title: Hepatic miRNA profiles and thyroid hormone homeostasis in rats exposed to dietary potassium perfluorooctanesulfonate (PFOS).
abstract: Perfluorooctanesulfonate (PFOS) has been widely used in a variety of industrial and commercial applications as a surfactant and stain repellent. PFOS causes liver damage (including liver tumors) in experimental animals, primarily via interaction with PPARα and CAR/PXR. We investigated the involvement of microRNAs (miRNAs) in PFOS-induced hepatotoxicity, and mechanisms involved in abnormal thyroid hormone (TH) homeostasis, in the livers of adult male rats exposed in feed to 50mg PFOS/kg diet for 28 days. PFOS-treated rats exhibited expected histopathological and clinical chemistry changes, and global gene expression changes consistent with the involvement of PPARα and CAR/PXR. Thirty-eight miRNAs were significantly altered. Three members of the miR-200 family were the most increased, while miR-122-5p and miR-21-5p were the most decreased, in PFOS-treated rats. Expression of the miR-23b-3p/27b-3p/24-3p cluster also decreased in PFOS-treated animals. Pathway analysis of miRNAs and associated gene expression changes suggests involvement of epithelial to mesenchymal transition (EMT), which is a primary process of tumor cell motility and cancer metastasis. Our analysis also revealed transcripts that may mediate PFOS-induced effects on TH homeostasis including: activation of the CAR/PXR pathway, phase II/III enzymes, and deiodinase. These changes are consistent with low serum TH due to enhanced metabolic clearance of TH. However, most TH hepatic target genes were not altered in a manner consistent with reduced TH signaling, suggesting that PFOS exposure did not induce functional hypothyroidism. Collectively, the study suggests an important role for miRNAs in PFOS-induced hepatotoxicity and provides insight into the effects of PFOS on TH homeostasis.
authors.affiliation: Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Ottawa, ON, Canada K1A 0K9.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Dong
authors.affiliation: Bureau of Chemical Safety, Health Canada, Ottawa, ON, Canada K1A 0K9.
authors.forename: Ivan
authors.initials: I
authors.lastname: Curran
authors.affiliation: Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Ottawa, ON, Canada K1A 0K9.
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: Bureau of Chemical Safety, Health Canada, Ottawa, ON, Canada K1A 0K9.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Bondy
authors.affiliation: Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Ottawa, ON, Canada K1A 0K9.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
authors.affiliation: Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Ottawa, ON, Canada K1A 0K9. Electronic address: mike.wade@hc-sc.gc.ca.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Wade
mesh_terms: D017738:Alkanesulfonic Acids / Q000009:adverse effects*; D000818:Animals; D005466:Fluorocarbons / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D008099:Liver / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D017419:Potassium, Dietary / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013963:Thyroid Hormones / Q000097:blood*; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D017738:Alkanesulfonic Acids; D005466:Fluorocarbons; D035683:MicroRNAs; D017419:Potassium, Dietary; D013963:Thyroid Hormones; C076994:perfluorooctane sulfonic acid
keywords: EMT; Liver; Microarray; PFOS; miRNA