{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:05:23Z","timestamp":1793117123136,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["52400011"],"award-info":[{"award-number":["52400011"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["52400011"],"award-info":[{"award-number":["52400011"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Zhejiang Province Science and Technology Project in the Field of Ecology and Environment","award":["2026HJA0107"],"award-info":[{"award-number":["2026HJA0107"]}]},{"name":"Project of Zhejiang Key Laboratory of Ecological and Environmental Monitoring, Forewarning and Quality Control","award":["EEMFQ-2024-6"],"award-info":[{"award-number":["EEMFQ-2024-6"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Chlorophenylacetonitriles are known as one of the emerging nitrogenous disinfection byproducts (N-DBPs) in chlorinated drinking water due to their concerned cytotoxicity and genotoxicity compared to regulated carbonaceous DBPs. However, under low-dose exposure, the in vivo pathological consequences of chlorophenylacetonitriles remain largely unresolved. Here, C57BL\/6J mice were exposed to 2-chlorophenylacetonitrile (2-CPAN) via drinking water (100 ug\/L) for six months, and an integrated histopathological and genome-wide transcriptomic approach was employed to mechanistically characterize its multi-organ toxicological consequences. 2-CPAN ingestion significantly suppressed body weight (35.9 \u00b1 2.0 g vs. 47.6 \u00b1 11.6 g, p &lt; 0.05) and induced severe gastroenteropathy\u2014including gastric lamina propria inflammatory infiltration, intestinal villous blunting, crypt disorganization, transmural mononuclear infiltration, and abrogating epithelial barrier integrity. Intestinal barrier failure drove portal translocation of luminal PAMPs, potentially triggering splenic white pulp atrophy, red\/white pulp boundary dissolution, and parenchymal changes consistent with fibrotic remodeling. Splenic RNA sequencing revealed a bipartite transcriptomic reprogramming: upregulated pathways were enriched in the ribosome, MAPK signaling, cytokine\u2013cytokine receptor interaction, and chemokine signaling pathways. A proteotoxic stress module (Hspa1a, 9.4-fold; Hspa1b, 10.2-fold) and a chemokine effector hub (Ccl2, 3.43-fold; Ccl5, 2.9-fold; Ccl19, 2.58-fold; Ccl21a, 2.15-fold) were identified by the STRING network. Downregulated pathways converged on cell cycle suppression, with concurrent loss of Ccne1\/Ccne2 and Cdc6 (G1\/S block), Ccnb1 and Plk1 (G2\/M arrest), and Rrm2\/Tars3\/TrnM (dNTP and aminoacyl-tRNA starvation), collectively forcing splenic lymphocytes into irreversible proliferative failure. These findings provide the first mechanistically resolved in vivo evidence that chronic 2-CPAN exposure drives a potential gut\u2013spleen toxicological axis, underscoring the urgent need to incorporate organ endpoints by long-term exposure into N-DBP risk assessment.<\/jats:p>","DOI":"10.3390\/toxics14080647","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:13:17Z","timestamp":1784826797000},"page":"647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Long-Term Oral Exposure to Chlorophenylacetonitrile Induces Gastrointestinal Morphological Alterations and Splenic Transcriptomic Reprogramming in Mice"],"prefix":"10.3390","volume":"14","author":[{"given":"Yayun","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Water Pollution Control and Green Resource Recycling, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China"},{"name":"Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Lake and Watershed Science for Water Security, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, Nanjing 210008, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"College of Nanjing, University of Chinese Academy of Sciences, Nanjing 211135, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2038-6572","authenticated-orcid":false,"given":"Hao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, No.8 Jiangwangmiao Street, Nanjing 210042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Agricultural Facilities and Equipment, Jiangsu Academy of Agricultural Sciences, Jiangsu Engineering Technology Research Center of Biomass Composites and Addictive Manufacturing, Key Laboratory for Protected Agricultural Engineering in the Middle and Lower Reaches of Yangtze River, Ministry of Agriculture and Rural Affairs, Nanjing 210014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, No.8 Jiangwangmiao Street, Nanjing 210042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changchun","family":"Yan","sequence":"additional","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, No.8 Jiangwangmiao Street, Nanjing 210042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8484-6318","authenticated-orcid":false,"given":"Xiaodong","family":"Li","sequence":"additional","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, No.8 Jiangwangmiao Street, Nanjing 210042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8380-7859","authenticated-orcid":false,"given":"Dingming","family":"Xue","sequence":"additional","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, No.8 Jiangwangmiao Street, Nanjing 210042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangfei","family":"Wang","sequence":"additional","affiliation":[{"name":"Ecological and Environmental Monitoring Center of Zhejiang Province, Hangzhou 310012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2021). 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