Activation of Estrogen Receptor-α by the Anion Nitrite

Abstract

In this study, the ability of nitrite and nitrate to mimic the effects of estradiol on growth and gene expression was measured in the human breast cancer cell line MCF-7. Similar to estradiol, treatment of MCF-7 cells with either 1 Mmol/L nitrite or 1 Mmol/L nitrate resulted in f4-fold increase in cell growth and 2.3-fold to 3-fold increase in progesterone receptor (PgR), pS2, and cathepsin D mRNAs that were blocked by the antiestrogen ICI 182,780. The anions also recruited estrogen receptor-A (ERA) to the pS2 promoter and activated exogenously expressed ERA when tested in transient cotransfection assays. To determine whether nitrite or nitrate was the active anion, diphenyleneiodonium was used to inhibit oxidation/reduction reactions in the cell. The ability of diphenyleneiodonium to block the effects of nitrate, but not nitrite, on the induction of PgR mRNA and the activation of exogenously expressed ERA suggests that nitrite is the active anion. Concentrations of nitrite, as low as 100 nmol/L, induced a significant increase in PgR mRNA, suggesting that physiologically and environmentally relevant doses of the anion activate ERA. Nitrite activated the chimeric receptor Gal-ER containing the DNA-binding domain of GAL-4 and the ligand-binding domain of ERA and blocked the binding of estradiol to the receptor, suggesting that the anion activates ERA through the ligand-binding domain. Mutational analysis identified the amino acids Cys381, His516, Lys520, Lys529, Asn532, and His547 as important for nitrite activation of the receptor. [Cancer Res 2008;68(10):3950-8]

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

“…One in vitro study ascribed estrogenic activity to the nitrite anion in a transcription assay 44. The relationship between NO and bone physiology is complex.…”

Integrative and comparative reproductive biology: From alligators to xenobiotics

“…Chloride depletion causes a chloride current across the membrane, which can enhance G-protein and cyclic AMP (cAMP)-dependent steroidogenesis, particularly when gonadotropin levels are low, as in juvenile animals (Choi and Cooke, 1990; Cooke, 1999; Cooke et al, 1999; Jensen, 2003; Panesar, 1999; Stocco et al, 2005). Furthermore, one study suggests that NO 2 can directly activate estrogen receptor alpha (ERα; ESR1) through the ligand-binding domain (Veselik et al, 2008). This latter effect could induce both negative and positive feedback control of steroidogenesis depending on other physiological parameters.…”

Endocrine Disruptors as Pollutants in Marine Ecosystem: A Case Study in Egypt

“…A new class of environmental estrogens referred to as metalloestrogens has been identified. Metalloestrogens include the heavy metals and metalloids cadmium, aluminum, antimony, arsenate, barium, cobalt, copper, chromium, lead, mercury, nickel, nitrite, selenite, tin, uranium and vanadate [62,63].…”