Transcriptional profiling of male CD-1 mouse lungs and Harderian glands supports the involvement of calcium signaling in acrylamide-induced tumors
- DOI
- Language of the publication
- English
- Date
- 2018-02-21
- Type
- Article
- Author(s)
- Chepelev, Nikolai L.
- Gagné, Rémi
- Maynor, Timothy
- Kuo, Byron
- Hobbs, Cheryl A.
- Recio, Leslie
- Yauk, Carole L.
- Publisher
- Elsevier
Abstract
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.
Plain language summary
Health Canada is responsible for the assessment and management of health risks posed to Canadians by environmental chemicals. Toxicogenomics investigates how genes respond to chemicals and provides useful information about the biology of disease, which is an important consideration for human health risk assessment. In this study, toxicogenomics approaches were used to investigate the chemical acrylamide, which is present in many foods and other industrial products. Acrylamide has been shown to cause cancer in the mouse lung and Harderian glands, but how this occurs is unknown. Although humans do not have Harderian glands, this tissue is still considered in risk assessments on a precautionary basis because it is a sensitive target tissue to detect compounds that are both genotoxic and carcinogenic in rodents. Understanding how a chemical causes cancer in rodent tissues is key to determining if these effects are important in humans. To better understand how acrylamide can induce cancer, Health Canada undertook a toxicogenomics study in collaboration with Integrated Laboratory Systems Inc., (Research Triangle Park, North Carolina, USA). Male mice were exposed to acrylamide at doses that span and exceed levels that are known to cause tumours. Lungs and Haderian gland samples were collected at various times up to 30 days post-exposure and subjected to genomic analyses. The data showed that acrylamide affected genes related to calcium processes in mice and this may be relevant to humans. Overall, the study provides further understanding of the biology of acrylamide-induced cancer and emphasizes the need for further research. This work also highlights the utility of genomics as an important tool to understand the biology leading to disease and as a practical approach for risk assessments by Health Canada regulatory scientists.
Subject
- Health,
- Health and safety