Formaldehyde metabolism and its impact on human health

Human health is threatened by exposure to reactive toxins that can damage fundamental biomolecules such as DNA and proteins. One of these molecules is formaldehyde, the simplest and one of the most reactive aldehydes. Formaldehyde is ubiquitous in the environment, and can be derived from some food components. However, a great burden of formaldehyde is also generated endogenously as a result of cellular metabolism. In fact, recent work has shown that endogenous formaldehyde is produced at sufficient levels to pose a significant threat to genome stability. To counteract this reactive molecule, organisms have evolved a detoxification system centered on the enzyme alcohol dehydrogenase 5 (ADH5). This system converts formaldehyde to formate, a less reactive molecule that can be used for nucleotide biosynthesis. The Fanconi Anemia (FA) DNA repair pathway guarantees additional protection against formaldehyde by alleviating DNA damage. Indeed, the simultaneous inactivation of both ADH5 and the FA DNA repair pathway in mice leads to dysfunction of vital organs and cancer. These findings suggest that formaldehyde might be a driver of the human disease FA. Additional work also links this genotoxin to the etiology of other human illnesses, such as the Ruijs-Aalfs syndrome and the cancer predisposition of BRCA2 mutation carriers. This review discusses the recent advances in formaldehyde biology and the impact of this toxic metabolite on human health.