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Food Chem Toxicol. 2017 Sep;107(Pt A):186-200. doi: 10.1016/j.fct.2017.06.019. Epub 2017 Jun 9.

Transcriptional profiling of male F344 rats suggests the involvement of calcium signaling in the mode of action of acrylamide-induced thyroid cancer.

Author information

1
Integrated Laboratory Systems Inc., Research Triangle Park, NC, USA.
2
Environmental Health Science and Research Bureau, Environmental and Radiation Health Sciences Directorate, HECSB, Health Canada, Ottawa, Ontario, Canada.
3
Environmental Health Science and Research Bureau, Environmental and Radiation Health Sciences Directorate, HECSB, Health Canada, Ottawa, Ontario, Canada. Electronic address: carole.yauk@canada.ca.

Abstract

Acrylamide (AA) exposure in 2-year cancer bioassays leads to thyroid, but not liver, adenomas and adenocarcinomas in rats. Hypothesized modes of action (MOAs) include genotoxicity/mutagenicity, or thyroid hormone dysregulation. To examine the plausibility of these two or any alternative MOAs, RNA-sequencing was performed on the thyroids and livers of AA-exposed rats, in parallel with measurement of genotoxicity (blood micronucleus and Pig-a mutant frequency) and serum thyroid hormone levels, following the exposure of male Fischer 344/DuCrl rats to 0.0, 0.5, 1.5, 3.0, 6.0, or 12.0 mg AA/kg bw-day in drinking water for 5, 15, or 31 days. Differentially expressed genes in both tissues provided marginal support for hormonal and genotoxic MOAs, which was consistent with negative/equivocal genotoxicity assay and marginal changes in thyroid hormone levels. Instead, there was a pronounced effect on calcium signaling/cytoskeletal genes in the thyroid. Benchmark dose modeling of RNA-sequencing data for the calcium signaling pathway suggests a point of departure (POD) of 0.68 mg/kg bw-day, which is consistent with a POD of 0.82 mg/kg bw-day derived from the thyroid 2-year cancer bioassay data. Overall, this study suggests a novel MOA for AA-induced thyroid carcinogenicity in male rats centered around perturbation of calcium signaling.

KEYWORDS:

Calcium signaling; Cytoskeleton; Gene expression; Human health risk assessment; Mode of action; Thyroid

PMID:
28606764
DOI:
10.1016/j.fct.2017.06.019
[Indexed for MEDLINE]
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