No description available.

No description available.

Graduation date: 1995

Haloalkenes were shown to react with cysteine, N-acetyl cysteine, or glutathione to form halogenated vinylthio (HVT) or saturated conjugates. When HVT were administered iv to rabbits, active transport in the renal tubules was inhibited 50% at doses as low as 20 mg/kg within 1 hr after dosing. There was sloughing of the renal brush border membrane with the injury progressing to a specific renal tubular necrosis of the S₃ segment. In vitro studies with renal tubules found that the HVT produced a dose-response related inhibition of acid/base transport, with complete inhibition of transport occurring at 1 mM. The cysteine conjugate synthesized from trichloroethylene, DCVC, inhibited tubular active transport 60 min after in vivo dosing (20-100 mg/kg), 45 min after exposure in the isolated perfused kidney (0.01-1 mM) and 15 min after incubation with isolated tubules (0.01-1 mM). All HVT conjugates had a similar potency with regard to transport inhibition in isolated tubules, with complete inhibition occurring at 1 mM within 15 min for cysteine conjugates compared to 45-60 min for the N-acetyl cysteine or glutathione conjugates. These latter conjugates are thought to be bioactivated to the cysteine conjugate prior to transport inhibition. Inhibition of tubular (gamma)-glutamyl transpeptidase by 1 mM AT-125 or 20 mM serine/borate prevented the inhibition of acid/base transport by the glutathione conjugate. In addition, the sequential formation of glutamate, glycine and the vinyl cysteine conjugate after tubule incubation with the glutathione conjugate provides further evidence for this bioactivation. The cysteine conjugates are thought to be further metabolized in tubules to a toxic intermediate by a brush border localized enzyme, C-S lyase. The inhibitor effect of this intermediate on acid/base transport is reversed in the presence of, or subsequent addition of, 6 mM exogenous glutathione. These studies provide further evidence for the nephrotoxicity of HVT, and formation of the nephrotoxic cysteine conjugates from glutathione and cysteine conjugates. The formation of saturated conjugates from CTFE was also demonstrated. These saturated and/or unsaturated conjugates may be responsible for haloalkene-induced nephrotoxicity.

Zebra mussels (Dreissena polymorpha) have invaded a great proportion of the waters of the eastern part of North America. This mollusk may be a useful sentinel species for bioaccumulation of heavy metals and organic contaminants in aquatic ecosystems. The zebra mussel's capacity to bioaccumulate cadmium at environmentally relevant exposure and to sequester metals in metal-binding proteins, metallothioneins, was investigated. Elevated (relative to control) concentrations of Cd$ sp{2+}$ were detected in Dreissena exposed to $ ge$2 $ mu$g Cd/liter suggesting that zebra mussels cannot regulate Cd$ sp{2+}$ of trace exposure concentration. More than 85% of the measured Cd$ sp{2+}$ was bound to metallothioneins. / Lesser scaup (Aythya affinis) was assessed as a model species for potential impacts of zebra mussels on higher trophic levels. The feasibility of incubating and rearing scaup in semi-natural conditions was evaluated. A series of biomarkers was assessed in 3 groups of scaup fed a contaminant-free diet or diets containing zebra mussels from the St-Lawrence River or Lake Erie. / Lesser scaup proved to be a suitable species to raise in captivity providing daily water misting through out incubation and strict hygiene conditions during brooding. A hatching success of 89% was achieved. Appropriate housing, feeding and bathing conditions yielded low (3%) post-hatching mortality. / Phagocytosis and respiratory burst activities of heterophils of scaup were suppressed after 6 weeks of feeding on zebra mussels, compared to the control group. These two heterophilic functions were negatively correlated with the incidence of pododermatitis (bacterial feet infection), suggesting a suppression of the non specific immunity. Increased liver/body mass ratio and decreased hepatic vitamin A (retinol and retinyl palmitate) concentrations were observed in scaups fed zebra mussels. Lipid accumulation and glycogen overload were found in the livers of scaups fed mussels from the St-Lawrence River and the Lake Erie groups, respectively. These immunological, biochemical and histopathological biomarkers show promise for monitoring "early" injury and may help in the understanding of health impairment of different species of waterfowl exposed to xenobiotics via contaminated food sources.

No description available.