Keywords
DBPs; Haloacetonitriles; Pyrimidine dimers; gamma-H2AX
Categories
Funding
- Kurita Water and Environment Foundation [18E030]
- JSPS KAKENHI [19K15793]
- Grants-in-Aid for Scientific Research [19K15793] Funding Source: KAKEN
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The study found that DBAN inhibits the NER repair mechanism, leading to a blockage in the DNA damage signaling pathway, which could be one of its carcinogenic mechanisms.
Dibromoacetonitrile (DBAN) is a carcinogenic disinfection byproduct (DBP) but how it precipitates cancer is unknown. Nucleotide excision repair (NER) is a versatile repair mechanism for removing bulky DNA lesions to maintain genome stability, and impairment of this process is associated with cancer development. In this study, we found that DBAN inhibited NER and investigated its mechanism with other DNA damage responses. Human keratinocytes HaCaT were treated with DBAN followed by ultraviolet (UV) as a model inducer of DNA damage, pyrimidine dimers, which require NER for the removal. DBAN pretreatment exacerbated UV-cytotoxicity, and inhibited the repair of pyrimidine dimers. DBAN treatment delayed the recruitment of NER proteins, transcription factor IIH (TFIIH) and xeroderma pigmentosum complementation group G (XPG), to DNA damaged sites, and subsequent gap filling process. Moreover, DBAN suppressed the UV-induced double strand breaks (DSBs) formation, as well as phosphorylated histone H2AX (gamma-H2AX), a widely used DNA damage marker. Altogether, DBAN could negatively impact the NER process and phosphorylation pathway responding to DNA damage. This study was the first to identify the inhibition of NER and damage response signaling as a genotoxicity mechanism of a class of DBPs and it may serve as a foundation for DBP carcinogenesis.
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