Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen

Abstract

SummaryEndogenous formaldehyde is produced by numerous biochemical pathways fundamental to life, and it can crosslink both DNA and proteins. However, the consequences of its accumulation are unclear. Here we show that endogenous formaldehyde is removed by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), and Adh5−/− mice therefore accumulate formaldehyde adducts in DNA. The repair of this damage is mediated by FANCD2, a DNA crosslink repair protein. Adh5−/−Fancd2−/− mice reveal an essential requirement for these protection mechanisms in hematopoietic stem cells (HSCs), leading to their depletion and precipitating bone marrow failure. More widespread formaldehyde-induced DNA damage also causes karyomegaly and dysfunction of hepatocytes and nephrons. Bone marrow transplantation not only rescued hematopoiesis but, surprisingly, also preserved nephron function. Nevertheless, all of these animals eventually developed fatal malignancies. Formaldehyde is therefore an important source of endogenous DNA damage that is counteracted in mammals by a conserved protection mechanism.

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice

“…10,11,13,29 In particular, endogenous formaldehyde, a highly reactive and abundant aldehyde generated by normal cellular processes such as DNA demethylation, has recently been shown to be an HSC genotoxin. 12 It is known that FA cells are sensitive to formaldehyde. 30 Consistent with these observations, we were able to demonstrate that cultured FA-G patient-derived lymphoblastoid cells (EUFA316) were sensitive to both the classic DNA cross-linking agent MMC and to formaldehyde ( Figure 5A,C).…”

“…10 Disruption of key aldehyde detoxifying enzymes such as the aldehyde dehydrogenases Aldh2 or Adh5 in Fanconi mice induces phenotypes resembling clinical FA and leads to spontaneous bone marrow failure. 11,12 Of note, human FA patients carrying a dominant-negative allele of ALDH2 demonstrate accelerated progression of bone marrow failure. 13 These observations suggest that attenuating aldehyde toxicity may provide a novel therapeutic approach to FA.…”

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

“…Generally, cases of KIN described in the literature exclude exposure to environmental genotoxins such as ochratoxin A, heavy metals, or herbal medicines (Mihatsch et al 1979;Bhandari et al 2002;Uz et al 2011;Radha et al 2014), leaving endogenously derived toxins as more likely candidates. Given the recent data implicating acetaldehyde and formaldehyde in the pathogenesis of FA (Langevin et al 2011;Garaycoechea et al 2012;Hira et al 2013;Pontel et al 2015), the contribution of aldehydes to the pathogenesis of KIN needs to be examined. Recent work demonstrates that an inactivation of alcohol dehydrogenase 5 (ADH5/GSNOR), which is responsible for formaldehyde detoxification, results in karyomegaly, kidney failure, and abnormal liver function when combined with Fancd2 deficiency (Pontel et al 2015).…”

“…Given the recent data implicating acetaldehyde and formaldehyde in the pathogenesis of FA (Langevin et al 2011;Garaycoechea et al 2012;Hira et al 2013;Pontel et al 2015), the contribution of aldehydes to the pathogenesis of KIN needs to be examined. Recent work demonstrates that an inactivation of alcohol dehydrogenase 5 (ADH5/GSNOR), which is responsible for formaldehyde detoxification, results in karyomegaly, kidney failure, and abnormal liver function when combined with Fancd2 deficiency (Pontel et al 2015). Although, the glomerular damage seen in the Fancd2…”

Defects in homologous recombination repair behind the human diseases: FA and HBOC

“…Using a mutant cell panel derived from the chicken DT40 cell line, it was shown that cells lacking Fancd2 or Brca2 are particularly sensitive to formaldehyde at concentrations similar to those in normal human serum (Ridpath et al 2007). Patel and coworkers indicated in a series of papers that aldehyde detoxifying enzymes ALDH2 (which mainly catalyzes acetaldehyde) and ADH5 (which mainly catalyzes formaldehyde) play critical roles in FA model mice in the suppression of bone marrow failure and leukemogenesis (Langevin et al 2011, Garaycoechea et al 2012, Oberbeck et al 2014, Pontel et al 2015. These results clearly indicate that endogenous aldehydes can damage DNA in hematopoietic stem cells.…”