Effective phytoestrogens in a relative of turmeric and ginger
Many spices are purported to have medicinal effects. Turmeric, a spice made from the rhizome of Curcurma longa, and ginger, the rhizome of Zingiber officinale are used medicinally in parts of Asia. A close relative of these plants-- Curcurma comosa –has also been used medicinally and chemicals extracted from its rhizomes have been shown to have estrogenic effects. While the active chemicals have been identified, it was not until a recent publication in Environmental Health Perspectives that their mechanism of action was identified. In a set of experiments in transfected cells, and murine uterotrophic assays researchers from Thailand and the NIEHS identified effects and mechanisms for the three estrogenically active chemicals (D1, D2, and D3) in C. comosa rhizome extracts. All three stimulated MCF-7 cells in an estrogen dependent manner. This activity required a functional AF2 region of the Estrogen Receptor(ER). One of these three chemicals (D3) worked also in a non-ER dependent manner—it was also the only one to stimulate uterine growth in mice. Only one of the three chemicals (D2) could effectively interact with ERbeta. Since other members of this family of plants are used medicinally ( and C. longa is used in some cases for cancer patients) the presence and activity of related chemicals in their rhizomes should be investigated...
The Aryl Hydrocarbon Receptor (AHR) is an odd protein which functions as a ligand-activated transcription factor. Its ancestral function seems to be in embryonic development—the invertebrate form binds only to endogenous ligands and regulates tissue differentiation and morphogenesis. Mammalian AHR has a role in development, but it binds xenobiotics like PCBs (many of dioxin’s developmental effects map to functions of AHR in differentiation). A recent report details the DNA binding targets of ARH. Using ChIP and a mouse hepatoma cell line. The investigation discovered that the AHR binds to many targets even in the absence of ligands, and that the targets differ greatly between ligand-bound and free AHRs...
Recent studies in both animal and tissue studies have linked environmental estrogens to obesity and diabetes. Reviewing relevant studies, Retha Newbold and her colleagues have summarized the evidence that environmental estrogens have are a factor in metabolic diseases. They conclude that brief exposure to exogenous estrogens in early development alters genetic markers for obesity and increases body weight gain later in life. They indicate that early exposure to PCBs, DDT, persistent organic pollutants and even genistein have been linked in epidemiological studies to obesity. Concluding their survey, they suggest that the DES animal model can be used to further investigate the effects of environmental chemicals on the development of metabolic diseases...
Bisphenol A Data Suggest Longer than Expected Half-Life, Substantial Nonfood Exposure, or Both
Bisphenol A (BPA) has a long history for a synthetic chemical. Developed in the 1930’s as a synthetic estrogen, it eventually found industrial use in plastics. Hard plastics like polycarbonate and polyvinylchloride (PVC) use polymerized BPA to form strong and long stiff backbones for forming plastics. Recently BPA has been at the center of much controversy, with independent scientists and those with the US EPA differing on it’s threat to environmental and human health; meanwhile studies of BPA levels in the human population reveal a significant body burden and experiments on BPA in animals and cell culture show deleterious effects.
This month a paper in Environmental Health Perspectives reports on its careful examination of data from the NHANES study—a large longitudinal examination of health data across the US population. Pulling data on the concentrations of BPA in the urine of fasting individuals, the researchers looked to examine the half-life of BPA in humans. They found a definite decrease in fasting for 4 to 9 hours, but longer fasting showed no significant decline in BPA excretion. The scientists involved identify two possible explanations—a significant amount of BPA is stored in body fat, or there are other non-food exposures to BPA.
BPA is used in many plastics used in prepared and preparing food, including the lining of cans, and is often found in disposable eating utensils. Recent studies show as well that it can move from PVC pipes to water, and that single-serving disposable plastic drink containers may leach BPA as well. Certainly more research needs to follow these results, but for now concern about BPA continues to grow...
Steroid Hormone Receptors are a type of protein known as Nuclear Receptors. Nuclear Receptors are actually transcription factors which, constitutively or after binding a ligand, may increase or decrease the expression of genes. They are important mechanisms in the regulation of homeostasis and developmental differentiation of tissues.
