Low-dose formaldehyde delays DNA damage recognition and DNA excision repair in human cells.
OBJECTIVE
Formaldehyde 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.


RESULTS
The 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
A 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.
Department of Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany.
Andreas
A
Luch
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.
Flurina C Clement
FC
Frey
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.
Regula
R
Meier
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.
Jia
J
Fei
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.
Hanspeter
H
Naegeli
D021581:Active Transport, Cell Nucleus; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry; D003470:Culture Media; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D036681:Fluorescence Recovery After Photobleaching; D005557:Formaldehyde / Q000633:toxicity*; D006801:Humans; D014466:Ultraviolet Rays
D002843:Chromatin; D003470:Culture Media; D004268:DNA-Binding Proteins; C086984:XPC protein, human; D005557:Formaldehyde