NDLI: Toxicogenomic assessment of liver responses following subchronic exposure to furan in Fischer F344 rats

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Toxicogenomic assessment of liver responses following subchronic exposure to furan in Fischer F344 rats

Content Provider	Springer Nature Link
Author	Dong, Hongyan Gill, Santokh Curran, Ivan H. Williams, Andrew Kuo, Byron Wade, Michael G. Yauk, Carole L.
Copyright Year	2015
Abstract	Furan is a widely used industrial chemical and a contaminant in heated foods. Chronic furan exposure causes cholangiocarcinoma and hepatocellular tumors in rats at doses of 2 mg/kg bw/day or greater, with gender differences in frequency and severity. The hepatic transcriptional alterations induced by low doses of furan (doses below those previously tested for induction of liver tumors) and the potential mechanisms underlying gender differences are largely unexplored. We used DNA microarrays to examine the global hepatic mRNA and microRNA transcriptional profiles of male and female rats exposed to 0, 0.03, 0.12, 0.5 or 2 mg/kg bw/day furan over 90 days. Marked gender differences in gene expression responses to furan were observed, with many more altered genes in exposed males than females, confirming the increased sensitivity of males even at the low doses. Pathway analysis supported that key events in furan-induced liver tumors in males include gene expression changes related to oxidative stress, apoptosis and inflammatory response, while pathway changes in females were consistent with primarily adaptive responses. Pathway benchmark doses (BMDs) were estimated and compared to relevant apical endpoints. Transcriptional pathway BMDs could only be examined in males. These median BMDs ranged from 0.08 to 1.43 mg/kg bw/day and approximated those derived from traditional histopathology. MiR-34a (a P53 target) was the only microRNA significantly increased at the 2 mg/kg bw/day, providing evidence to support the importance of apoptosis and cell proliferation in furan hepatotoxicity. Overall, this study demonstrates the use of transcriptional profiling to discern mode of action and mechanisms involved in gender differences.
Starting Page	1351
Ending Page	1367
Page Count	17
File Format	PDF
ISSN	03405761
Journal	Archives of Toxicology
Volume Number	90
Issue Number	6
e-ISSN	14320738
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2015-07-21
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Low dose furan Rat liver Gender differences Pathway benchmark dose miRNA Thryoid hormone Pharmacology/Toxicology Occupational Medicine/Industrial Medicine Environmental Health Biomedicine general
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Medicine Toxicology

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