Nuclear Receptors are relatively ancient, being found in all metazoans, and thus reaching back to the origin of multicellular organisms. Thus it should come as no surprise that mulitcellular organisms should show the evolution of parallel systems to coordinate extrinsic and intrinsic signaling using different Nuclear Receptors. An organism in which Nuclear Receptors are best studied is the model nematode Caenorhabditis elegans. A recent review of Nuclear Receptor function in C elegans suggests that they have developed their own functional version of an endocrine system which uses ligand-gated proteins analogous to, but different from, those in the chordate endocrine system.
Comparing the functions of these two systems should be a very productive path to further understanding the function and dysfunction of these transcription factors their control networks, and their downstream effects...
Exogenous estrogens have been shown to effect sex reversal in invertebrates, fish and amphibians. While feminization is known to occur in amniotes, there are no cases of sex reversal due to exogenous estrogens in amniotes. This may be due to the nature of sex determination in amniotes.
A recent review examines sex determination in amphibians, and suggests why sex reversal is possible in these animals. The diversity of genetic sex determination in modern amphibians suggests that chromosomal sex determination has occurred multiple times in this clade. In addition, the development of amphibian gonads is determined by levels of either CYP19 (for feminization) or CYP17 (for masculinization). Thus the sex of any individual, no matter their sex chromosome configuration, may be reversed. Since Fox and Sox genes, which are autosomally located, control CYP19 levels, exogenous effectors of these factors, or of CYP19 and CYP17 directly, may influence sex...
Hormone-activated estrogen receptors in annelid invertebrates: implications for evolution and endocrine disruption
The evolutionary role of estrogen has been a topic of increased research interest in the last two years. A study of the Mollusk estrogen receptor had called into question the ancestral role of the estrogen receptor, since the receptor of Octopus and other mollusks is constitutively active, and does not bind estrogen.
Another study, from the same lab, now reports that the estrogen receptor of annelid worms binds not only estrogen, but is either activated or antagonized by several known endocrine receptors. Thus, estrogen appears to have bound to an estrogen receptor since the origin of bilaterians about 600 million years ago...
Maternal regulation of estrogen receptor a methylation
Epigenetic silencing of genes by adding methyl groups to DNA is a primary developmental means of cell differentiation. Eyes become eyes, and skin becomes skin not because the cells have different DNA, but because these different types of cells selectively turn genes on and off by binding sections of the DNA tightly to enfolding proteins.
The estrogen receptor is a relatively well-studied example of an epigenetically controlled gene. Since the estrogen receptor is so important developmentally, behaviorally, and in susceptibility and recovery from disease, its epigenetic control is very important to understand.
This review summarizes evidence of maternal behavior affecting estrogen receptor epigenetics, suggesting that maternal behavior may be non-genetically inherited...
Bisphenol A at Low Nanomolar Doses Confers Chemoresistance in Estrogen Receptor-α–Positive and –Negative Breast Cancer Cells
Bisphenol A (BPA), originally synthesized as an artificial estrogen in the 1930’s, is now a widely used plastic in consumer and industrial goods. BPA has had a good deal of news attention recently, with scientists, industry, and regulators arguing its risks, and consumers demanding BPA free products. Some recent studies have suggested that the sources of BPA are more diverse than previously thought, and that it can be stored at significant levels in human bodies for a long time.
A research article just published reports on experiments exposing cancer cells to common anticancer drugs in the presence of BPA at low nanomolar concentrations. The authors report that BPA conferred protection to both estrogen receptor a positive and negative cell cultures...
Bisphenol-A and the Great Divide: A Review of Controversies in the Field of Endocrine Disruption
This review summarizes evidence about the risk to humans of Bisphenol A (BPA). It summarizes mechanisms by which low doses of BPA can have strong effects, and the levels of BPA to which humans are exposed (and whether those doses could have negative consequences). It also reviews routes of exposure, the primary diseases that might be caused by BPA, and outlines the disagreements between scientists and regulators on the risks of BPA...
Insight into estrogenicity of phytoestrogens using in silico simulation
Among the important questions that must be answered regarding the medicinal uses of phytoestrogens is the issue of how they bind to the estrogen receptor. This paper reports on computer simulations of docking of miroestrol and deoxymiroestrol to estrogen receptor a. The authors suggest that molecular dynamics simulations and binding energy calculations match well with bioassays. If this result is correct, it might be possible to use such simulations to test different phytoestrogens and even to design medical interventions
with plant chemicals...