Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

Langevin, Frédéric; Crossan, Gerry P.; Rosado, Iván V.; Arends, Mark J.; Patel, Ketan

doi:10.1038/nature10192

Cited by 450 publications

(458 citation statements)

References 39 publications

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“…Most strikingly, those patients entirely deficient for ALDH2 developed BMF within the first 7 months of life (Hira et al, 2013). Patel's laboratory has demonstrated that blocking ADH5 (formaldehyde dehydrogenase) or ALDH2 triggered DNA damage and was indeed genotoxic to hematopoietic stem cells, causing FA mice to spontaneously develop acute leukemia and profound BMF (Garaycoechea et al, 2012;Garaycoechea and Patel, 2014;Langevin et al, 2011). These reports confirm unequivocally that endogenous aldehydes are sufficient to cause DNA damage and induce leukemia and BMF in both humans and mice deficient in aldehyde detoxification and DNA repair.…”

Section: Discussionsupporting

confidence: 67%

“…K.J. Patel's laboratory has recently reported that mice deficient in both acetaldehyde catabolism (ALDH2 À/À ) and the Fanconi anemia (FA) DNA repair pathway (FANCD2 À/À ), spontaneously develop severe bone marrow toxicity and acute leukemia (Garaycoechea et al, 2012;Langevin et al, 2011). Moreover, they have shown endogenous formaldehyde to be more abundant and more genotoxic than acetaldehyde , demonstrating that endogenous aldehyde concentrations are sufficient to cause DNA damage and induce leukemia in FA mice (Garaycoechea et al, 2012;Langevin et al, 2011).…”

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confidence: 99%

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Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

Yu¹,

Lai²,

Hartwell³

et al. 2015

Toxicol. Sci.

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Formaldehyde is not only a widely used chemical with well-known carcinogenicity but is also a normal metabolite of living cells. It thus poses unique challenges for understanding risks associated with exposure. N 2-hydroxymethyl-dG (N 2 -HOMedG) is the main formaldehyde-induced DNA mono-adduct, which together with DNA-protein crosslinks (DPCs) and toxicityinduced cell proliferation, play important roles in a mutagenic mode of action for cancer. In this study, N 2 -HOMe-dG was shown to be an excellent biomarker for direct adduction of formaldehyde to DNA and the hydrolysis of DPCs. The use of inhaled [ 13 CD 2 ]-formaldehyde exposures of rats and primates coupled with ultrasensitive nano ultra performance liquid chromatography-tandem mass spectrometry permitted accurate determinations of endogenous and exogenous formaldehyde DNA damage. The results show that inhaled formaldehyde only reached rat and monkey noses, but not tissues distant to the site of initial contact. The amounts of exogenous adducts were remarkably lower than those of endogenous adducts in exposed nasal epithelium. Moreover, exogenous adducts accumulated in rat nasal epithelium over the 28-days exposure to reach steady-state concentrations, followed by elimination with a half-life (t 1/2 ) of 7.1 days. Additionally, we examined artifact formation during DNA preparation to ensure the accuracy of nonlabeled N 2 -HOMe-dG measurements. These novel findings provide critical new data for understanding major issues identified by the National Research Council Review of the 2010 Environmental Protection Agency's Draft Integrated Risk Information System Formaldehyde Risk Assessment. They support a data-driven need for reflection on whether risks have been overestimated for inhaled formaldehyde, whereas underappreciating endogenous formaldehyde as the primary source of exposure that results in bone marrow toxicity and leukemia in susceptible humans and rodents deficient in DNA repair.

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Section: Discussionsupporting

confidence: 67%

mentioning

confidence: 99%

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

Yu¹,

Lai²,

Hartwell³

et al. 2015

Toxicol. Sci.

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“…Acetaldehyde is known to be a compound with high reactivity, which causes DNA damage. Lack of ALDH2 enzyme has negative effect on mammal embryo development (Langevin et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

The Association of Early Pregnancy Loss with Polymorphism in Xenobiotics Detoxification Genes

Машкина¹,

Saraev²,

Butenko³

et al. 2015

American Journal of Applied Sciences

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Pregnancy loss and other pregnancy complication can be connected with environmental and lifestyle risk factor, among which effect of chemical compounds is the strongest. Effects of xenobiotics can be modified by allele variants of xenobiotic detoxification enzymes phase I or II. A total of 71 women with early pregnancy loss and 101 control patients were examined by a case-control methodology. The Ile462Val CYP1A1, Arg47His ADH1B, Glu487Lys ALDH, I105V GSTP1 polymorphisms were genotyped by allele-specific polymerase chain reaction. Our data demonstrated that the heterozygous Glu487Lys ALDH genotypes rate were higher in the pregnancy loss patients (12.71%) compared to the control group (2.0%). There was no difference between two groups detected for other polymorphisms. However, presence of polymorphic variants of genes of 1st and 2nd detoxification phases can have additive effect and cause multifactorial pathology risk increase. It is shown, that combination of polymorphic variants of ALDH2 и GSTP1 genes in genotype results in 5 fold pregnancy loss risk increase. Combination of polymorphic variants of ALDH2, ADH1B и GSTP1 genes in genotype results in 9 fold pregnancy loss risk increase. The results demonstrated that combination of allele variants of 1st and 2nd detoxification phases in woman genotype increases the risk of early pregnancy loss.

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“…Interestingly, the development of HCCs in β2SP heterozygote mutants establishes β2SP as a nontraditional and functional tumor suppressor. Spectrins have been observed to associate with Fanconi proteins (G and D) as well as with DNA interstrand cross‐links 70, 71. Similarly, by virtue of its involvement in Smad3/4 localization and subsequent activation of Smad3/4, β2SP may enhance TGF‐β tumor suppressor function.…”

Section: Liver Stem Cells and Tgf‐β: Evidence From Mouse Knockout LImentioning

confidence: 99%

Transforming growth factor‐β in liver cancer stem cells and regeneration

Rao

Zaidi

Banerjee

et al. 2017

Hepatology Communications

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Cancer stem cells have established mechanisms that contribute to tumor heterogeneity as well as resistance to therapy. Over 40% of hepatocellular carcinomas (HCCs) are considered to be clonal and arise from a stem‐like/cancer stem cell. Moreover, HCC is the second leading cause of cancer death worldwide, and an improved understanding of cancer stem cells and targeting these in this cancer are urgently needed. Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC; however, unlike the transforming growth factor β (TGF‐β) pathway, loss of p53 and/or activation of β‐catenin do not spontaneously drive HCC in animal models. Despite many advances in cancer genetics that include identifying the dominant role of TGF‐β signaling in gastrointestinal cancers, we have not reached an integrated view of genetic mutations, copy number changes, driver pathways, and animal models that support effective targeted therapies for these common and lethal cancers. Moreover, pathways involved in stem cell transformation into gastrointestinal cancers remain largely undefined. Identifying the key mechanisms and developing models that reflect the human disease can lead to effective new treatment strategies. In this review, we dissect the evidence obtained from mouse and human liver regeneration, and mouse genetics, to provide insight into the role of TGF‐β in regulating the cancer stem cell niche. (Hepatology Communications 2017;1:477–493)

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Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

Cited by 450 publications

References 39 publications

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

The Association of Early Pregnancy Loss with Polymorphism in Xenobiotics Detoxification Genes

Transforming growth factor‐β in liver cancer stem cells and regeneration

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