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Developmental estradiol exposure results in microbiota-dependent effects on locomotor activity in larval zebrafish
Citation:
Catron, T., A. Swank, L. Wehmas, D. Phelps, J. McCord, R. Singh, J. Sobus, S. Keely, N. Brinkman, C. Wood, M. Strynar, AND T. Tal. Developmental estradiol exposure results in microbiota-dependent effects on locomotor activity in larval zebrafish. Society of Environmental Toxicology and Chemistry (SETAC), Sacramento, California, November 04 - 08, 2018.
Impact/Purpose:
Intestinal microbes are thought to play important roles in development of the nervous system. It has been proposed that microbiota can 1) interact with environmental chemicals through bioactivation or detoxification, or 2) be targeted by chemical exposures. This work shows that exposure to estradiol, a potent estrogen receptor agonist and reference chemical for estrogen receptor activation, causes neurobehavioral toxicity only in zebrafish with microbes. Following exposure, colonized zebrafish also contain three times less estradiol relative to microbe-free zebrafish, suggesting that microbes bioactivate estradiol. These data support the concept that microbiota have the potential to modify the toxicokinetics of chemical exposures.
Description:
Both natural and synthetic endocrine disrupting chemicals are known widespread environmental contaminants. During early vertebrate development, estrogen receptor signaling plays an important role in proper brain and nervous system development and function. Because host-associated microbial communities play important roles in nervous system development and can biotransform xenobiotics, we hypothesized that microbial colonization status may influence the neurobehavioral toxicity and chemical toxicokinetics of exogenous 17beta-estradiol (E2), a classic estrogen receptor agonist. To test this, conventionally colonized zebrafish were developmentally exposed to E2 in a semi-static system. At 10 days post-fertilization (dpf), mortality was assessed. 16S rRNA gene sequencing was used to evaluate potential shifts in microbial community composition and predicted metagenomic function following exposure to five non-teratogenic E2 concentrations (0.34–3.5 µM). Locomotor activity was assessed in colonized and axenic (microbe-free) zebrafish exposed to 0.4 or 1.2 µM E2 using a standard light/dark behavioral assay and zebrafish tissue was collected and analyzed using targeted and non-targeted chemistry techniques. Developmental exposure to E2 did not alter microbial composition or predicted function. Locomotor hypoactivity was observed in the light epoch in E2-exposed larvae colonized with microbes only; axenic larvae exposed to E2 exhibited a normal behavioral phenotype in the light. Targeted chemistry analysis revealed that axenic zebrafish contained three times more E2 than colonized zebrafish. Combined, these results suggest that host-associated microbiota bioactivate E2, resulting in an altered behavioral phenotype. These data demonstrate for the first time that chemical-induced neurobehavioral toxicity is dependent on the presence of microbiota and suggest that current hazard identification strategies have the potential to misestimate toxicological risk if chemical-microbiota interactions are not considered. This abstract does not necessarily reflect EPA policy.