Long-Term Oral Exposure to Chlorophenylacetonitrile Induces Gastrointestinal Morphological Alterations and Splenic Transcriptomic Reprogramming in Mice
8 affiliations
- 1Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China
- 2State Key Laboratory of Water Pollution Control and Green Resource Recycling, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China
- 3College of Nanjing, University of Chinese Academy of Sciences, Nanjing 211135, China
- 4Key Laboratory of Lake and Watershed Science for Water Security, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, Nanjing 210008, China
- 5University of Chinese Academy of Sciences, Beijing 100049, China
- 6Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, No.8 Jiangwangmiao Street, Nanjing 210042, China
- 7Institute 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
- 8Ecological and Environmental Monitoring Center of Zhejiang Province, Hangzhou 310012, China
Abstract
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 ± 2.0 g vs. 47.6 ± 11.6 g, p < 0.05) and induced severe gastroenteropathy—including 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–cytokine 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–spleen toxicological axis, underscoring the urgent need to incorporate organ endpoints by long-term exposure into N-DBP risk assessment.
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BibTeX
@article{zhang2026longterm,
title = {{Long-Term Oral Exposure to Chlorophenylacetonitrile Induces Gastrointestinal Morphological Alterations and Splenic Transcriptomic Reprogramming in Mice}},
author = {Yayun Zhang and Fei Liu and Hao Zhou and Jingwen Chen and Lei Jiang and Changchun Yan and Xiaodong Li and Ding‐Ming Xue and Jiangfei Wang},
journal = {Toxics},
year = {2026},
month = jul,
doi = {10.3390/toxics14080647},
url = {https://doi.org/10.3390/toxics14080647},
note = {CC BY},
}
RIS
TY - JOUR
TI - Long-Term Oral Exposure to Chlorophenylacetonitrile Induces Gastrointestinal Morphological Alterations and Splenic Transcriptomic Reprogramming in Mice
AU - Yayun Zhang
AU - Fei Liu
AU - Hao Zhou
AU - Jingwen Chen
AU - Lei Jiang
AU - Changchun Yan
AU - Xiaodong Li
AU - Ding‐Ming Xue
AU - Jiangfei Wang
PY - 2026
DA - 2026/07/23
JO - Toxics
DO - 10.3390/toxics14080647
UR - https://doi.org/10.3390/toxics14080647
AB - 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 ± 2.0 g vs. 47.6 ± 11.6 g, p < 0.05) and induced severe gastroenteropathy—including 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–cytokine 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–spleen toxicological axis, underscoring the urgent need to incorporate organ endpoints by long-term exposure into N-DBP risk assessment.
SN - 2305-6304
ER -