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Environmental chemicals disrupt the microbiota-gut-brain axis during zebrafish development
Citation:
Tal, T., D. Phelps, T. Catron, A. Swank, S. Keely, N. Brinkman, D. Hunter, C. Wood, AND M. Strynar. Environmental chemicals disrupt the microbiota-gut-brain axis during zebrafish development. Society of Toxicology, San Antonio, Texas, March 11 - 15, 2018.
Impact/Purpose:
Intestinal microbes are thought to influence mood, anxiety, and increasingly, brain development. It is currently unknown whether and how microbiota might influence the developmental neurotoxicity of environmental chemicals although it has been proposed that intestinal microbiota may mediate developmental neurotoxicity effects of environmental chemicals either by performing biotransformations or serving as a target of chemical exposures. This work shows that exposure to the antimicrobial agent triclosan causes behavioral hypoactivity in zebrafish larvae that contain microbes (conventionally colonized), but has no effect on zebrafish that are microbe-free. By exposing conventionally colonized zebrafish at different times over development, our data suggest that microbes that are permitted to grow in the presence of triclosan may harbor the ability to bioactivate the chemical. As a test case, we are using a combination of targeted and non-targeted mass spectrometry to understand whether host-associated microbiota produce novel biotransformation products that cause hypoactivity in conventionally colonized zebrafish larvae.
Description:
Growing evidence indicates that host-associated microbiota modify the toxicokinetics and/or toxicodynamics of environmental chemicals; however, current toxicological assessments do not consider interactions between microbiota and chemical toxicity. We previously reported that microbial colonization is required for normal neurobehavioral development in zebrafish. We therefore hypothesized that neurobehavioral toxicity may be mediated by altered microbial colonization during development. We explored differences in swimming behavior, microbial community structure, and chemical metabolism in axenic (microbe-free) and conventionally colonized zebrafish larvae that were exposed to the antimicrobial triclosan (0.1-0.3 µM) or vehicle (0.1% DMSO) on 1, 6, 7, 8, and 9 days post fertilization (dpf). At 10 dpf, neurobehavioral function was assessed. Triclosan exposure had no effect on locomotor activity in axenic larvae. In comparison, locomotor hypoactivity was observed in conventionally colonized larvae exposed to 0.3, but not 0.1 µM triclosan. Also on 10 dpf, triclosan exposure triggered concentration-dependent shifts in microbial community structure. To understand the temporal dynamics of triclosan-induced hypoactivity, conventionally colonized larvae were exposed to 0.3 µM triclosan in four scenarios: 1 dpf; 1 and 6 dpf; 1 and 9 dpf; or 1, 6, 7, 8, and 9 dpf. Triclosan exposure caused hypoactivity at 10 dpf in larvae exposed on 1 and 9 dpf or 1, 6, 7, 8, and 9 dpf. These two groups contained elevated concentrations of triclosan (ng/larva) at 10 dpf compared to larvae exposed to triclosan on 1 dpf as measured by high resolution mass spectrometry. Ultimately, this study will serve as a test case to apply non-targeted chemical analyses to reveal unique biotransformation products in axenic and conventionally colonized zebrafish exposed to triclosan during development. In summary, these data suggest that triclosan may exert behavioral effects via dysregulation of microbial colonization during development. More work is needed to understand the implications of these results to current toxicity assessment strategies. This abstract does not necessarily reflect EPA policy.