ER Alpha

Octamethylcyclotetrasiloxane exhibits estrogenic activity in mice via ERalpha

ABSTRACT Octamethylcyclotetrasiloxane (D4) is a low molecular weight cyclic silicone used in the synthesis of larger silicone polymers and in the formulation of a variety of personal care products. The effects of oral D4 exposure in mice on serum estradiol levels, uterine wet weight, and uterine peroxidase activity were investigated. Additionally, in vitro estrogen receptor binding activity was evaluated. Serum estradiol levels decreased in a dose-dependent manner after exposure to 100 mg/kg to 1000 mg/kg D4. Studies with adrenalectomized animals demonstrated that the decreased serum estradiol levels were not due to elevated serum corticosterone levels. Uterine wet weights in ovariectomized mice were significantly increased in a dose-dependent manner by exposure to 250-1000 mg of D4/kg, but not by exposure to other silicone compounds tested (hexamethylcyclotrisiloxane, decamethylcyclopentasiloxane, decamethyltetrasiloxane, and octaphenylcyclotetrasiloxane). Uterine peroxidase activity, a marker for estrogenic activity, was also significantly increased in D4-exposed mice, but not in mice exposed to the other siloxanes. Pretreating mice with the estrogen receptor antagonist ICI 182,780 completely blocked the D4-induced increase in uterine weight, and ovariectomized estrogen receptor-alpha knockout mice showed no increases in uterine weights when orally exposed to D4 or estradiol. In an in vitro estrogen receptor binding assay, D4 showed significant competition with (3)H-estradiol for binding to estrogen receptor-alpha, but not estrogen receptor-beta. The data presented here indicate that D4 has weak estrogenic activity, and that these effects are mediated through estrogen receptor-alpha.

Estrogen receptor

Estrogen receptors are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol).[1] Two classes of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 (GPER), which is a G protein-coupled receptor. This article refers to the former (ER).

Once activated by estrogen, the estrogen receptor is able to translocate into the nucleus and bind to DNA to regulate the activity of different genes (i.e. it is a DNA-binding transcription factor). However, it also has additional functions independent of DNA binding.[2]

Proteomics

There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene (ESR1 and ESR2, respectively). Hormone-activated estrogen receptors form dimers, and, since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.[3] Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five domains (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER):(A-F domain) >>

D4 bindt zich aan oestrogeen receptor alpa >>

ER-alpha a nuclear hormone receptor and transcription factor. Regulates gene expression and affects cellular proliferation and differentiation in target tissues. Two splice-variant isoforms have been described. Note: This description may include information from UniProtKB.

Protein type: DNA binding protein; Nuclear receptor

Cellular Component: nucleoplasm; Golgi apparatus; chromatin remodeling complex; membrane; perinuclear region of cytoplasm; T-tubule; integral to membrane; plasma membrane; terminal button; perikaryon; nucleus

Molecular Function: identical protein binding; estrogen receptor activity; hormone binding; zinc ion binding; type 1 metabotropic glutamate receptor binding; nitric-oxide synthase regulator activity; beta-catenin binding; estrogen response element binding; transcription factor binding; steroid binding; protein binding; enzyme binding; protein complex binding; steroid hormone receptor activity; chromatin binding; transcription factor activity

Biological Process: estrogen receptor signaling pathway; positive regulation of nitric oxide biosynthetic process; uterus development; signal transduction; response to estradiol stimulus; regulation of apoptosis; positive regulation of fibroblast proliferation; regulation of transcription, DNA-dependent; positive regulation of epidermal growth factor receptor signaling pathway; epithelial cell development; transcription initiation from RNA polymerase II promoter; transcription, DNA-dependent; positive regulation of nitric-oxide synthase activity; negative regulation of transcription factor activity; antral ovarian follicle growth; androgen metabolic process; vagina development; Sertoli cell proliferation; positive regulation of retinoic acid receptor signaling pathway; negative regulation of I-kappaB kinase/NF-kappaB cascade; osteoblast development; response to estrogen stimulus; positive regulation of transcription from RNA polymerase II promoter; positive regulation of transcription factor activity; gene expression