Abstract
Estrogen plays fundamental roles in a range of developmental processes and exposure to estrogen mimicking chemicals has been associated with various adverse health effects in both wildlife and human populations. Estrogenic chemicals are found commonly as mixtures in the environment and can have additive effects, however risk analysis is typically conducted for single-chemicals with little, or no, consideration given for an animal’s exposure history. Here we developed a transgenic zebrafish with a photoconvertable fluorophore (Kaede, green to red on UV light exposure) in a skin pigment-free mutant element (ERE)-Kaede-Casper model and applied it to quantify tissue-specific fluorescence biosensor responses for combinations of estrogen exposures during early life using fluorescence microscopy and image analysis. We identify windows of tissue-specific sensitivity to ethinylestradiol (EE2) for exposure during early-life (0–5 dpf) and illustrate that exposure to estrogen (EE2) during 0–48 hpf enhances responsiveness (sensitivity) to different environmental estrogens (EE2, genistein and bisphenol A) for subsequent exposures during development. Our findings illustrate the importance of an organism’s stage of development and estrogen exposure history for assessments on, and possible health risks associated with, estrogen exposure.
Highlights
Exposure to endocrine disrupting chemicals (EDCs) is linked with a range of adverse health disorders and further understanding of EDCs effects is crucial for safe-guarding long-term human and environmental health[1,2]
Tissue-specific responses in the estrogen response elements (EREs)-Kaede-Casper model were consistent in subsequent generations for homozygous individuals as assessed via regular screening
In all water control samples chemicals were below the limit of quantitation (LOQ)
Summary
Exposure to endocrine disrupting chemicals (EDCs) is linked with a range of adverse health disorders and further understanding of EDCs effects is crucial for safe-guarding long-term human and environmental health[1,2]. Estrogen responsive transgenic zebrafish models have been developed with an estrogen response element (ERE) transgene[32,33,34,35] or brain-specific cyp19a1b transgene[17] to study responses to environmental estrogens These transgenic zebrafish include an inserted green fluorescent protein (GFP) sequence and the expression of this reporter sequence is driven by ligand-receptor binding to either inserted or endogenous EREs. Alternative fluorescent reporter sequences to GFP used in transgenic (TG) models include those that are photoconvertible such as the Kaede protein, where upon exposure to UV light, there is an irreversible spectral shift of the native (green) state from 508 nm (absorption) and 518 nm (emission) to longer wavelength peaks at 572 nm and 582 nm, respectively, resulting in a red state, comparable to the green state in terms of brightness and stability[36,37]. In this study we generated a novel estrogen responsive transgenic zebrafish model with a Kaede photoconvertable (green to red) fluorescent protein (ERE-Kaede-Casper zebrafish) and applied it to assess for windows of tissue-sensitivity to estrogen exposure during early-life and to investigate how exposure to estrogen during early life affects responsiveness to environmental estrogens for subsequent exposures
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