Endocrine disruptors binding

The chemical structure of the substances capable of interacting with a determinate nuclear receptor is tremendously varied. For now no pattern exists that permits one to assure that a particular substance is going to interact with the receptor to produce an agonist or antagonist effect. In recent years the concept of endocrine disruptors has been introduced to describe the substances that are capable of modifying the endocrine equilibrium. Some of them act by binding with nuclear hormone receptors, while others interfere with the processes of regulation of hormone secretion (Lathers 2002 Melnick et al. 2002 Nakata 2002 Powles 2002 Brown et al. 2002 Sonnenschein et al. 1998). 

Most of the knowledge that we have regarding the interaction of chemicals with the endocrine system comes from in vitro receptor binding data. These receptor interaction data form the basis for many of the structure-activity relationships that have been derived for potential endocrine disruptors. It is important to note that potency measured in in vitro studies may or may not be relevant to the in vivo situation. The relative binding affinity (RBA) and potency of binding vary significantly within a given class of substances. For example, Branham et al. [11] reported... 

Prominent among toxicants that adversely affect both male and female reproductive systems are endocrine disruptors (see Section 9.7). Toxicants that mimic the actions of sex hormones are agonists, and those that prevent hormonal action or bind competitively to hormone receptor sites are antagonists,12 Male patients treated with cimetidine for peptic ulcers have exhibited low sperm counts and abnormal breast enlargement, a condition called gynecomastia. Gynecomastia has also been caused in men working in oral contraceptive production. Ketoconozole inhibits the enzymes required to produce hormones involved in sperm production and can immobilize sperm in seminal fluid. 

The MultiCASE system has been used to identify a common 6-A unit biophore on a range of hormonally active chemicals with estrogenic activity that act as endocrine disruptors. This structural feature is a spacer biophore that is thought to be involved in the molecules binding to the estrogen receptor and is found on the standard estrogenic chemical, 17-beta-estradiol (see Combes, 2000). Other examples of molecules possessing this biophore include 4-hydroxytamoxifen, 2-chloro-4-hydroxybiphenyl, 3,4-dihydroxyfluorene, and 2,2-(fcE-4-hydroxyphenyl-1,1,1 -trichloroethane). 

Fig. 14). The DNA-immobilized columns effectively accumulated more DNA-intercalating materials than the planar DNA films. The DNA-immobilized columns bound endocrine disruptors with a planar structure, such as dioxins, and benzo[a]pyrene. Bisphenol A and diethylstilbestrol, which lack a planar structure, did not bind to the DNA-coated columns. Table 1 shows the selective adsorptions of the insoluble DNA-based materials. 

The term endocrine disruptors was first used by Theo Colborn and Peter Thomas in 1992. In 1996, the US Environmental Protection Agency (EPA) convened a panel called the Endocrine Disruptors Screening and Testing Advisory Committee to make recommendations to EPA concerning endocrine disruptors. The term endocrine disruptors has been used interchangeably with hormonally active agents and endocrine modulators. As the term is used now, endocrine disruptors include any substance that affects the synthesis, secretion, transport, binding, action, inactivation, or elimination of natural hormones in the body. 

Endocrine disruptors often are structural analogs of endogenous hormones (hormones produced naturally in the host). Hormone analogs may act like the endogenous hormone if the analog-receptor complex in the target cell mimics the function of the hormone-receptor complex. Hydroxy metabolites of both o,p -DDT and methoxychlor bind to estrogen... 

The health effect of endocrine disruptors is further complicated by the fact that an endocrine disrupter or a family of endocrine disruptors may have multiple mechanisms of actions. For example, PCBs may mimic estrogen, prevent binding of thyroid hormone to thyroid binding globulin, and accelerate the metabolism and excretion of several steroid hormones. 

Xenoestrogens, exhibiting a wide molecular diversity, are found in a number of cosmetic products, such as plasticizers, perfume fixatives, and solvents (e.g., dibutyl phthalate), industrial chemicals and pollutants such as insecticides (e.g., methoxychlor, DDT, and DDE), epoxy resins, and polycarbonate (e.g., bisphenol A), and herbicides (e.g., simazine). This group of chemicals has been classified as environmental endocrine disruptor compounds (EDCs), defined as exogenous agents that interfere with the synthesis, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development, and/or behavior. A list of representative chemicals is shown in Table 1 based on commercial usage. 

A different form of toxicity occurs in the estrogen and androgen receptors when environmental chemicals have the ability to bind to them. Acting both as agonists or antagonists, these so-called endocrine disruptors are responsible for a number of hormone-related cancers, in addition to their roles in adversely affecting sexual development and reproductive fertility. 

The effect of these compounds on human health has been a major cause of concern. Toxicity to humans depends on exact structure, but exposure is ubiquitous and involves a mixture of compounds, from fossil fuel and natural and anthropogenic burning and from food, mainly grilled or barbecued meat. In the broader environment, PAHs are endocrine disruptors and bind to the aryl hydrocarbon receptor. They have been shown to depress immune function in some wildlife. They may be responsible for reproductive disorders in aquatic organisms, especially in shellfish and sediment dwellers. 

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