Transcriptional profiling of male CD-1 mouse lungs and Harderian glands supports the involvement of calcium signaling in acrylamide-induced tumors
| Autor: | Cheryl A. Hobbs, Timothy Maynor, Nikolai L. Chepelev, Byron Kuo, Leslie Recio, Carole L. Yauk, Rémi Gagné |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Metabolite 010501 environmental sciences Biology Toxicology medicine.disease_cause 01 natural sciences Mice 03 medical and health sciences Harderian gland chemistry.chemical_compound Neoplasms Internal medicine Gene expression medicine Animals Bioassay Calcium Signaling Mode of action Lung Carcinogen 0105 earth and related environmental sciences Acrylamide Harderian Gland Sequence Analysis RNA Gene Expression Profiling General Medicine 030104 developmental biology Endocrinology chemistry Transcriptome Genotoxicity |
| Zdroj: | Regulatory Toxicology and Pharmacology. 95:75-90 |
| ISSN: | 0273-2300 |
| DOI: | 10.1016/j.yrtph.2018.02.005 |
| Popis: | Acrylamide (AA) exposure causes increased incidence of forestomach, lung, and Harderian gland tumors in male mice. One hypothesized mode of action (MOA) for AA-carcinogenicity includes genotoxicity/mutagenicity as a key event, possibly resulting from AA metabolism to the direct genotoxic metabolite glycidamide. Alternatively, altered calcium signaling (CS) has been proposed as a central key event in the MOA. To examine the plausibility of these proposed MOAs, RNA-sequencing was performed on tumor target tissues: Harderian glands (the most sensitive tumor target tissue in the rodent 2-year cancer bioassay) and lungs of AA-exposed male CD-1 mice. Animals were exposed to 0.0, 1.5, 3.0, 6.0, 12.0, or 24.0 mg AA/kg bw-day in drinking water for 5, 15, or 31 days. We observed a pronounced effect on genes involved in CS and cytoskeletal processes in both tissues, but no evidence supporting a genotoxic MOA. Benchmark dose modeling suggests transcriptional points of departure (PODs) of 0.54 and 2.21 mg/kg bw-day for the Harderian glands and lungs, respectively. These are concordant with PODs of 0.17 and 1.27 mg/kg bw-day derived from the cancer bioassay data for these tissues in male mice, respectively. Overall, this study supports the involvement of CS in AA-induced mouse carcinogenicity, which is consistent with a recently proposed CS-based MOA in rat thyroid, and with other published reports of aberrant CS in malignant tumors in rodents and humans. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect