A toxicogenomic approach for the risk assessment of the food contaminant acetamide
| Autor: | Melvin E. Andersen, Patrick D. McMullen, Kamala Kannan, Bryan Bals, S. Sathish Kumar, Bhavesh Dhirajlal Patel, Venkataraman Bringi, Neetha Paul, Rance Nault, Seetha Krishnan, James E. Klaunig, Nagesh Kuravadi, Lakshmanan Alagappan, Kenneth T. Bogen, K.C. Jayachandra, Timothy R. Zacharewski, B. Bhaskar Gollapudi, Farzaneh Teymouri, Michael B. Black |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cell signaling Carcinogenesis Down-Regulation Food Contamination Biology Pharmacology Toxicology Models Biological Risk Assessment Article 03 medical and health sciences 0302 clinical medicine Gene expression Acetamides Animals Humans Computer Simulation RNA-Seq Rats Wistar Mode of action Toxicity Tests Chronic Carcinogen Cancer Cell Proliferation Dose-Response Relationship Drug Cell growth Cell Cycle Liver Neoplasms Immunity Lipid metabolism Cell cycle Toxicogenomics Lipid Metabolism Rats Up-Regulation Gene Expression Regulation Neoplastic 030104 developmental biology Ki-67 Antigen Liver 030220 oncology & carcinogenesis Carcinogens Female Acetamide |
| Zdroj: | Toxicology and Applied Pharmacology |
| ISSN: | 1096-0333 0041-008X |
| Popis: | Acetamide (CAS 60-35-5) is detected in common foods. Chronic rodent bioassays led to its classification as a group 2B possible human carcinogen due to the induction of liver tumors in rats. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 or 28 days at doses of 300 to 1500 mg/kg/day (mkd) to determine a point of departure (POD) and investigate its mode of action (MoA). Ki67 labeling was increased at doses ≥750 mkd up to 3.3-fold representing the most sensitive apical endpoint. Differential gene expression analysis by RNA-Seq identified 1110 and 1814 differentially expressed genes in male and female rats, respectively, following 28 days of treatment. Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Benchmark dose (BMD) modeling of the Ki67 labeling index determined the BMD10 lower confidence limit (BMDL10) as 190 mkd. Transcriptional BMD modeling revealed excellent concordance between transcriptional POD and apical endpoints. Collectively, these results indicate that acetamide is most likely acting through a mitogenic MoA, though specific key initiating molecular events could not be elucidated. A POD value of 190 mkd determined for cell proliferation is suggested for risk assessment purposes. Highlights • Toxicogenomics can be used as weight-of-evidence to derive PODs for risk assessment. • Acetamide's POD for cell proliferation was 190 mg/kg/day. • Acetamide's rodent cancer induction is not consistent with other rodent carcinogens. • There is strong concordance between transcriptional and apical PODs. |
| Databáze: | OpenAIRE |
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