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To elucidate how early-life environmental mutagenic exposures promote latent liver tumorigenesis, we performed longitudinal studies in wild-type and MGMT-deficient (Mgmt\u2212\/\u2212) mice. Neonatal mice received NDMA intraperitoneally on postnatal days 8 and 15 and were followed for up to 10 months post-exposure. Phenomics, transcriptomics, phosphoproteomics, spatial transcriptomics, and histopathology revealed that NDMA exposure in Mgmt\u2212\/\u2212 mice produced a nine-fold increase in liver tumors, including hepatocellular carcinomas and adenomas. Early molecular profiling revealed elevated O6MeG adducts, sustained \u03b3H2AX activation, and increased micronucleus formation in Mgmt\u2212\/\u2212 livers. Transcriptomics showed persistent interferon response and immune cell infiltration, particularly in Mgmt\u2212\/\u2212 mice, up to 10 months post-exposure. Clonal expansion, quantified by RaDR-GFP expression, was significantly higher in NDMA-exposed Mgmt\u2212\/\u2212 mice. Spatial transcriptomics of clonally expanded cells demonstrated activation of oncogenic and inflammatory pathways. These findings demonstrate that acute early-life NDMA exposure drives persistent DNA damage signaling, chronic interferon activation, and clonal expansion that together promote MGMT-dependent hepatocarcinogenesis. Collectively, these processes link early environmental mutagen exposure to long-term premalignant evolution and tumor emergence, and define mechanistic biomarkers and potential interception targets for NDMA-induced liver cancer.<\/jats:p>","DOI":"10.1093\/narcan\/zcag014","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T12:23:04Z","timestamp":1781612584000},"source":"Crossref","is-referenced-by-count":0,"title":["Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0209-7814","authenticated-orcid":false,"given":"Lee J","family":"Pribyl","sequence":"first","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5891-0689","authenticated-orcid":false,"given":"Jennifer E","family":"Kay","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]},{"name":"Silent Spring Institute , Newton, MA 02460 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6252-4960","authenticated-orcid":false,"given":"Joshua J","family":"Corrigan","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8472-3836","authenticated-orcid":false,"given":"Lindsay B","family":"Volk","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mon\u00e9t","family":"Norales","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norah A","family":"Owiti","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan A","family":"Kowal","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishwar N","family":"Kohale","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilana S","family":"Nazari","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilda R","family":"Swanson","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimee C","family":"Moise","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duanduan","family":"Ma","sequence":"additional","affiliation":[{"name":"David H. 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