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<p><i>N</i>-Nitrosodimethylamine (NDMA) is a probable human carcinogen found in contaminated pharmaceuticals and drinking water, yet the impact of age on NDMA susceptibility remains poorly understood. Using DNA repair-deficient (<i>Aag</i><sup>-/-</sup>;<i>Mgmt</i><sup>-/-</sup>) and wild-type mice, we systematically compare the effects of NDMA exposure in juveniles and adults. Juvenile <i>Aag</i><sup>-/-</sup>;<i>Mgmt</i><sup>-/-</sup> 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.</p>

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Early life exposure to N-nitrosamine drives genotoxicity, mutagenesis, and tumorigenesis in DNA repair-deficient mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月14日

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  • Lindsay B. Volk,
  • Monét Norales,
  • Callie Karjane,
  • Joshua J. Corrigan,
  • Alper J. Alcaraz,
  • Lee J. Pribyl,
  • Nicolette A. Bugher,
  • Megan Blawas,
  • Isabella Dulski,
  • Einthavy Arunachalam,
  • Nina Gubina,
  • Emily Michelsen,
  • Kannammai Pichappan,
  • Natalya Yakimchuk,
  • Matilda Swanson,
  • Duanduan Ma,
  • Stuart S. Levine,
  • Desiree L. Plata,
  • Robert G. Croy,
  • Leona D. Samson,
  • John M. Essigmann,
  • Carole L. Yauk,
  • Sebastian E. Carrasco,
  • Bevin P. Engelward

摘要

N-Nitrosodimethylamine (NDMA) is a probable human carcinogen found in contaminated pharmaceuticals and drinking water, yet the impact of age on NDMA susceptibility remains poorly understood. Using DNA repair-deficient (Aag-/-;Mgmt-/-) and wild-type mice, we systematically compare the effects of NDMA exposure in juveniles and adults. Juvenile Aag-/-;Mgmt-/- 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.