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Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

  • Embryo Biology
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The purpose of the present study is to test whether metformin, aspirin, or diet supplement (DS) BioResponse-3,3′-Diindolylmethane (BR-DIM) can induce AMP-activated protein kinase (AMPK)-dependent potency loss in cultured embryos and whether metformin (Met) + Aspirin (Asa) or BR-DIM causes an AMPK-dependent decrease in embryonic development.

Methods

The methods used were as follows: culture post-thaw mouse zygotes to the two-cell embryo stage and test effects after 1-h AMPK agonists’ (e.g., Met, Asa, BR-DIM, control hyperosmotic stress) exposure on AMPK-dependent loss of Oct4 and/or Rex1 nuclear potency factors, confirm AMPK dependence by reversing potency loss in two-cell-stage embryos with AMPK inhibitor compound C (CC), test whether Met + Asa (i.e., co-added) or DS BR-DIM decreases development of two-cell to blastocyst stage in an AMPK-dependent (CC-sensitive) manner, and evaluate the level of Rex1 and Oct4 nuclear fluorescence in two-cell-stage embryos and rate of two-cell-stage embryo development to blastocysts.

Result(s)

Met, Asa, BR-DIM, or hyperosmotic sorbitol stress induces rapid ~50–85 % Rex1 and/or Oct4 protein loss in two-cell embryos. This loss is ~60–90 % reversible by co-culture with AMPK inhibitor CC. Embryo development from two-cell to blastocyst stage is decreased in culture with either Met + Asa or BR-DIM, and this is either >90 or ~60 % reversible with CC, respectively.

Conclusion

These experimental designs here showed that Met-, Asa-, BR-DIM-, or sorbitol stress-induced rapid potency loss in two-cell embryos is AMPK dependent as suggested by inhibition of Rex1 and/or Oct4 protein loss with an AMPK inhibitor. The DS BR-DIM or fertility drugs (e.g., Met + Asa) that are used to enhance maternal metabolism to support fertility can also chronically slow embryo growth and block development in an AMPK-dependent manner.

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Acknowledgments

Thanks to Jose Cibelli, Michael Diamond, and Erica Louden for comments on the manuscript.

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Author notes

  1. Yufen Xie

    Present address: Fertility and Surgical Associates of California, Thousand Oaks, CA, 91361, USA

Authors and Affiliations

  1. CS Mott Center for Human Growth and Development, Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, 275 East Hancock, Detroit, MI, 48201, USA

    Alan Bolnick, Mohammed Abdulhasan, Brian Kilburn, Jing Dai, Elizabeth E Puscheck & Daniel A Rappolee

  2. EmbryoTech Laboratories, 140 Hale Street, Haverhill, MA, 01830, USA

    Mindie Howard

  3. Ob/Gyn, IVF Clinic, University Physician Group, Wayne State University School of Medicine, 26400 W 12 Mile Road, Suite 140, Southfield, MI, 48034, USA

    Paul Andresen

  4. University of Utah, 201 Presidents Circle, Salt Lake City, UT, 84112, USA

    Alexandra M Shamir

  5. Program for Reproductive Sciences and Department of Physiology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Daniel A Rappolee

  6. Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Daniel A Rappolee

  7. Institutes for Environmental Health Science, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Daniel A Rappolee

  8. Department of Biology, University of Windsor, Windsor, ON, N9B 3P4, Canada

    Daniel A Rappolee

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  1. Alan Bolnick
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  2. Mohammed Abdulhasan
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  9. Elizabeth E Puscheck
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  10. Daniel A Rappolee
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Corresponding author

Correspondence to Alan Bolnick.

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Funding

DAR and EEP from the Office of the Vice President for Research at Wayne State University, from the REI fellows’ fund (AB), and from the funding of the Mary Iacobell and Kamran Moghissi Endowed Chairs.

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Capsule

Drugs metformin and aspirin and diet supplement BR-DIM cause AMPK-dependent potency loss and decrease embryonic development from two-cell to blastocyst stage.

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Bolnick, A., Abdulhasan, M., Kilburn, B. et al. Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos. J Assist Reprod Genet 33, 1027–1039 (2016). https://doi.org/10.1007/s10815-016-0735-z

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  • DOI: https://doi.org/10.1007/s10815-016-0735-z

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