Transcriptional profiling of male CD-1 mouse lungs and Harderian glands supports the involvement of calcium signaling in acrylamide-induced tumors

Regul Toxicol Pharmacol. 2018 Jun;95:75-90. doi: 10.1016/j.yrtph.2018.02.005. Epub 2018 Feb 21.

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.

Keywords: Calcium signaling; Dose-response; Gene expression; Harderian gland; Human health risk assessment; Lung; Mode of action.

MeSH terms

  • Acrylamide / toxicity*
  • Animals
  • Calcium Signaling / drug effects*
  • Calcium Signaling / genetics
  • Gene Expression Profiling
  • Harderian Gland / drug effects*
  • Harderian Gland / metabolism
  • Lung / drug effects*
  • Lung / metabolism
  • Male
  • Mice
  • Neoplasms / chemically induced*
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Sequence Analysis, RNA
  • Transcriptome

Substances

  • Acrylamide