**Background**
Estrogen receptors (ERα and ERβ) play a critical role in regulating various physiological processes, including reproductive development, bone density, and cardiovascular health. Dysregulation of these receptors or exposure to exogenous estrogenic compounds can lead to significant hormonal toxicity, reproductive disorders, and certain types of cancer. Understanding the modulation of these receptors is essential for treating menopausal disorders and studying the epigenetic mechanisms of hormonal toxicity. In this context, we will introduce a potent non-steroidal estrogenic compound – Diethylstilbestrol.
**Definition**
Diethylstilbestrol is a non-steroidal female hormone and a 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) inhibitor. It acts as a potent agonist for both ERα and ERβ, with an EC50 value as low as 0.007 nM for ERα transcriptional activation in MCF-7 cells.
**In Vitro and In Vivo Studies**
The Diethylstilbestrol biological activity is characterized by its ability to mimic estrogen and induce various cellular responses. Diethylstilbestrol in vitro studies have demonstrated that concentrations of 0-100 μM activate CatSper and promote Ca2+ flux into human spermatozoa, while concentrations of 0-10 μM for 1 hour induce oxidative DNA damage and apoptosis in spermatogonial stem cells. Furthermore, it exhibits significant antiproliferative and cytotoxic effects across various cell lines; for instance, it shows an IC50 of 0.4 nM against human MCF7 cells and an IC50 of 0.5 μM in BCRP-expressing K562 cells.
Regarding Diethylstilbestrol in vivo applications, administration of 2 μg/day (s.c.) in mice stimulates ERα-mediated hormonal toxicity in the seminal vesicle, which involves Diethylstilbestrol Epigenetics through the alteration of target gene methylation patterns and modifiers such as DNMT3A, MBD2, and HDAC2. In adult mice, a dose of 5 μg/kg (i.p.) reduces the number of thymocytes and induces Diethylstilbestrol Autophagy, evidenced by the increased expression of Becn1, LC3 I, and LC3 II. Additionally, oral administration of 340 μg/kg every 2 days for 2 weeks in rats decreases adrenal cholesterol and corticosterone, while 0.5 mg/kg (p.o.) decreases HSD11B2 activity in both rat and human placenta. In conclusion, Diethylstilbestrol is a versatile non-steroidal estrogenic agent used to study hormonal toxicity, epigenetic modulation, and reproductive dysfunction.
Keywords
Diethylstilbestrol, 56-53-1, Estrogen Receptor/ERR, Apoptosis, Autophagy, DES, HSD11B2, Inhibitor, ERR Agonist, Spermatogonial stem cells, inhibitor, inhibit
References
[1] Troisi, R., et al., Medical conditions among adult offspring prenatally exposed to diethylstilbestrol. Epidemiology, 2013. 24(3): p. 430-8.
[2] Kebir, O. and M.O. Krebs, Diethylstilbestrol and risk of psychiatric disorders: a critical review and new insights. World J Biol Psychiatry, 2012. 13(2): p. 84-95.
[3] Li Y, et al. Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ERα alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle. Environ Health Perspect. 2014 Mar;122(3):262-8.
[4] Haeno S, et al. Diethylstilbestrol decreased adrenal cholesterol and corticosterone in rats. J Endocrinol. 2014 Apr 22;221(2):261-72.
[5] Zou QX, et al. Diethylstilbestrol activates CatSper and disturbs progesterone actions in human spermatozoa. Hum Reprod. 2017 Feb;32(2):290-298.
[6] Singh NP, et al. Diethylstilbestrol (DES) induces autophagy in thymocytes by regulating Beclin-1 expression through epigenetic modulation. Toxicology. 2018 Dec 1;410:49-58.
[7] Habas K, et al. Diethylstilbestrol induces oxidative DNA damage, resulting in apoptosis of spermatogonial stem cells in vitro. Toxicology. 2017 May 1;382:117-121.
[8] Wang Y, et al. Diethylstilbestrol inhibits human and rat 11β-hydroxysteroid dehydrogenase 2. Endocr Connect. 2019 Jul;8(7):1061-1069.