The tissue-specific effects of different 17β-estradiol doses reveal the key sensitizing role of AF1 domain in ERα activity

Abstract

17β-Estradiol (E2) action can be mediated by the full-length estrogen receptor alpha (ERα66), but also by the AF1 domain-deficient ERα (ERα46) isoform, but their respective sensitivity to E2 is essentially unknown. To this aim, we first performed a dose response study using subcutaneous home-made pellets mimicking either metestrus, proestrus or a pharmacological doses of E2, which resulted in plasma concentrations around 3, 30 and 600 pM, respectively. Analysis of the uterus, vagina and bone after chronic exposure to E2 demonstrated dosedependent effects, with a maximal response reached at the proestrus-dose in wild type mice expressing mainly ERα66. In contrast, in transgenic mice harbouring only an ERα deleted in AF1, these effects of E2 were either strongly shifted rightward (10 to 100-fold) and/or attenuated, depending on the tissue studied. Finally, experiments in different cell lines transfected with ERα66 or 46 also delineated varying profiles of ERα AF1 sensitivity to E2. Altogether, this work emphasizes the importance of dose in the tissue-specific actions of E2 and demonstrates the key sensitizing role of AF1 in ERα activity.

A Tale of Ice and Fire: The Dual Role for 17β-Estradiol in Balancing DNA Damage and Genome Integrity

“…Nonetheless, it is well known that in vitro the concentration-dependent effects of E2 on both ERα-triggered ERE-based gene transcription and cell proliferation usually follow a bell-shaped curve with low-and supra-physiological concentrations of E2 (i.e., pM and µM, respectively) having the same effects. Remarkably, these observations have been also confirmed in animal models where different tissues are differentially sensitive to low or high levels of E2 [37].…”

“…In addition, in this case, the regulation of DNA synthesis induced by different E2 concentrations has not been thoroughly investigated. Recent evidence in mice shows that supraphysiological concentrations of E2 inhibit uterine epithelial cell proliferation and, consequently, the E2-induced increase of uterine weight [37]. In ERα overexpressing cells, E2-induced DNA synthesis occurs as rapid as 6 h [44,45].…”

“…uterine weight [37]. In ERα overexpressing cells, E2-induced DNA synthesis occurs as rapid as 6 hours [44,45].…”

“…Because nanomolar concentrations of E2 at the ovulation peak (i.e., 1 nM) activate E2:ERα complex-dependent gene expression and DNA duplication at maximal levels and supra-physiological concentrations of E2 can inhibit cell proliferation [37], high concentrations of E2 could be detrimental for cellular and tissue functions by damaging the genome through physical breaks on the DNA helix (please see below).…”

Transcriptome Sequencing Reveals Sex Differences in Human Meniscal Cell Response to Estrogen Based on Dosing Kinetics

“…14 Specific 17β-estradiol (E2) effects are dose-dependent and differ between tissues. 15 Additionally, several studies have found that the effect of estrogen varies based on dosing kinetics both in vitro 16; 17 and in vivo . 18 Typically, estrogen exerts its effects on cells by activating the nuclear estrogen receptors alpha and beta, which then regulate transcription of many genes.…”