Citation:

Rosen, Mitch, S. Jeffay, H. Nichols, M. Hoopes, AND S. Hunter. ATP Binding Cassette Sub-Family Member 2 (ABCG2) And Xenobiotic Exposure During Early Mouse Embryonic Stem Cell Differentiation. Birth Defects Research. John Wiley & Sons, Inc., Hoboken, NJ, 110(1):35-47, (2017). https://doi.org/10.1002/bdr2.1114

Impact/Purpose:

As a xenobiotic transporter, ABCG2 has been identified as a useful marker in the ToxCast screening program. Data from our team also suggests regulation of ABCG2 might be a critical molecular initiating event associated with adverse development. Hence, ABCG2 transporter function could be a consideration when creating adverse outcome pathways linked to developmental phenotype.

Description:

Background: ATP binding cassette sub-family member 2 (ABCG2) is a well-defined efflux transporter found in various tissues. The role of ABCG2 during early embryonic development, however, is not established. Previous work suggests an association between exposure to xenobiotics that regulate Abcg2 transcription and differentiation of mouse embryonic stem cells (mESC), a relationship potentially related to redox homeostasis. Methods: mESC were seeded onto culture plates and grown for up to 9 days. Pharmacological inhibitors were utilized to assess transporter function with and without xenobiotic exposure. mESC proliferation and differentiation were evaluated using RedDot1 and qRT-PCR, respectively. ABCG2 activity was assessed using a Pheophorbide a-based fluorescent assay. Protein expression of ABCG2 was measured by capillary-based immunoassay. Results: ABCG2 activity was increased in differentiating mESC. Treatment of mESC with K0143, an inhibitor of ABCG2, had no effect on proliferation or differentiation. As expected, mitoxantrone and topotecan, two chemotherapeutics, displayed increased toxicity in the presence of K0143. Exposure of cells to K0143 in combination with chemicals predicted by the ToxCast screening program to regulate ABCG2 expression did not alter xenobiotic-induced toxicity. Moreover, inhibition of ABCG2 did not shift the toxicity of either tert-Butyl hydroperoxide or paraquat, two oxidative stressors. Conclusions: As previously reported, ABCG2 serves a protective role in mESC as a xenobiotic transporter. The role of ABCG2 in regulating redox status, however, was unclear. The hypothesis that ABCG2 plays a fundamental role during mESC differentiation or that regulation of the receptor by xenobiotics may be associated with altered mESC differentiation could not be supported.

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