Low-Dose Formaldehyde Delays DNA Damage Recognition and DNA Excision Repair in Human Cells

Abstract

ObjectiveFormaldehyde is still widely employed as a universal crosslinking agent, preservative and disinfectant, despite its proven carcinogenicity in occupationally exposed workers. Therefore, it is of paramount importance to understand the possible impact of low-dose formaldehyde exposures in the general population. Due to the concomitant occurrence of multiple indoor and outdoor toxicants, we tested how formaldehyde, at micromolar concentrations, interferes with general DNA damage recognition and excision processes that remove some of the most frequently inflicted DNA lesions.Methodology/Principal FindingsThe overall mobility of the DNA damage sensors UV-DDB (ultraviolet-damaged DNA-binding) and XPC (xeroderma pigmentosum group C) was analyzed by assessing real-time protein dynamics in the nucleus of cultured human cells exposed to non-cytotoxic (<100 μM) formaldehyde concentrations. The DNA lesion-specific recruitment of these damage sensors was tested by monitoring their accumulation at local irradiation spots. DNA repair activity was determined in host-cell reactivation assays and, more directly, by measuring the excision of DNA lesions from chromosomes. Taken together, these assays demonstrated that formaldehyde obstructs the rapid nuclear trafficking of DNA damage sensors and, consequently, slows down their relocation to DNA damage sites thus delaying the excision repair of target lesions. A concentration-dependent effect relationship established a threshold concentration of as low as 25 micromolar for the inhibition of DNA excision repair.Conclusions/SignificanceA main implication of the retarded repair activity is that low-dose formaldehyde may exert an adjuvant role in carcinogenesis by impeding the excision of multiple mutagenic base lesions. In view of this generally disruptive effect on DNA repair, we propose that formaldehyde exposures in the general population should be further decreased to help reducing cancer risks.

On the epigenetic role of guanosine oxidation

“…Other Lys-demethylases such as the Jumonji C family of mono-, di- and trimethylated Lys-demethylases operate on histones, but use Fe 2+ and the α-ketoglutarate-to-succinate co-reaction [33]. Intriguingly, LSD-mediated methyl group oxidation results in the release of formaldehyde, whose role in the inhibition of 8-oxo-dG removal has been reported [34]. On this basis, LSDs activity can indirectly promote the formation of 8-oxo-dG in the nucleus.…”

Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis

“…Thus, carcinogens may act not only by producing DNA damage directly, but also by altering the processes that control normal DNA replication or repair of DNA damage. Examples include the inhibition of DNA repair by cadmium ( Candéias et al 2010 ) and formaldehyde ( Luch et al 2014 ).…”

Application of the Key Characteristics of Carcinogens to Per and Polyfluoroalkyl Substances

“…In addition to direct genotoxicity, xenobiotics can contribute to changes in DNA through alteration of DNA replication or repair [6]. These alterations can be mediated by modulation of specific DNA enzymes and impact on genome-wide processes such as nucleotide excision repair [63]. Our literature search did not identify studies that evaluated these endpoints for PFAS, precluding an evaluation of whether PFAS impact this key characteristic.…”