Genotoxicity of formaldehyde: molecular basis of DNA damage and mutation

Abstract

Formaldehyde is commonly used in the chemical industry and is present in the environment, such as vehicle emissions, some building materials, food, and tobacco smoke. It also occurs as a natural product in most organisms, the sources of which include a number of metabolic processes. It causes various acute and chronic adverse effects in humans if they inhale its fumes. Among the chronic effects on human health, we summarize data on genotoxicity and carcinogenicity in this review, and we particularly focus on the molecular mechanisms involved in the formaldehyde mutagenesis. Formaldehyde mainly induces N-hydroxymethyl mono-adducts on guanine, adenine and cytosine, and N-methylene crosslinks between adjacent purines in DNA. These crosslinks are types of DNA damage potentially fatal for cell survival if they are not removed by the nucleotide excision repair pathway. In the previous studies, we showed evidence that formaldehyde causes intra-strand crosslinks between purines in DNA using a unique method (Matsuda et al., 1998). Using shuttle vector plasmids, we also showed that formaldehyde as well as acetaldehyde induces tandem base substitutions, mainly at 5-GG and 5-GA sequences, which would arise from the intra-strand crosslinks. These mutation features are different from those of other aldehydes such as crotonaldehyde, acrolein, glyoxal, and methylglyoxal. These findings provide molecular clues to improve our understanding of the genotoxicity and carcinogenicity of formaldehyde.

Re-evaluation of the WHO (2010) formaldehyde indoor air quality guideline for cancer risk assessment

“…Formaldehyde is genotoxic due to its covalent binding to DNA, causing DNA mono-adducts, DNA–DNA cross-links, DPX and DNA glutathione cross-links that can cause mutations and clastogenic effects such as DNA strand breaks, chromosomal aberration (CA), micronucleus (MN) formation and sister chromatid exchange (SCE) as reviewed (IARC 2006; RAC 2012; NRC 2014; Kawanishi et al 2014; Yu et al 2015). Repair of the FA–DNA mono-adducts may include the base excision repair (BER) pathway, and the intra-strand cross-links may be by the nucleotide excision repair (NER) pathway (Kawanishi et al 2014).…”

“…Repair of the FA–DNA mono-adducts may include the base excision repair (BER) pathway, and the intra-strand cross-links may be by the nucleotide excision repair (NER) pathway (Kawanishi et al 2014). FA-induced DPX may be repaired by the NER repair and by the homologous recombination (HR) pathways (de Graaf et al 2009; Kawanishi et al 2014; McHale et al 2014). Furthermore, DPX may partly be broken down by specific proteolytic enzymes, allowing translesion synthesis polymerases (a potentially mutagenic pathway) to replicate across DNA-peptide lesions.…”

Toxic Effects of Formaldehyde on Cellular Immunity and Possible Relationship to Its Risk of Carcinogenesis: An Experimental Study

“…Also, Gomaa et al (2012) studied the genotoxic effects of FA both in rats and workers occupationally exposed to FA and concluded that FA resulted in DNA damage proven by Comet assay in the form of increased tail length and moment in bone marrow of rats and in blood lymphocytes of the workers. Kawanishi et al (2014) studied the molecular basis for possible genotoxicity and carcinogenicity of FA and detected induction of hydroxymethyl mono-adducts on adenine, guanine and cytosine together with methylene crosslinks in DNA.…”

Nose, Larynx, and Trachea

“…Formaldehyde can cause inter-and intra-DNA crosslinks, base adducts and DNA-protein crosslinks. It induces N-hydroxymethyl mono-adducts primarily on guanine, adenine and cytosine, and N-methylene crosslinks between adjacent purines in DNA resulting in DNA damage (Kawanishi et al, 2014). Examination of Tp53 mutations from formaldehyde-induced rat nasal squamous cell carcinomas indicated G:C to T:A/C:G transversions, and G:C to A:T transitions (Recio et al, 1992).…”