CYTOPHOTOMETRIC ANALYSES OF NUCLEAR HEPATOCYTE RNA AND CHROMATIN RESPONSES IN RATS SUBJECTED TO SOMAN TOXICATION AND ANTIDOTAL TREATMENTS (HEPATOTOXICITY, PLOIDY, ORGANOPHOSPHATES).
- MOORE, RICHARD ALAN
- Physical Description:
- 184 pages
- Additional Creators:
- Pennsylvania State University
- Studies were conducted to assess the effects of acute soman, soman with various antidotal treatments, and chronic sublethal soman toxication on regulatory aspects of hepatocyte transcriptional-translational activity. Hepatic periportal (PP) and centrilobular (CL) parenchymal cell nucleic acid (RNA, DNA) levels in Sprague-Dawley x Wistar rats exposed to soman (33, 65, 120, or 190 (mu)g/kg) with and without atropine sulfate, pralidoxime chloride (2-PAM), and/or physostigmine salicylate treatments were used to assess the metabolic responses in individual PP and CL hepatocytes. Correlative data were also obtained on plasma and RBC cholinesterase levels. An additional aspect of this project was the validation of utility of azure B-RNA and Feulgen-DNA cytophotometry in quantification of toxin-induced cellular nucleic acid changes using scanning-integrating microdensitometry. and It was demonstrated that soman, a potent and irreversible cholinesterase inhibitor, elicits: (1) a severe depletion of blood ChE levels; (2) alterations in regulatory aspects of RNA-protein metabolism as evidenced by a marked hepatocyte RNA depletion notably with lethal dosages; (3) measurable nuclear chromatin changes in hepatocytes; and (4) histopathic alterations (vacuolization) in liver parenchymal cells. Currently recommended therapeutic regimens involving the use of various combinations of atropine, pralidoxime, and physostigmine did not prove effective in amelioration of hepatotoxic effects of soman; this was attributed in part to the fact that the antidotes themselves cause a measurable impairment in the RNA-protein synthetic capacity of hepatocytes. Both the cytochemical nucleic acid and cytomorphological alterations observed in soman toxicated rats appear to be indirectly mediated via a disruption or impairment of CNS-endocrine homeostatic mechanisms. On the other hand, the existence of direct hepatocellular damage with lethal doses cannot be predicted. An additional contribution of the present study was providing further documentation of the potential value of using analytical microscopic histochemistry in the evaluation of responses in target tissues such as the liver to toxic stress.
- Dissertation Note:
- Ph.D. The Pennsylvania State University 1985.
- Source: Dissertation Abstracts International, Volume: 46-09, Section: B, page: 2966.
View MARC record | catkey: 13612635