Joshua A. Harrill, Ph.D.
B.S., Biochemistry, North Carolina State University, Raleigh, NC, 2002.
Ph.D., Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 2008.
Liver stem cell biology and AhR-receptor mediated toxicity
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with high affinity for polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD). The canonical signaling pathway for gene regulation via the aryl hydrocarbon receptor activation includes ligand binding, translocation of AhR to the nucleus, dimerization with ARNT protein and regulation of the expression of numerous genes. AhR receptor activation and subsequent downstream gene regulatory networks are believed to play a critical role in the immunosuppressive and tumorigenic actions of TCDD. However, these networks have not been fully characterized and some question remains as to what aspects TCDD toxicity observed in rodent models are due to AhR activation and not off target effects. In order to investigate the role of the AhR and other unknown signaling pathways in TCDD toxicity, we have generated an AhR knockout rat on a Sprague-Dawley outbred background (i.e. a rat strain currently used by the National Toxicology Program in cancer bioassays). A primary research goal is to compare the response of AhR knockouts and wild-type controls in order elucidate which toxicities are mediated by AhR-receptor activation.
In addition, the tumor profile of TCDD in rodent cancer bioassays is unique in that a dose-dependent increase in the incidence of hepatocellular adenomas and cholangiocarcinomas is observed. TCDD also produces rat oval cell (i.e. the putative liver stem cell) hyperplasia. Given the ability of rat liver stem cells to differentiate along a hepatocellular or cholangiocyte lineage, we hypothesize that the liver tumor profile of TCDD may arise from an initiating event in the rat liver stem cell niche. We plan to investigate the effects of TCDD and AhR receptor activation on the proliferation and differentiation of primary rat liver stem cells isolated from both wild type and AhR knockout animals.
Alternative methods for developmental neurotoxicity hazard identification and characterization
Developmental neurotoxicity occurs when early life exposure to chemicals results in persistent deficits in nervous system function or changes in nervous system tissue structure at later life stages. Currently, in vivo guideline studies for assessing developmental neurotoxicity (US EPA 1998; OECD 2007) are costly, time consuming, labor intensive and impractical for use in characterizing the large number of chemicals in commerce for which there is no developmental neurotoxicity data. Alternative methods are needed to streamline developmental neurotoxicant hazard identification and characterization. My research interests focus upon the development of cell-based, in vitro test systems for examining chemical effects on the critical processes of nervous system development including neural progenitor cell proliferation, differentiation, apoptosis, neurite outgrowth and synapse formation. Each of these cellular processes can be quantitatively assessed in a medium- to high-throughput manner using high content image analysis technology. The research goals are two-fold: 1) development of an in vitro developmental neurotoxicity screening battery for rapid hazard identification and 2) investigation of cellular signaling pathways which underlie chemical effects on critical neurodevelopmental processes.
Selected Publications - click to view
Comparative sensitivity of human and rat neural cultures to chemical-induced inhibition of neurite outgrowth. Harrill, JA, Freudenrich, TM, Robinette, BL, Mundy, WR. Toxicol Appl Pharmacol. 2011; in press.
In vitro assessment of developmental neurotoxicity: use of microelectrode arrays to measure functional changes in neuronal network ontogeny. Robinette, BL, Harrill, JA, Mundy, WR, Shafer, TJ. Front Neuroengineering. 2011; 4(1): 1-9.
Use of high content image analysis to detect chemical-induced changes in synaptogenesis in vitro. Harrill JA, Robinette, BL, Mundy, WR. Toxicol In Vitro. 2011; 25(1): 368-387.
Quantitative assessment of neurite outgrowth in human embryonic stem cell-derived hN2 cells using automated high-content image analysis. Harrill, JA, Freudenrich, TM, Machacek, DW, Stice, SL, Mundy, WR. Neurotoxicology. 2010; 31(3): 277-290.
- Alison H. Harrill, Ph.D.
- Barbara A. Wetmore, Ph.D.
- Brett A. Howell, Ph.D.
- Darol E. Dodd, Ph.D., DABT
- Edward L. LeCluyse, Ph.D.
- Harvey J. Clewell III, Ph.D., DABT
- Jeffrey L. Woodhead, Ph.D.
- Jerry Campbell, Jr., Ph.D.
- Jingbo Pi, M.D., Ph.D.
- Joshua A. Harrill, Ph.D.
- Kyoungju Choi, Ph.D.
- Melvin E. Andersen, Ph.D., DABT, CIH
- Miyoung Yoon, Ph.D.
- O. Joe Trask, B.S.
- Paul B. Watkins, M.D.
- Qiang Zhang, M.D., Ph.D.
- Rebecca A. Clewell, Ph.D.
- Russell S. Thomas, Ph.D.
- Sudin Bhattacharya, Ph.D.
- Yuching Yang, Ph.D.