Endocrine Disruption
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Actions : Delivery :: Transport Proteins Communication is key to making any relationship – whether a business, a friendship, or an organism - run smoothly. In animals, a wide assortment of chemical messengers start and stop communication signals in cells, organs, and tissues. One group, the essential hormones, moves endlessly to and fro. These transitory messengers, released by endocrine glands and specialized cells, passively travel around the body in blood and other fluids to reach suitable target cells. But, getting around in the watery blood is not easy for some types of hormones. Two large and important groups - the steroid and thyroid hormones - face this problem. Although their chemical makeup differs, both have an aversion to water (hydrophobic) and a preference for fatty surroundings (lipophilic). Protein companion escort these hormones around, a system that can sometimes be sabotaged by endocrine disrupting chemicals (EDCs). The steroid hormones, including estrogens, androgens, and other sex hormones, are derived from a kind of fat called cholesterol. Their lipid-based beginning makes them fat-loving (fat or lipid soluble) but prevents them from freely dissolving in water (water insoluble). Thyroid hormones, such as thyroxine and others released from the thyroid gland, are made from tyrosine, a ringed amino acid that dissolves more easily in fat than water. Since blood plasma - the liquid part of blood that carries hormones and other signaling molecules to tissues and cells throughout the body - is about 90 percent water, steroid and thyroid hormones have trouble mixing with and traveling in the blood. To get around, the hormones attach to water soluble proteins that shuttle them in the blood’s aqueous environment. These transport proteins deliver the hormones to their target cells and protect them from being chemically altered, inactivated, and eliminated from the body by the liver and kidneys. Transport Proteins Some hormone transport proteins in plasma are highly selective, transporting only steroid or only thyroid hormones. These highly selective transport proteins include sex hormone binding globulin (SHBG), which carries estradiol and testosterone; corticosteroid binding globulin (CBG), which carries glucocorticoids; and thyroid binding globulin (TBG) and transthyretin (TTR), both of which carry thyroid hormones. All vertebrates except birds have SHBG; only four-legged vertebrates have CBG; only some mammals, including humans, have TBG; and all vertebrates use TTR. Other hormone transport proteins are relatively non-selective, transporting almost any lipophilic molecule that enters the bloodstream, including steroid and thyroid hormones, plant-derived flavonoids, retinoids (vitamin A), fatty acids, and antibiotics. Albumin is a relatively non-selective transport protein found in all vertebrates. As the most abundant plasma protein, albumin's blood concentration often far exceeds even the flavonoids that flood the bloodstream after fruits and vegetables are eaten. Although albumin is not strongly attracted to particular molecules, there is so much of it in the blood that it simply mops up and shuttles stray fat soluble molecules. back to topEndocrine Disrupters Interfere Certain endocrine disrupting compounds (EDs) interfere with hormone delivery by binding to the selective steroid hormone or thyroid hormone transport proteins. Three kinds of problems can result. First, the endocrine disrupter may push off the natural hormone, preventing it from reaching its target cells and allowing the liver and kidneys to eliminate it from the body. Certain PCB breakdown products act like this. These chemicals can out compete thyroid hormones for binding to thyroid hormone transport proteins (specifically TTR) allowing the liver and kidney to dispose of the free-floating hormone too quickly. The body then perceives too low a level of thyroid hormone even though the thyroid gland is making enough. Second, an endocrine disrupter can attach to the transport protein, denature it, and destroy its ability to bind to other molecules. Equol, a plant flavonoid, causes this “suicide inhibition” of the sex steroid transport protein. Third, an endocrine disruptor could change how quickly or slowly the transport protein unloads hormone molecules. Pentachlorophenol, a persistent organohalogen used as an herbicide, pesticide, and product additive, greatly slows down testosterone unloading from the sex steroid transport protein at the target cell. In all these cases, the predicted consequences are the same: too little hormone reaches the target cells and the body perceives a low hormone level. The hormone-producing gland goes into overdrive making more and more of the apparently lacking hormone that never reaches its intended targets cells. back to topConsequences Currently, the overall consequences of disrupted sex steroid hormone transport are unknown. Many chemicals, including phenols used in detergents and plastics, phthalates used in plastics, and flavonoids present in fruits and vegetables can compete with estradiol and testosterone for binding to sex steroid transport proteins. But, nonhormone chemicals investigated so far do not easily attach to sex steroid transporters. The substances must be present in the bloodstream at 1,000 times higher concentrations than natural hormones before they can interfere. Only the flavonoids are likely to reach concentrations this high. Scientists are more certain about the consequences of disrupted thyroid hormone transport. Unlike with sex hormone transport proteins, certain EDs, especially PCB breakdown products, easily bind to thyroid transport proteins. Interfering with these proteins increases breakdown of thyroid hormone and causes the thyroid gland to compensate by over-producing thyroid hormone. The thyroid gland then enlarges and forms a goiter. Rainbow trout and coho salmon exposed to PCB pollution in the Great Lakes during the 1970s and 1980s and rats exposed to PCBs in laboratory experiments show exactly these symptoms. EDs interfering with the non-selective transporter albumin could have positive and negative effects with unknown results. Albumin's indiscriminate nature and abundance could protect vertebrates by soaking up EDs in the bloodstream and reducing their capacity to interfere with selective transport proteins and with cellular receptors (Baker 2002). On the other hand, albumin easily unloads attached fat soluble (lipophilic) molecules. Because of its weak specificity, albumin might shuttle EDs to other transport proteins or even to receptors that bind them more tightly. Generally, ED’s don’t bind strongly to most receptors or transporters and have 100-1000 fold lower binding affinity than the natural hormones. back to topReferences
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