Supraphysiological estrogen levels adversely impact proliferation and histone modification in human embryonic stem cells: possible implications for controlled ovarian hyperstimulation assisted pregnancy.

Objective: Controlled ovarian hyperstimulation (COH) results in supraphysiologic levels of maternal serum estradiol (E(2)) during the luteal phase, thus promoting oocyte production at unknown risk to the subsequently developing embryo. Human embryonic stem cells (hESCs) have been identified as a model system to assess the impact of COH on early embryonic development, specifically 17β-estradiol mediated effects on proliferation, gene expression, and histone modification.

Study Design: Cell proliferation and associated factors, such as HDAC1, as well as histone modification patterns were evaluated in ERα and β expressing hESCs after exposure to 17β-estradiol (1×10(-10) M to 1×10(-7) M), as well as in an untreated control.

Results: Resultant data revealed that while physiologically relevant E(2) levels (1×10(-9)M E(2)) induced cell cycle progression from G1 to the proliferation phase, supraphysiologic levels akin to those observed after COH (1×10(-7) M E(2)) adversely affected hESCs proliferation via down regulation of HDAC1. Modification of H3K9me2, PhH3S10, H4K5ac, and H2A.Z histone patterns were also dependent on 17β-estradiol concentration.

Conclusion: While physiologic levels of 17β-estradiol induced cell proliferation, possibly via HDAC1 involvement in histone modification, cell proliferation in hESCs was suppressed at supraphysiologic levels.