Hepatic Encephalopathy (HE), and resultant elevated blood and tissue ammonia concentrations (i.e., hyperammonemia, HA), has profound central nervous system (CNS) effects, and can have environmental causes. In particular, liver damage due to exposure to toxicants such as carbon tetrachloride, toluene, DDT, heptachlor, etc., as well as chronic alcoholism and direct exposure to environmental ammonia, can elicit symptoms of HE/HA. However, there are such a wide variety of CNS effects produced in the disease in humans, and in rodent experimental models, that it is difficult to determine which disease biomarkers are the most critical indicators of disease progression. Furthermore, characteristics of the rodent model present several weaknesses in the study of HE/HA. Because of this gap in our knowledge, no practical and effective clinical intervention strategies are available to prevent or reverse biomarkers or symptoms of the disease. Recently, we have identified a vertebrate model, the gulf toadfish (Opsanus beta), which is both extremely tolerant of ammonia insult, and which, by virtue of its aquatic lifestyle, enables a line of experimentation not practical in mammalian models, namely rapid """"""""ammonia washout"""""""" protocols. Therefore, we propose to test several hypotheses aimed at exploiting these and other characteristics of this new model to address the lack of biomarkers and intervention strategies for HE/HA. In particular, we will: (1) test the hypothesis that there are reversible vs. irreversible biomarkers of HE/HA, and that these can be readily identified and distinguished in an aquatic model like the toadfish; (2) test the hypotheses that extreme ammonia tolerance in the toadfish, relative to mammals, is due to an unusual aspect of its physiology, in particular, either to a more robust ammonia detoxification system in the brain, or to an inherent insensitivity of brain mitochondrial metabolism to ammonia insult. As a further test of this second hypothesis, we will also explore the possibility that the toadfish has higher levels of naturally occurring ammonia protectant compounds (e.g., carnitine, trimethylamine oxide, etc.) in its brain tissues than do mammals. In sum, these experiments will lead to information which is not readily obtainable from humans and existing mammalian models concerning the mechanisms of action of ammonia and cellular capacity for tolerance and recovery, and thus to a better understanding of the causes and mechanisms underlying HE/HA that could lead to therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011005-03
Application #
6684175
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Heindel, Jerrold
Project Start
2002-02-08
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2005-11-30
Support Year
3
Fiscal Year
2004
Total Cost
$151,000
Indirect Cost
Name
University of Miami Rosenteil School
Department
Type
DUNS #
152764007
City
Miami
State
FL
Country
United States
Zip Code
33149
Veauvy, C M; Walsh, Patrick J; McDonald, M D (2009) Effect of elevated ammonia on tissue nitrogen metabolites in the ureotelic gulf toadfish (Opsanus beta) and the ammoniotelic midshipman (Porichthys notatus). Physiol Biochem Zool 82:345-52
Walsh, Patrick J; Veauvy, Clemence M; McDonald, M Danielle et al. (2007) Piscine insights into comparisons of anoxia tolerance, ammonia toxicity, stroke and hepatic encephalopathy. Comp Biochem Physiol A Mol Integr Physiol 147:332-43
Wood, Chris M; Walsh, Patrick J; Chew, Shit F et al. (2005) Greatly elevated urea excretion after air exposure appears to be carrier mediated in the slender lungfish (Protopterus dolloi). Physiol Biochem Zool 78:893-907
Veauvy, Clemence M; McDonald, M Danielle; Van Audekerke, Johan et al. (2005) Ammonia affects brain nitrogen metabolism but not hydration status in the Gulf toadfish (Opsanus beta). Aquat Toxicol 74:32-46
Rodicio, Lenore P; Sternberg, Leonel da Silveira Lobo; Walsh, Patrick J (2003) Metabolic fate of exogenous 15NH4Cl in the gulf toadfish (Opsanus beta). Comp Biochem Physiol C Toxicol Pharmacol 136:157-64
Veauvy, Clemence M; Wang, Yuxiang; Walsh, Patrick J et al. (2002) Comparison of the effects of ammonia on brain mitochondrial function in rats and gulf toadfish. Am J Physiol Regul Integr Comp Physiol 283:R598-603