Formaldehyde (FA) is a ubiquitous environmental and occupational toxicant that is associated with an increasing number of human cancers. FA is also generated endogenously as a product of lipid peroxidation, drug biotransformation and several normal metabolic processes, such as histone demethylation during chromatin remodeling. Molecular mechanisms of FA carcinogenicity are poorly understood, in part reflecting its past association only with rare nasal cancers. A growing list of human cancers recently linked to FA exposure is difficult to explain by the cytotoxicity-based risk assessment models developed for nasal cancers in rodents. This application is designed to address major research gaps that hinder mechanistic understanding of FA-induced carcinogenic effects.
Three specific aims are proposed to (1) determine main causes of FA mutagenicity in human cells, (2) identify genomic sites and genes that are prone to large rearrangements and (3) examine a role of epigenetic injury in the formation of large genetic changes by FA in human adult stem cells. A successful completion of these studies can lead to the identification of the mechanistically important biomarkers of genetic damage by FA and help resolve current uncertainties regarding its mode of carcinogenic action and ability to initiate leukemogenic events.

Public Health Relevance

Formaldehyde is a ubiquitous environmental toxicant with a growing list of human cancers associated with its exposure. The molecular mechanisms underlying carcinogenic properties of formaldehyde are poorly understood, which makes it difficult to adequately assess human risks. This proposal is focused on the determination of DNA lesions that cause mutations and gross chromosomal damage in formaldehyde-exposed human cells. The completion of the proposed studies could lead to the identification of the important forms of genetic damage by formaldehyde and improve human risk assessment.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Shaughnessy, Daniel
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Brown University
Schools of Medicine
United States
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Ortega-Atienza, Sara; Krawic, Casey; Watts, Lauren et al. (2017) 20S immunoproteasomes remove formaldehyde-damaged cytoplasmic proteins suppressing caspase-independent cell death. Sci Rep 7:654
Ortega-Atienza, Sara; Rubis, Blazej; McCarthy, Caitlin et al. (2016) Formaldehyde Is a Potent Proteotoxic Stressor Causing Rapid Heat Shock Transcription Factor 1 Activation and Lys48-Linked Polyubiquitination of Proteins. Am J Pathol 186:2857-2868
Ortega-Atienza, Sara; Wong, Victor C; DeLoughery, Zachary et al. (2016) ATM and KAT5 safeguard replicating chromatin against formaldehyde damage. Nucleic Acids Res 44:198-209
Ortega-Atienza, Sara; Green, Samantha E; Zhitkovich, Anatoly (2015) Proteasome activity is important for replication recovery, CHK1 phosphorylation and prevention of G2 arrest after low-dose formaldehyde. Toxicol Appl Pharmacol 286:135-41
Wong, Victor Chun-Lam; Cash, Haley L; Morse, Jessica L et al. (2012) S-phase sensing of DNA-protein crosslinks triggers TopBP1-independent ATR activation and p53-mediated cell death by formaldehyde. Cell Cycle 11:2526-37