April Technical Webinar: Renal Toxicology of Trichloroethylene, Dr. Larry LashWatch on Youtube

On Monday, April 13th from 1:00pm to 2:00pm EST, PROTECT will host its spring technical webinar of the 2019-2020 academic year. This webinar will feature Dr. Larry Lash, Ph.D. professor and associate chair of pharmacology at Wayne State University School of Medicine based in Detroit, Michigan. This webinar, titled “Renal Toxicology of Trichloroethylene,” will provide background knowledge on the toxicology of one of the main chemicals researched within PROTECT, Trichloroethylene (TCE).

For information on joining the webinar, please contact Kristin Hicks at k.hicks@northeastern.edu.

Read on to learn more about the webinar and Dr. Lash’s biography.

Abstract: Trichloroethylene (TCE) is a fairly simple 2-carbon, halogenated solvent that is a major environmental and occupational contaminant and has been categorized by multiple national and international agencies as a known human carcinogen. It is metabolized by both cytochrome P450 and glutathione (GSH) conjugation pathways. Significant sex- and species-dependent differences exist in TCE metabolism and in susceptibility and target organs. Reactive intermediates derived from the GSH conjugation pathway are those involved in renal toxicity and kidney cancer. The cysteine conjugate of TCE, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), is the penultimate nephrotoxic metabolite. Although a large number of mechanistic studies have been conducted in rodents and with in vitro models derived from rodent kidneys, studies in primary cultures of human proximal tubular (hPT) cells have several advantages, including maintenance of differentiated function, the ability to precisely define exposure conditions and study cellular mechanisms of action, and to obtain data from human tissue that can be directly used for hazard and risk assessment in humans without the uncertainty of species-dependent differences. Mechanistic studies of DCVC-induced cytotoxicity in hPT cells have identified mitochondria as early, sensitive intracellular targets, shown apoptosis and increased cell proliferation to be low-concentration, early responses whereas necrosis is a high-concentration, late response, and shown changes in gene expression for proteins involved in regulating cell proliferation, cell death, DNA damage and cellular repair. Recent studies in hPT cells and exosomes derived from those cells to identify novel biomarkers of DCVC exposure are summarized, using proteomics and lipidomics assays. The underlying hypothesis of these studies is that exposure of primary cultures of hPT cells to environmentally-relevant concentrations of toxicants (DCVC, mercuric chloride) results in interactions with mitochondria and release into the extracellular medium of specific proteins, lipids and altered patterns of metabolites. This hypothesis is also being applied to several drugs whose therapeutic utility is dose-limited by nephrotoxicity.

Biography: Lawrence Lash is currently a Professor and Associate Chair of Pharmacology at Wayne State University School of Medicine in Detroit, Michigan, USA, where he has been on the faculty since 1988. He received his Ph.D. in Biochemistry from Emory University in 1985, working on thiol oxidation and transport under the direction of Dean P. Jones. After a postdoctoral fellowship under the direction of M.W. Anders at the University of Rochester, where he studied the enzymology and toxicity of nephrotoxic halogenated solvents, he moved to Wayne State. Since 1988, his research has focused on studying various aspects of metabolism, transport, and disease models that influence susceptibility to chemically induced kidney injury. His research has identified mechanisms for renal mitochondrial and plasma membrane transport for glutathione, has defined cellular mechanisms of bioactivation and cytotoxicity of the nephrotoxic metabolite of the environmental contaminant trichloroethylene, and has developed and optimized use of primary cultures of human proximal tubular cells as a model for toxicology and biomarker identification studies. He has published more than 120 peer-reviewed manuscripts, more than 70 reviews and book chapters, has advised the U.S. Environmental Protection Agency, National Research Council, National Institutes of Health, and National Institute of Occupational Health and Safety, has served on three workshop committees for the International Agency for Research on Cancer, is an Associate Editor for three prominent journals in the fields of pharmacology and toxicology, was the founding Editor-in-Chief of Toxicology Reports, and is the current Editor-in-Chief of Toxicology and Applied Pharmacology. Dr. Lash is also extensively involved in education of medical and graduate students. In preclinical medical education, Dr. Lash oversees the longitudinal coverage of pharmacology in the curriculum, runs an online Clinical Pharmacology elective for Year-4 medical students, and provides lectures in several areas, including toxicology, renal pharmacology and toxicology, drug metabolism, pharmacogenetics, and immunopharmacology.