{
  "abstract": "Longitudinal studies of liver injury require models that can be maintained with simple administration, low procedure-related stress, and acceptable survival. Drinking-water thioacetamide (TAA-DW) is useful for this purpose, but it mainly produces centrilobular hepatocellular injury. Few drinking-water models are available for cholestatic liver injury. Here, we tested whether 4,4'-methylenedianiline (MDA), a known bile-duct-damaging hepatotoxicant, can be used to build a practical drinking-water model of cholestatic liver injury in mice. Male C57BL/6JJcl mice received MDA in drinking water for up to 28 days. A route- and administration-schedule-matched TAA-DW model was used as a reference. Drinking-water MDA (MDA-DW) caused sustained ALT elevation without observed mortality under the tested regimen. Compared with TAA-DW, MDA-DW produced stronger cholestatic biochemical features, including increased ALP, TBIL, and TCHO. Histology showed bile duct hyperplasia with degeneration, periportal/peribiliary fibrosis, and scattered focal hepatocellular necrosis. Whole-slide image analysis supported the distinct lesion distribution between MDA-DW and TAA-DW. Early time-resolved multimodal profiling showed model-specific responses: MDA-DW showed ALT elevation around Days 2-3, increased CD8-positive T cells on Day 8, and enrichment of fibrinolysis-related gene sets, whereas TAA-DW showed a sharp early injury peak and transient eosinophil increase. Impact Statement: This study expands the range of drinking-water liver injury models by providing a low-mortality MDA-DW model with cholestatic liver injury. The model offers a simple platform for time-resolved studies of liver injury progression, tissue remodeling, and model-specific inflammatory responses.",
  "abstract_shown": true,
  "affiliations": [
    "the University of Tokyo Graduate School of Pharmaceutical Sciences, , Bunkyo-ku, Tokyo, 113-0033,",
    "Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo, 3-0033, Japan",
    "Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan",
    "Laboratory for Drug Discovery and Development, SHIONOGI & Co.,Ltd . Toyonaka, Osaka, 561-0825,"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Takumi Iwasaka"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Katsuhisa Morita"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Iori Azuma"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Tomoka Nakagawa"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Eri Nakashima"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Tomomi Kamei"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Yuki Kato"
    },
    {
      "affs": [
        0
      ],
      "name": "Hiroyuki Kusuhara",
      "orcid": "0000-0002-3641-8746"
    },
    {
      "affs": [
        0
      ],
      "name": "Tadahaya Mizuno",
      "orcid": "0000-0002-1638-602X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bqgx1nqp3c7t4.bib",
  "cited_by": 5,
  "doi": "10.1093/toxsci/kfag142",
  "fulltext_url": null,
  "id": "bqgx1nqp3c7t4",
  "issns": [
    "1096-0929",
    "1096-6080"
  ],
  "landing_url": "https://doi.org/10.1093/toxsci/kfag142",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "3004|Drug-Induced Hepatotoxicity and Protection"
    ]
  ],
  "openalex": "W4391310797",
  "pdf_url": null,
  "pmcid": null,
  "pmid": "42969399",
  "published": "2026-10-31",
  "publisher": "Oxford University Press",
  "ris": "https://research.draconitic.com/paper/bqgx1nqp3c7t4.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T13:20:37Z",
      "native_id": "W4391310797",
      "source": "openalex",
      "url": "https://doi.org/10.1093/toxsci/kfag142"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:3004|Drug-Induced Hepatotoxicity and Protection",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Drinking-Water 4,4′-Methylenedianiline Establishes a Longitudinally Tractable Mouse Model of Cholestatic Liver Injury",
  "title_text": "Drinking-Water 4,4′-Methylenedianiline Establishes a Longitudinally Tractable Mouse Model of Cholestatic Liver Injury",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T13:20:37Z",
  "url": "https://research.draconitic.com/paper/bqgx1nqp3c7t4",
  "venue": "Toxicological Sciences",
  "versions": []
}