Inferred inactivation of the Cftr gene in the duodena of mice exposed to hexavalent chromium (Cr(VI)) in drinking water supports its tumor-suppressor status and implies its potential role in Cr(VI)-induced carcinogenesis of the small intestines.
Administration, Oral
Animals
Cell Transformation, Neoplastic
/ chemically induced
Chromium
/ administration & dosage
Cystic Fibrosis Transmembrane Conductance Regulator
/ genetics
Databases, Genetic
Drinking Water
Duodenal Neoplasms
/ chemically induced
Duodenum
/ drug effects
Gene Expression Profiling
Gene Silencing
/ drug effects
Mice
Risk Assessment
Systems Biology
Transcriptome
Tumor Suppressor Proteins
/ genetics
Water Pollutants, Chemical
/ administration & dosage
CFTR
Carcinogenesis
Chromium
Duodenal cancer
Toxicogenomics
Journal
Toxicology and applied pharmacology
ISSN: 1096-0333
Titre abrégé: Toxicol Appl Pharmacol
Pays: United States
ID NLM: 0416575
Informations de publication
Date de publication:
15 12 2021
15 12 2021
Historique:
received:
15
06
2021
revised:
12
10
2021
accepted:
19
10
2021
pubmed:
25
10
2021
medline:
30
12
2021
entrez:
24
10
2021
Statut:
ppublish
Résumé
Carcinogenicity of hexavalent chromium [Cr (VI)] has been supported by a number of epidemiological and animal studies; however, its carcinogenic mode of action is still incompletely understood. To identify mechanisms involved in cancer development, we analyzed gene expression data from duodena of mice exposed to Cr(VI) in drinking water. This analysis included (i) identification of upstream regulatory molecules that are likely responsible for the observed gene expression changes, (ii) identification of annotated gene expression data from public repositories that correlate with gene expression changes in duodena of Cr(VI)-exposed mice, and (iii) identification of hallmark and oncogenic signature gene sets relevant to these data. We identified the inactivated CFTR gene among the top scoring upstream regulators, and found positive correlations between the expression data from duodena of Cr(VI)-exposed mice and other datasets in public repositories associated with the inactivation of the CFTR gene. In addition, we found enrichment of signatures for oncogenic signaling, sustained cell proliferation, impaired apoptosis and tissue remodeling. Results of our computational study support the tumor-suppressor role of the CFTR gene. Furthermore, our results support human relevance of the Cr(VI)-mediated carcinogenesis observed in the small intestines of exposed mice and suggest possible groups that may be more vulnerable to the adverse outcomes associated with the inactivation of CFTR by hexavalent chromium or other agents. Lastly, our findings predict, for the first time, the role of CFTR inactivation in chemical carcinogenesis and expand the range of plausible mechanisms that may be operative in Cr(VI)-mediated carcinogenesis of intestinal and possibly other tissues.
Identifiants
pubmed: 34688701
pii: S0041-008X(21)00377-X
doi: 10.1016/j.taap.2021.115773
pmc: PMC9659473
mid: NIHMS1837088
pii:
doi:
Substances chimiques
Cftr protein, mouse
0
Drinking Water
0
Tumor Suppressor Proteins
0
Water Pollutants, Chemical
0
Chromium
0R0008Q3JB
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
chromium hexavalent ion
18540-29-9
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
115773Subventions
Organisme : Intramural EPA
ID : EPA999999
Pays : United States
Informations de copyright
Published by Elsevier Inc.
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