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ROLE OF ATP BINDING CASSETTE SUB-FAMILY MEMBER 2 (ABCG2) IN MOUSE EMBRYONIC STEM CELL DEVELOPMENT.
Citation:
Rosen, Mitch, K. Chandler, S. Jeffay, S. Charla, H. Nichols, M. Hoopes, AND S. Hunter. ROLE OF ATP BINDING CASSETTE SUB-FAMILY MEMBER 2 (ABCG2) IN MOUSE EMBRYONIC STEM CELL DEVELOPMENT. 2016 annual SOT meeting, New Orleans, LA, March 13 - 17, 2016.
Impact/Purpose:
To be presented at annual SOT meeting.
Description:
ATP binding cassette sub-family member 2 (ABCG2), is a member of the ABC transporter superfamily and a principal xenobiotic transporter. ABCG2 is also highly expressed in certain stem cell populations where it is thought to be related to stem cell plasticity, although the role of ABCG2 during early embryonic development is not established. While ABCG2-null mice exhibit a normal phenotype, inhibition of ABCG2 in mouse embryonic stem cells (mESC) has been shown to reduce colony expansion and promote differentiation. Furthermore, our earlier evaluation of ToxCast Phase 1 chemicals suggested an association between xenobiotics that regulate Abcg2 transcription and altered differentiation of mESC. J1 cells were seeded onto 96 well plates and allowed to attach for 24 hrs. Cells were cultured for various days in combination with K0143, a specific ABCG2 inhibitor, and either chemicals predicted by ToxCast Phase I assays to regulate the transporter expression or known substrates of ABCG2 (mitoxantrone or topotecan). Cell number was determined by RedDot1 staining and ABCG2 transport activity assessed using pheophorbide a. Differentiation was evaluated by real-time qRT-PCR using Pou5f1, Nanog, T, Gsc, Bmp4, Nes, Ncam1, Des, Ttr, Gata4, Myl4, and Myl. K0143 treatment alone had no effect on mESC differentiation or cell number and did not alter the toxicity of chemicals shown to regulate Abcg2 transcription in ToxCast Phase I assays. On the other hand, K0143 increased the toxicity of mitoxantrone and topotecan. The hypothesis that ABCG2 plays a fundamental role in mESC differentiation or that regulation of the receptor may be a toxic mode of action could not be supported. However, these data show that ABCG2 has a protective role as a xenobiotic transporter during early mESC differentiation. This analysis aids in developing a predictive model for identification of developmental toxicants. (This abstract does not reflect EPA policy.)