Transcripts upregulated in human colon cancer and after PBDE treatment included cyp2b6 , famb , chek1 , rcan2 , ccng2, ccl5 , and acacb. Hepatocellular vacuolization, as seen in PBDE rat livers, is often indicative of accumulation of fat deposits Eustis et al. Non-alcoholic fatty liver is a hepatic manifestation of the metabolic syndrome Lucero et al.
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The occurrence of hepatocellular hypertrophy and vacuolization may predispose rats to liver cancer. However, not all exposures that result in these liver histopathologic features lead to liver cancer Maronpot et al.
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Thus, there is a need for additional biomarkers to predict disease. PBDE induced liver gene transcript changes that modify cell pathways and functions that, along with the liver toxicity, may lead to disease susceptibilities.
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This includes alterations in lipid and metabolic pathways. An increase in lipoprotein lipase activity has been associated with diabetes and metabolic diseases Lopaschuk et al. PBDE decreased the cyp7a transcript which codes for an enzyme critical in metabolism of cholesterol to bile acids and in controlling hepatic triglyceride levels Lee et al. The PBDE transcript patterns reported here, support other findings which show that PBDE exposures lead to increased body weights in rodents and alterations in adipocyte metabolism Hoppe and Carey ; Suvorov and Takser Thyroid homeostasis is important in preventing metabolic, reproductive, developmental and cardiac disease Choksi et al.
Liver gene transcript analysis in the current study supports a finding of altered lipid metabolism.
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The PBDE induced liver toxicity was accompanied by increases in liver P transcripts including those for cyp2a3a , cyp1a 1 cyp1b1 , cyp2c7 , cyp2c13 , cyt2c , cyp2b , coding for enzymes critical in metabolism of chemicals, drugs, fatty acids, and steroids Yang et al. Up regulation of these cytochrome P liver enzymes has been found with other chemicals causing fatty liver steatosis Lee et al.
An adaptive response to the PBDE liver toxicity was suggested by fewer significant liver gene transcript changes at week 13 than at PND 22, and induced liver transcripts for enzymes involved in decreasing aldehyde loads Ellis and this may be part of an adaptive response to toxicity.
PBDE and dioxin exposures are both associated with increases in liver P enzyme levels Boverhof et al.
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The PBDE mixture used in our studies contained a low level of brominated dioxins and furans that by themselves would not be expected to cause cancers Dunnick and Nyska , but in combination with the PBDEs may have synergistic carcinogenic effects. Whether that occurred in our studies would require further investigation. Not all of these liver gene transcripts were upregulated in our PBDE studies, although a different strain of rat Long Evans rat was used in the Szabo et al studies. The liver gene expression profile generated by PBDE at PND 22 was similar to the transcriptional profile produced by phenobarbital in rodents Nesnow et al.
The changes include transcript abundance increases for Ps, chemokines, carboxylesterases, and growth factor arrest gadd45b gene transcript levels, and were similar to liver gene transcript patterns found in human liver cancers Frau et al. Liver genotoxic carcinogens are characterized by a specific liver fingerprint after 14 days or 13 weeks of exposure upregulaton of mybl2 , cyp1A1 , and adam8 and downregulation of wwox , fhi t, RGD Auerbach et al.
Based on these findings, the PBDE liver toxic mechanisms appear to differ from those of genotoxic liver toxins. PBDE liver transcript patterns include those found in metabolic disease conditions. Metabolic disease conditions may contribute to the development of cancer e. PBDE liver gene transcript patterns overlapped those seen in human cancer colon including upregulation of cyclins Koliadi et al.
In other studies, we reported that brominated chemicals may have a particular propensity to cause intestinal tumors Dunnick et al. Bromide radical formation in the intestine resulting in DNA damage Ballmaier and Epe is one hypothesis for the cause of a brominated chemical carcinogenic response in the intestine, and additional studies would be needed to determine if this cancer occurs after long-term PBDE exposures. PBDE treatment decreased expression of cyp17a1 , a decrease that is associated with blocking androgen production Hofland et al. PBDE and its metabolites e. For these reasons, PBDE exposures could contribute to the develop of carcinogenesis processes as suggested by our findings Figure 5.
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Transcript changes at PND 22 coded for proteins in xenobiotic, sterol, and lipid metabolism, and cell cycle regulation, and overlapped rodent liver transcript patterns after a high-fat diet or phenobarbital exposure. The snippet could not be located in the article text.
This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Toxicol Pathol. Author manuscript; available in PMC Mar PMID: Dunnick , a A. Brix , H. Cunny , M.
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Vallant , and K. June K. Dunnick, vog. Copyright notice. The publisher's final edited version of this article is available at Toxicol Pathol. See other articles in PMC that cite the published article. Keywords: polybrominated diphenyl ethers, liver toxicity, lipid metabolism. Necropsy and collection of liver samples for toxcogenomic analysis Animals at PND 22 and 13 weeks were euthanized with carbon dioxide. Comparison of gene transcript expression to human disease Gene lists and the normalized gene expression estimates see Equation 1 — Equation 4 above were compared against results in the literature using the NextBio Platform Kupershmidt et al.
Open in a separate window. Figure 1. Table 1 Treatment-related effects of polybrominated diphenyl ether, male rats, week Figure 2.
Figure 3. Figure 4. Table 3 Selected liver gene transcript changes in postnatal day 22 male pup liver a. Most of these gene transcripts were not significantly changed in week13 male rat livers. Figure 5. Supplementary Material Supplement1 Supplement 1. Liver gene transcript changes — PND 22 males Click here to view. Supplement2 Supplement 2. Liver gene transcript changes — PND 22 females Click here to view. Supplement3 Supplement 3. Liver gene transcript changes — week 13 males Click here to view. Supplement4 Supplement 4.
Supplement5 Supplement 5. GO Analysis Click here to view. Supplement6 Supplement 6. Supplement7 Supplement 7.
Prediction of rodent carcinogenesis: an evaluation of prechronic liver lesions as forecasters of liver tumors in NTP carcinogenicity studies. Gene expression analysis of hepatic roles in cause and development of diabetes in Goto-Kakizaki rats. J Endocrinol. The cytotoxic effects of synthetic 6-hydroxylated and 6-methoxylated polybrominated diphenyl ether 47 BDE47 Environ Toxicol.
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