Researchers in the Klaunig Lab are working on the following projects:
(1) Mechanistic Studies of Chemically Induced Liver Focal Necrosis in Rat
In these studies, we are investigating the potential mechanisms of n=1PMPA(N) induced pathological changes and more specifically, address whether a PPAR-alpha MOA similar to that of PFOA is involved in these processes. The chemical n=1PMPA(N) was invented as a replacement compound for Perfluorooctanoic acid (PFOA), which has been shown to produce liver toxicity and induce liver tumors following acute and chronic dietary exposure (Butenhoff et al. 2012; Cui et al. 2009; Elcombe et al. 2010; Biegel et al. 2001). Action of PPAR alpha receptor is considered the major mode of action of PFOA induced hepatotoxicity and hepatic tumors in animals (Klaunig et al. 2012). Though n=1PMPA(N) was predicted to be less toxic compared with POFA, it has been shown to cause a dose-dependent increase in rat liver focal necrosis and hypertrophy as well as decreases in hemoglobin and hematocrit in a series of short-term studies.
(2) Development of a Multiscale Mechanistic Computer Model of Acetaminophen Induced Liver Toxicity
The hepatotoxicity of Acetaminophen in rodents has been studied extensively (Gillette, 2000). Early work showed that acetaminophen is metabolically activated by CYP450 to a protein binding metabolite (Mitchell, 1973). It was also found that glutathione (GSH) was depleted and that supplementation of GSH reduces the extent of the liver necrosis. Subsequent studies identified roles for oxidative stress (Nakae, 1990), inflammatory derived cytokines such as TNFalpha and IL1alpha (Kuo, 1997) and mitochondrial dysfunction (James, 2003). Based on these findings, these studies aim to examine the pathways of acetaminophen induced liver toxicity in three differentially susceptible strains of mice (i.e., the normal or midrange sensitive strain C57BL/6J, the highly resistant strain Cast/EiJ, and the highly sensitive strain B6C3F1/J). The unique, coordinated multi-parameter analyses used in these studies will determine the degree to which different effects reflect a multi-faceted coordinated response to toxicity, a temporal sequence of responses, or artifacts of in vitro systems.
(3) MOA Analysis of Liver Tumors In Rodents Induced by Organochlorine Insecticides
In these studies, we are investigating the mode-of-action by which chlorinated insecticide compounds, such as toxaphene and dieldrin, induce liver tumors in the mouse. These studies encompass the evaluation of common mouse liver. These studies involve the examination of the commonly seen mode-of-action of chemical agents in the induction of liver cancer including oxidative stress, compensatory hyperplasia, receptor mediated changes, as well as, genotoxicity. Using in vivo mouse models these endpoints are being examined following short-term treatment to the chlorinated compounds in a dose-response manner. Results to date show a dose dependent increase in cell growth parameters and gene expression correlating with changes in oxidative stress and modulation of the CAR-receptor.
(Klaunig, Casseret and Doull, 2013)
(4) Interaction of Environmental Chemical with the Progression of Nonalcoholic Fatty Liver Disease
(5) Mechanistic Investigation of Retro-Element Mediated Non-genotoxic Carcinogenicity in Rodents
In this collaborative study, the Klaunig lab and researchers from Pfizer, University of British Columbia and University of Miami will utilize Wy-14643, a model compound of mouse-specific non-genotoxic carcinogenicity, to investigate the reactivation of retro-elements as a potential mechanism for the occurrence of some mouse-specific non-genotoxic tumorigenesis events. High-throughput next-generation sequencing of cDNA (RNA-seq) analysis will be deployed to identify retro-element expression changes induced by Wy-14,643. The successful identification of re-activated retro-elements would yield primers for early screening and/or in-situ hybridization and provide deeper understanding of some of the risks associated with drugs targeting epigenetic mechanisms.
(6) Understanding the Mechanism of PFOA Carcinogenesis in the Rodent and the Application of these Findings to Human Health Risk Assessment