The peripheral-type benzodiazepine receptor (PTBR) of trout brain was pharmacologically characterized and pyrethroid interaction with this site investigated. High-affinity binding sites for [³H]PK 11195 were detected in brain membranes of rainbow trout; these shared some of the characteristics of the PTBR of rodent brain (i.e., high affinity for PK 11195 and an endogenous ligand protoporphyrin IX) but were unique in the low affinity for Ro5-4864. Permethrin displaced [³H]PK 11195 binding with micromolar affinity while deltamethrin had less than 50% efficacy at displacement. Thus the PTBR appeared not to be relevant to pyrethroid toxicity in rainbow trout. Pyrethroid interaction with the GABA, receptor was investigated using [³⁵S]TBPS as a radioligand probe and by measurement of GABA-stimulated ³⁶c1- influx in vesicle preparations. At micromolar concentrations, deltamethrin, cypermethrin isomers and other pyrethroids inhibited [³⁵S]TBPS binding by 55- 95% with limited stereoselectivity. Pyrethroids were found to effect a GABAdependent inhibition of [³⁵S]TBPS binding. Ro5-4864, which showed micromolar affinity for the trout PTBR, produced a GABA-modulated interaction with [³⁵S]TBPS binding. These results delineate the reciprocal allosteric interactions between a pyrethroid binding site, a Ro5-4864 binding site, the GABA recognition moiety and the TBPS binding site in trout brain. However, pyrethroids exhibited a modest affinity for this binding site on the GABAA receptor. Pyrethroids indirectly inhibited the GABA-dependent influx of ³⁶Cl⁻into trout brain synaptoneurosomes by increasing the basal uptake of chloride, thereby compromising the ability of the vesicles to respond to applications of GABA. This pyrethroid effect was of nanomolar potency, stereospecific, tetrodotoxinsensitive and mimicked by veratridine. These results suggest that the primary effect of pyrethroids in trout brain, as measured by this assay, was due to an interaction with voltage-dependent sodium channels, increasing sodium conductance and thereby increasing the basal uptake of ³⁶Cl⁻ through a voltagesensitive channel. The convulsant activity of deltamethrin was tested in rainbow trout. The EC₅₀ for convulsant severity was 32 μg /kg body weight. By comparison, pyrethroids at these concentrations in rodents produce no overt toxicity but act as potent proconvulsants. / Graduation date: 1990

The ubiquitous presence of anthropogenic chemicals and their transformation products in surface water represents a toxicological concern from both an ecological standpoint and a human perspective as many of these chemicals are capable of altering hormonal function. Endocrine disrupting compounds can be traced back to numerous sources and may fall under the class of pesticide, industrial chemical, pharmaceutical, personal care product, and/or heavy metals. The adrenal gland is the most common target for endocrine disruptors, although in comparison to the sex steroids, this system has received much less attention in published research. Corticosteroids play a pivotal role in many physiological processes, including immunity, cognitive function, growth, metabolism, reproduction, mineral balance, and blood pressure. A primary cell culture of rainbow trout adrenocortical cells was used to investigate the endocrine disrupting activity of two commonly detected water-borne toxicants, a personal care product, triclosan (TCS), a pesticide, dichlorophenoxyacetic acid (2,4-D), and their transformation products, methyl-triclosan (M-TCS) and dichlorophenol (DCP). Previously, it has been shown that TCS, 2,4-D, and DCP exhibit a potential for endocrine disruption, although it is currently unknown if these chemicals are capable of affecting corticosteroid balance. In this study, all four chemicals showed significant inhibitory effects on corticosteroid synthesis, even though there were considerable differences in their activity. The chemical that exhibited the highest toxicity was 2,4-D, followed by TCS, DCP, and M-TCS. Both parent-compounds proved to be more toxic than their degradation products. More research with suitable test systems is needed to determine the mechanism(s) of action of these corticosteroid disruptors and the health risk that they may present. / ix, 139 leaves : ill. ; 29 cm