Statins inhibit blastocyst formation by preventing geranylgeranylation

Area of Science:

• Developmental Biology
• Molecular Biology
• Reproductive Science

Background:

• Statins, used to treat hypercholesterolemia, inhibit HMG-CoA reductase in the mevalonate pathway.
• The mevalonate pathway and HIPPO signaling are critical for early embryonic development, specifically trophectoderm specification.
• Previous research indicated statins impede mouse blastocyst formation, but the precise mechanism remained unclear.

Purpose of the Study:

• To elucidate the role of the mevalonate pathway in preimplantation mouse development.
• To investigate how statins, via HMG-CoA reductase inhibition, affect trophectoderm specification and blastocyst formation.
• To determine the involvement of HIPPO signaling and its downstream effectors in statin-induced embryotoxicity.

Main Methods:

• Mouse embryos (E2.5-E4.5) were cultured with statins and pathway intermediates (MVA, GGPP).
• Blastocyst formation efficiency was assessed morphologically and by cavity size measurement.
• Trophectoderm specification and HIPPO signaling (YAP localization) were analyzed via immunohistochemistry and RT-PCR.

Main Results:

• All tested statins inhibited blastocyst formation, an effect rescued by mevalonic acid (MVA) or geranylgeranyl pyrophosphate (GGPP).
• HMG-CoA reductase activity is essential for blastocyst formation primarily through GGPP production, not cholesterol synthesis.
• Statin treatment reduced YAP nuclear localization, indicating HIPPO pathway disruption, which was restored by MVA or GGPP.

Conclusions:

• The mevalonate pathway, via GGPP production, is indispensable for blastocyst formation by regulating HIPPO signaling and trophectoderm specification.
• Statins interfere with this pathway, leading to impaired blastocyst development and potential early conceptus demise.
• These findings highlight the risks of statin use for women attempting conception due to potential embryotoxic effects.