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• W4377029119 abstract "<b>Abstract ID 16745</b> <b>Poster Board 585</b> P-glycoprotein (Pgp; MDR1; ABCB1) is central to the disposition of drugs and toxicants in adults, and is also crucial for protection of the developing embryo. Despite this fact, there are few developmental models of drug transporter biology. My research takes advantage of the sea urchin, a classical developmental model which produces millions of embryos per spawn, and which has well characterized cell lineages and regulatory networks of development. Here we recently utilized CRISPR/Cas9 mutagenesis to establish a homozygous knockout of Pgp (Pgp^-/-) and leverage its unique biology to perform high-content imaging of Pgp activity during the early cleavage stages. We found that Pgp^-/-embryos (n = 322) had a mean 2.67 ± 0.23-fold increase in the accumulation of 250 nM calcein-AM, a fluorescent Pgp substrate, as compared to their wildtype counterparts. In addition the Pgp^-/- embryos showed increased sensitivity to the cell cycle poisons vinblastine and taxol, with respective EC₅₀ values of 3.10 μM and 7.69 μM in wildtypes (n = 55 - 787, x¯ = 202) compared to 2.68 μM and 5.28 μM in crispant animals (n = 355 - 806, x¯ = 453). This study represents the first high content pharmacological study of sea urchin embryos and sets the stage for further investigation into developmental windows of vulnerability to xenobiotics. This embryo, which has functionally differentiated cell types forming a digestive system, skeleton, immune system, and germline precursors by the first 24 hours of development, is uniquely powerful for understanding perturbations to these embryonic structures. Each embryonic cell type has a unique suite of drug transporter expression patterns, potentially resulting in differences of xenobiotic penetrance and toxicity between cell types as the embryo develops. By establishing and screening additional drug transporter knockout lines targeting the pharmacologically-relevant genes MDR3/ABCB4, MRP1/ABCC1, and BCRP/ABCG2, we aim to understand the role of these transporters in protecting specific embryonic cell types from xenobiotics during early development. Support/Funding Information: National Institutes of Health (ES 027921) National Science Foundation (1840844)" @default.
• W4377029119 created "2023-05-19" @default.
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• W4377029119 date "2023-05-18" @default.
• W4377029119 modified "2023-09-24" @default.
• W4377029119 title "Discovery of Developmental Windows of Drug Sensitivity Using High Content Screening of Normal and Pgp-Knockout Sea Urchin Embryos" @default.
• W4377029119 doi "https://doi.org/10.1124/jpet.122.167450" @default.
• W4377029119 hasPublicationYear "2023" @default.
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