The third installment of the ATTi 2020 webinar lecture series was presented on Dec. 3 by Dr. Rance Nault, Postdoctoral Research Associate in the Department of Biochemistry and Molecular Biology and Institute for Integrative Toxicology at Michigan State University.
A toxicogenomic approach for the risk assessment of the food contaminant acetamide Acetamide 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.
Rance Nault, PhD
Rance Nault is a Postdoctoral Research Associate in the Department of Biochemistry and Molecular Biology and Institute for Integrative Toxicology at Michigan State University. Dr. Nault obtained his master’s degree in Physiology and Chemical and Environmental Toxicology at the University of Ottawa, Canada, where he investigated the role of environmental contaminants on energy metabolism. He subsequently obtained his doctorate degree at Michigan State University where his research focused on leveraging novel high-throughput technologies to investigate mechanisms of liver toxicants. In his recent work, Dr. Nault is actively involved in evaluating the incorporation of transcriptomic technologies in the current risk assessment paradigm. His goal is to bridge emerging technologies with established toxicology approaches to improve our understanding toxicity mechanisms.