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

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...

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Published in:Journal of assisted reproduction and genetics 2016-08, Vol.33 (8), p.1027-1039
Main Authors: Bolnick, Alan, Abdulhasan, Mohammed, Kilburn, Brian, Xie, Yufen, Howard, Mindie, Andresen, Paul, Shamir, Alexandra M, Dai, Jing, Puscheck, Elizabeth E, Rappolee, Daniel A
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases - metabolism
Animals
Aspirin
Aspirin - pharmacology
Cloning
Diabetes
Diet
Dietary Supplements
Drug dosages
Embryo Biology
Embryo Culture Techniques
Embryo, Mammalian - cytology
Embryonic Development - drug effects
Embryos
Enzymes
Fertility
Fertility Agents - pharmacology
Gynecology
Human Genetics
Indoles - pharmacology
Infertility
Kinases
Medicine
Medicine & Public Health
Metabolism
Metformin - pharmacology
Mice
Polycystic ovary syndrome
Pregnancy
Prostate cancer
Proteins
Reproductive Medicine
Sorbitol - pharmacology
Stem cells
Stem Cells - cytology
Stress, Physiological
Toxicity
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Summary: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.
ISSN:1058-0468
1573-7330
DOI:10.1007/s10815-016-0735-z