Scientific Society Offices

Recent Publications

Lab

Honors and Awards

Home

This laboratory is engaged in investigating mechanisms of toxicity. The outcomes of this effort may be viewed as a two-sided coin: one side represents contribution to science-based knowledge useful the assessment of risk from exposure to individual or combinations of toxicants; the other side represents emergence of new knowledge regarding how life processes respond to noxious insult. Laboratory animal models, organs, cellular and sub-cellular systems are used in these studies.

Intact laboratory animal models, isolated perfused organ systems, as well as in vitro bio-systems such as tissue slices, cells, and sub-cellular preparations are employed in an attempt to discover, integrate and validate new information. Experimental strategies include cutting edge genomic and proteomic approaches to test the conceptualized mechanisms at the level of biomolecules and are tested at sub-cellular, cellular, organ and whole animal systems. Studies are designed to discover mechanisms of initiation of injury, and progression or regression of injury using in vivo models of disease, so that new mechanistic concepts can be tested and validated using these models. Mechanistic concepts are developed in the context of verifiable, validatable animal models of toxicity and disease.

While discovery of new knowledge is emphasized in hypothesis-driven objectives, training top-class scientists to meet our future challenges in environmental and public health arena is the principal goal of this laboratory. Current research activity is focused on the following areas:

• Diabetics are known to be highly sensitive to hepatotoxic effects of drugs and environmental toxicants. Studies have shown that this is due to a combination of higher bioactivation of toxic chemicals and compromised tissue repair. The latter is more critical of the two factors and the underlying molecular mechanisms are the target of our focus in both Type I and Type II diabetic animal models.
• Moderate diet restriction is known to protect from lethal effects of hepatotoxicants such as thioacetamide. Protection is due to highly augmented tissue repair and occurs despite highly induced infliction of liver injury attendant to induced CYP2E1 in the liver.
• The molecular mechanisms behind augmented tissue repair in moderate diet restriction are the focus of current investigations. The roles of cytokines such as TNF-a, IL-6 and NO as well as growth factors such as TGF-a, EGF, and HFG in stimulated cell division and tissue repair are of interest. On-going investigations are designed to probe into the role of the respective receptors. The working hypothesis is that up-regulation of these factors as well as receptors might underlie the highly stimulated tissue repair in diet restriction.
• An additional are of research focus is the development of methods that might be useful in the assessment of risk from exposure to combinations of chemicals. Dose response relationships for individual model hepatoxicants as well as their mixtures (binary, ternary and quaternary) are being established. Current studies use sub-chronic (30 days) exposures to individual, binary, ternary and quaternary mixtures of four environmentally relevant toxicants.
• Acute renal failure is a serious clinical problem in elderly. Despite many new developments in the diagnosis and care of patients suffering from renal disease, today, very little can be done to save patients suffering from terminal renal failure. We have begun a series of investigations to examine and validate the concept that renal proximal tubule cells can divide upon injury and ensuing tissue repair restores renal function abrogated by selective renal toxicants. Initial studies indicate that renal toxicant, 1,2-dichlorovinyl L-cysteine (DCVC) promptly stimulates renal tissue repair after injury leading to complete recovery due to structural and functional restoration. Tissue repair shows a dose-response to low to moderate doses of DCVC and is inhibited at high doses. Current investigations are directed at understanding the underlying molecular mechanisms.
• Much is known about the powerful interactive toxicity of chlordecone and carbon tetrachloride at individually nontoxic doses. In young adult rats carbon tetrachloride toxicity (100 ul/kg ip, single dose on day 16) and lethality is amplified 67-fold upon exposure to 10 ppm chlordecone in the diet for 15 days. The dramatic amplification of carbon tetrachloride-induced liver toxicity and lethality is due to failed tissue repair. Because newborns have growing livers, they are completely resistant to this interactive toxicity until the age of 35 days. In recent studies, we observed that one- and two-year-old Sprague Dawley and Fischer 344 rats are completely resistant to the same combination of chlordecone and carbon tetrachloride. Studies have revealed that this is not due to any decrease in bioactivation of carbon tetrachloride, not due to any lower uptake or other toxicokinetic differences in the aged rats. The aged rats escape death because of earlier and robust stimulation of liver tissue repair. Current efforts are directed towards understanding the molecular mechanisms of this efficient tissue repair in old aged rats.
• Two additional areas of study are in the exploratory stage. First, the possibility of following clinical markers to correlate with survival and/or death upon exposure to known hepatotoxicants in animal models is being studied. Second, methods for quantitative analysis of advanced glycosylated end-products (AGE) are being assessed. Glucose is known to form AGE and the role of AGE in higher sensitivity of diabetes to toxic chemicals is not known. Present efforts are focused on establishing quantitative methodology to estimate AGE in Type I and Type II diabetic models.