We have explored transcriptional patterns associated with spontaneous cancer development and chemically-induced carcinogenesis. In these studies, it is necessary to control mixed directional false discovery rate due to the fact that we tested for multiple comparisons and there is a potential for directional errors when declaring genes to be up- or downregulated. Global gene expression patterns of tumors arising in response to the toxicant vinylidene chloride (VDC) were compared to spontaneous mesotheliomas and F344/N rat mesothelial cells (Fred-PE) in order to discover the functions associated with VDC exposure. The data produced from VDC-treated animals suggested that exposure to this asbestos-related chemical is associated with the gene regulation of oncogenes, growth factors, and cell cycle response (Blackshear et al., 2015). In addition, comparisons of control and renal cell carcinoma from VDC exposed B6C3F1 mice showed overrepresentation of chronic xenobiotic and oxidative stress and dyregulation of TP53 cell cycle checkpoint and DNA damage repair pathways (Hayes et al., 2016). A separate study examined the relationship between hepatoblastoma and hepatocellular carcinoma using global gene expression analysis. The samples used in the study were obtained from HB, HCC and adjacent liver in a National Toxicology Program bioassay. There were large differences between HB and HCC samples. HB samples showed dysregulation of embryonic development, stem cell pluripotency and genomic imprinting pathways compared to HCC samples. Mouse HB was shown to be similar to human disease at the pathway level and therefore may be a good model for evaluating human cancer hazard (Bhusari et al., 2015). Another study examined the molecular consequences exposing male F344/N rats to N,N-dimethyl-p-toluidine (DMPT) on naval cavity tissue. Rat nasal tumors were previously found to occur in a two-year cancer study of female and male F344/N rats exposed to DMPT. In this study, rats were exposed to DMPT (0, 1, 6, 20, 60 and 120 mg/kg) by oral gavage for 5 days. Gene expression patterns were compared between 0 and 120 mg/kg and revealed that DMPT exposure was associated with an antioxidative damage response, cell proliferation and decreased signaling for apoptosis. The gene expression signature found here was similar to the signature found in rat nasal cavities after formaldehydge exposure, with over 1,000 shared transcriptional changes. (Dunnick et al., 2016).

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4
Fiscal Year
2016
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Indirect Cost
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U.S. National Inst of Environ Hlth Scis
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Perron, Isaac J; Keenan, Brendan T; Chellappa, Karthikeyani et al. (2018) Dietary challenges differentially affect activity and sleep/wake behavior in mus musculus: Isolating independent associations with diet/energy balance and body weight. PLoS One 13:e0196743
Dunnick, June K; Merrick, B Alex; Brix, Amy et al. (2016) Molecular Changes in the Nasal Cavity after N, N-dimethyl-p-toluidine Exposure. Toxicol Pathol 44:835-47
Hayes, Schantel A; Pandiri, Arun R; Ton, Thai-vu T et al. (2016) Renal Cell Carcinomas in Vinylidene Chloride-exposed Male B6C3F1 Mice Are Characterized by Oxidative Stress and TP53 Pathway Dysregulation. Toxicol Pathol 44:71-87
Blackshear, Pamela E; Pandiri, Arun R; Nagai, Hiroaki et al. (2015) Gene expression of mesothelioma in vinylidene chloride-exposed F344/N rats reveal immune dysfunction, tissue damage, and inflammation pathways. Toxicol Pathol 43:171-85
Bhusari, Sachin; Pandiri, Arun R; Nagai, Hiroaki et al. (2015) Genomic Profiling Reveals Unique Molecular Alterations in Hepatoblastomas and Adjacent Hepatocellular Carcinomas in B6C3F1 Mice. Toxicol Pathol 43:1114-26
George-Raizen, Julia B; Shockley, Keith R; Trojanowski, Nicholas F et al. (2014) Dynamically-expressed prion-like proteins form a cuticle in the pharynx of Caenorhabditis elegans. Biol Open 3:1139-49
Arnardottir, Erna S; Nikonova, Elena V; Shockley, Keith R et al. (2014) Blood-gene expression reveals reduced circadian rhythmicity in individuals resistant to sleep deprivation. Sleep 37:1589-600
Blackshear, Pamela E; Pandiri, Arun R; Ton, Thai-Vu T et al. (2014) Spontaneous mesotheliomas in F344/N rats are characterized by dysregulation of cellular growth and immune function pathways. Toxicol Pathol 42:863-76
Hoenerhoff, Mark J; Pandiri, Arun R; Snyder, Stephanie A et al. (2013) Hepatocellular carcinomas in B6C3F1 mice treated with Ginkgo biloba extract for two years differ from spontaneous liver tumors in cancer gene mutations and genomic pathways. Toxicol Pathol 41:826-41
Anafi, Ron C; Pellegrino, Renata; Shockley, Keith R et al. (2013) Sleep is not just for the brain: transcriptional responses to sleep in peripheral tissues. BMC Genomics 14:362

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