Scholarlink

<p>The contamination of <i>N</i>-nitrosamines (<i>N</i>-NAs) in pharmaceuticals has raised global concerns, due to potential carcinogenic risks. <i>N</i>-nitrosodimethylamine (NDMA) is a rodent carcinogen and the most prevalent <i>N</i>-NAs impurity in drug products. Current acceptable intake of NDMA (96&#xa0;ng/day) is a simple linear extrapolation from rodent carcinogenicity data, which may not comprehensively characterize its genotoxic potential in humans. Most <i>N</i>-NAs react with DNA to form DNA adducts after metabolic activation, leading to mutations and carcinogenesis. Here, we combined high-accuracy LC–MS/MS with error-corrected next-generation sequencing (ecNGS) to assess NDMA-induced DNA adduction and somatic mutations in mice using the quantitative benchmark dose (BMD) approach. NDMA induced dose-dependent increases in both DNA adduction and somatic mutations in liver tissues, with significant increases in mutation frequencies observed at ≥ 1&#xa0;mg/kg/day. NDMA induced mutations mainly with CG &gt; TA and TA &gt; CG transitions, exhibiting a signature resembling COSMIC signature 11, the mutational profile of alkylating agents. BMD<sub>50</sub> (90% CI) was estimated as 0.08–0.32&#xa0;mg/kg for <i>N</i>7-methylguanine and 1.64–3.83&#xa0;mg/kg for mutations. Permitted daily exposure (PDE) for NDMA was calculated from the lower confidence limit of BMD<sub>50</sub> (BMDL<sub>50</sub>) of genotoxic endpoints using appropriate uncertainty factors, revealing a PDE value of 245&#xa0;ng/day for NDMA-induced mutation. This PDE value was higher than the limit of 96&#xa0;ng/day recommended by regulatory agencies. Based on the quantitative genotoxicity assessment, our findings may improve the risk assessment of NDMA-contaminated pharmaceuticals and demonstrate the potential implementation of ecNGS in regulatory decision-making.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Quantitative genotoxicity assessment of N-nitrosodimethylamine in mice by error-corrected next-generation sequencing and DNA methylation quantification for toxicity threshold determination

  • 期刊论文

  • 发表日期：

    2025年8月24日

查看全文
  • Xinyue You,
  • Chen Sun,
  • Yiyi Cao,
  • Jing Xi,
  • Weiying Liu,
  • Jiaying Wu,
  • Jiang Zheng,
  • Yang Luan

摘要

The contamination of N-nitrosamines (N-NAs) in pharmaceuticals has raised global concerns, due to potential carcinogenic risks. N-nitrosodimethylamine (NDMA) is a rodent carcinogen and the most prevalent N-NAs impurity in drug products. Current acceptable intake of NDMA (96 ng/day) is a simple linear extrapolation from rodent carcinogenicity data, which may not comprehensively characterize its genotoxic potential in humans. Most N-NAs react with DNA to form DNA adducts after metabolic activation, leading to mutations and carcinogenesis. Here, we combined high-accuracy LC–MS/MS with error-corrected next-generation sequencing (ecNGS) to assess NDMA-induced DNA adduction and somatic mutations in mice using the quantitative benchmark dose (BMD) approach. NDMA induced dose-dependent increases in both DNA adduction and somatic mutations in liver tissues, with significant increases in mutation frequencies observed at ≥ 1 mg/kg/day. NDMA induced mutations mainly with CG > TA and TA > CG transitions, exhibiting a signature resembling COSMIC signature 11, the mutational profile of alkylating agents. BMD50 (90% CI) was estimated as 0.08–0.32 mg/kg for N7-methylguanine and 1.64–3.83 mg/kg for mutations. Permitted daily exposure (PDE) for NDMA was calculated from the lower confidence limit of BMD50 (BMDL50) of genotoxic endpoints using appropriate uncertainty factors, revealing a PDE value of 245 ng/day for NDMA-induced mutation. This PDE value was higher than the limit of 96 ng/day recommended by regulatory agencies. Based on the quantitative genotoxicity assessment, our findings may improve the risk assessment of NDMA-contaminated pharmaceuticals and demonstrate the potential implementation of ecNGS in regulatory decision-making.