In Vitro Cell-Free Neurochemical Screening Assays to Predict Adverse Outcomes in Fish, Birds, and Mammals
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Owner/Developer: Society of Environmnetal Toxicology and Chemistry (SETAC)
United States of America
10 November 2014
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In vitro methods
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An estimated 30,000+ current commercial chemicals contain neurotoxic properties. As current animal studies are expensive, time-consuming, and overlook many at-risk organisms, development of a new, high-throughputscreening method is required. In vitro, cell free assays have potential as relatively inexpensive, reliable screening mechanisms to flag neurotoxic compounds. Thus, compounds can be prioritized according to their toxicity for more in-depth animal dose-response studies. Given the current lack of screening methods and a limited ability to conduct whole-animal bioassays on at-risk organisms, development of such bioassays is essential for future ecological risk assessment. Here, we report on results from a series of in vitro screening assays assessing neurotransmitters receptors (n=10) and enzymes (n=3) associated with essential behavior and reproduction, including components of the glutamatergic, GABAergic, dopaminergic, serotonergic, cholinergic, and other neurochemical pathways. Such neurochemical receptor and enzymes were isolated from at-risk organisms (n=20) of multiple taxa, including a fish (king mackerel, yellowfin tuna, goldfish, rainbow trout, and perch), birds (bald eagle, Japanese quail, chicken, and zebra finch), mammals (river otter, mink, pilot whale, common dolphin, narwhal, ringed seal, and polar bear), and biomedical species (rat, mouse, and human). The isolated neurochemical receptors and enzymes were dosed in vitro with a diverse set of 100 potentially neurotoxic chemicals, such as metals, rare-earth elements, pesticides, personal care products, flame-retardants, water/sediment extracts, and others. This was accomplished via development of neurochemical receptor binding and enzyme activity assays in a 96-well plate format. Specifically for receptors, total uninhibited binding of a specific radioligand was compared with radioligand binding in the presence of 50 uM of each potential toxicant. For enzymes, total product was compared with product formed in the presence of 50 uM of each potential neurotoxicant. In this presentation, we will 1) elaborate on the execution of such cell free assays and discuss 'pros and cons' of our current screening method, 2) explain initial results from our current assays and discuss potential conclusions that can be drawn from such data, and 3) discuss a strategy by which large volumes of in vitro data outputs may be modeled to predict individual-based adverse outcomes pathways.
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