Early life exposure to N-nitrosamine drives genotoxicity, mutagenesis, and tumorigenesis in DNA repair-deficient mice
mice are profoundly more vulnerable, exhibiting persistent DNA damage, inflammation, and mutations that lead to liver pathology and tumorigenesis, particularly in males. Adults, by comparison, are resistant to NDMA. Wild-type mice show similar, attenuated trends. NDMA-induced DNA adduct levels are comparable across age groups, implicating proliferation-dependent responses to adducts, rather than adduct formation, as the primary driver of age-related risk. Supporting this mechanism, triiodothyronine-stimulated cell proliferation in adults partially recapitulates juvenile sensitivity, linking cell division to NDMA genotoxicity. Our findings identify developmental stage, sex, and DNA repair capacity as key modifiers of NDMA-induced carcinogenesis, with potential implications for environmental risk assessment and regulatory policy.
Authors
- Lindsay B. Volk (ORCID: https://orcid.org/0000-0001-8472-3836)
- Nicolette A. Bugher (ORCID: https://orcid.org/0000-0002-8343-3017)
- Einthavy Arunachalam (ORCID: https://orcid.org/0000-0003-3474-7535)
- Joshua J. Corrigan
- Stuart S. Levine (ORCID: https://orcid.org/0000-0001-7363-562X)
- Nina Gubina (ORCID: https://orcid.org/0000-0003-1706-1451)
- Megan Blawas
- Leona D. Samson
- Robert G. Croy (ORCID: https://orcid.org/0000-0002-3498-3311)
- Bevin P. Engelward (ORCID: https://orcid.org/0000-0003-4322-3573)
- Carole L. Yauk (ORCID: https://orcid.org/0000-0002-6725-3454)
- Lee J. Pribyl (ORCID: https://orcid.org/0000-0003-0209-7814)
- Desirée L. Plata (ORCID: https://orcid.org/0000-0003-0657-7735)
- Sebastian E. Carrasco
- Kannammai Pichappan
- Callie Karjane
- Natalya Yakimchuk (ORCID: https://orcid.org/0009-0000-1620-1825)
- Duanduan Ma
- John M. Essigmann
- Monét Norales (ORCID: https://orcid.org/0009-0002-7426-6170)
- Isabella Dulski (ORCID: https://orcid.org/0009-0006-8986-2740)
- Matilda Swanson (ORCID: https://orcid.org/0009-0004-0769-5543)
- Alper J. Alcaraz (ORCID: https://orcid.org/0000-0002-3213-6805)
- Emily Michelsen (ORCID: https://orcid.org/0009-0008-1667-1067)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of Ottawa (CA)
- Cornell University (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-14
- DOI
- https://doi.org/10.1038/s41467-026-71753-w
- Primary Topic
- Carcinogens and Genotoxicity Assessment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institute of Environmental Health Sciences