Endocrine Disruption
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Actions : Docking :: Receptor Binding
Every second of your life, hormone messengers are working to keep your body on track. These powerful endocrine system signalers regulate a variety of cell processes. Among other things, they stimulate cells to release chemicals, send electrical or chemical signals, grow, or produce proteins. All of these actions begin with the same step: a hormone binding to a specific hormone receptor either embedded in the cell’s outer surface membrane or floating inside the cell’s cytoplasm or nucleus. Regardless of location, the union of hormone and receptor spurs action by relaying instructions through a cell’s molecular signaling networks. Binding produces two distinct signaling routines: either slower via gene expression (hours to days) or very rapidly via molecular exchanges, or cascades (seconds to minutes). In both cases, the cell responds to the signals by manipulating proteins or building new ones. The affected workhorse proteins carry out specialized functions, such as controlling cell processes, building cells and tissues, or carting messages elsewhere within the cell or around the body. Some natural and synthetic compounds called endocrine disrupters (EDs) can sometimes interfere with normal hormone binding to convey inaccurate signals or send mixed messages that may result in altered health outcomes. Water Loving/Fat Loving? Whether a hormone binds to a receptor inside or outside a cell depends on the chemical nature of the hormone and its compatibility with the cell’s fatty outer membrane. The membrane’s fat layers impede water-friendly hormones from passing through but allow fat-derived hormones to readily enter the cell. Some hormones can easily go into cells to find matching receptors. The fat-based steroid hormones - estrogens, androgen, progestins, etc. - belong to this category. These messengers prefer fat (fat, or lipid, soluble) surroundings and shun water (water insoluble). They can easily pass through the cell membrane but need chaperone proteins to accompany them through the watery bloodstream. Steroid receptors, then, can be found in either the cell’s outer membrane, cytoplasm, or nucleus. Other hormones stay outside the cell and attach to the receptors wedged in the outer membrane. Insulin, growth hormone, and other protein-based peptide hormones dissolve in water (water soluble) and shun fat (fat insoluble). The cell’s fatty membrane impedes these water-loving messengers from readily entering the cell. Therefore, peptide hormones stay outside the cell and bind only with receptors in the cell’s outer membrane. Hormone messengers can also mix it up. The amino-acid derived thyroid hormones, which behave more like steroids than like their peptide cousins, can bind to receptors located both on the cell surface and inside the cell. click here to read about Hormone Receptors In and On Cells... Hormone Receptors Hormone receptors are large, flexible protein molecules that interlock with hormones and read and respond to their signals. Compatible structures facilitate binding between the two - like a baseball in a glove - but the fit is not restrictive, perfect, stiff, or permanent. Hormone and receptor both bend and flex, slightly changing shape to accommodate the other - similar to two hands coming together in a handshake. Hormones, though, only bind to certain, compatible receptor types. Thyroid hormones and each steroid hormone group - the estrogens, androgens, progestins, glucocorticoids (stress hormones), and mineralocorticoids (water and ion-regulating hormones) - have a matching hormone receptor type. For instance, estrogen hormones, like estrone, bind to estrogen receptors (ER); androgen hormones, such as testosterone, bind to androgen receptors; and so on. But, steroid hormone receptors for each hormone group can occur in several versions that differ in form, function, and location. So, steroid and thyroid hormones are not restricted to interact with only one receptor, in one tissue, to produce one kind of action. The hormones can easily bind and activate several versions of their matching receptor type. An example is the estrogen 17-beta-estradiol. It binds to both the ER alpha and ER beta receptors but not to androgen, progestin, or thyroid receptors. Each receptor version may turn on and off different responses in different cells in different parts of the body. For instance, ER alpha, promotes tissue growth and is found in greater amounts in the uterus, pituitary gland, and epididymis (the male sperm storing structure). ER alpha stimulates certain breast cancer cells to grow in response to estrogen hormones. The other version, ER beta, inhibits growth (possibly suppressing cancer) and prevails in the ovary and prostate. It can act like a dimmer switch for ER alpha, turning down its growth-stimulating effect. click here to read about Steroid Hormone Receptors... back to topInside the Cell
click here to read about how Nuclear Receptors Trigger Genes... back to topOn the Cell Surface Steroid and thyroid hormones can also interact with membrane receptors embedded in the membrane surface of the cell. Hormones binding these receptors from the outside of the cell can produce a lightening fast cascade of molecular signals ending in immediate actions. This molecular response is dramatically different from the gene expression response. It takes only seconds to minutes to complete versus hours to days for gene expression. How it happens goes something like this:
In the cell, some of the most vital players are enzymes - the proteins that speed up chemical processes (pink and dark green). Like the electricity released when a car key turns, the enzymes turned on by hormone binding jumpstart and propel a chain of molecular conversions that end with specific cell functions. In the case of the fish oocyte, the enzymes cause the resting cell’s nucleus to dissolve. The cell switches on and grows into a mature egg that can be released by the ovary (ovulated) and fertilized. click here to read about Steroid Receptors on Cells... back to topEndocrine Disruption At one point, scientists thought only a specific hormone could trigger a specific receptor into action, similar to how one key opens only one lock. But, they have found the mechanism is not so simple. A more fluid and less structured molecular process allows for related natural hormones, such as the estrogens 17-beta estradiol, estrone, and estriol to dock with the same receptor, such as ER alpha. Likewise, a single hormone, such as 17-beta estradiol, can bind with multiple related receptors, such as ER alpha and ER beta. Unexpectedly, other, nonhormone molecules were found to exploit the system, too. Many, vastly different natural compounds and synthetic chemicals do bind to hormone receptors. o,p’-DDT, nonylphenols, some PCBs, some chemicals used to make plastics (bisphenol A), and many plant flavonoids, also known as phytoestrogens, are examples.
How intensely and accurately the imposters imitate or block natural hormones by binding to hormone receptors varies widely. The most studied EDs, known as environmental estrogens, bind best to estrogen receptors. Other classes of EDs can attach to androgen or progestin receptors. Some can even bind to multiple types of hormone receptors. All in all, most EDs bind less tightly, or with lower affinity, than natural hormones.
Once bound, EDs can produce a variety of outcomes. The mimics can produce a normal hormone response, cause an abnormal response, or elicit no response by blocking the receptor and preventing natural hormones from binding. Many substances mimic natural hormones and produce a normal hormone response. Some pharmaceuticals, such as the synthetic estrogen ethinylestradiol in birth control pills, and plant compounds, such as the soy isoflavone genistein, provide the best examples of this. Chemicals that produce an abnormal response include compounds like the insecticides kepone and o,p’-DDT and its metabolite o,p’-DDD or the detergent alkylphenol polyethoxylate (used in household and industrial detergents). Kepone, o,p’-DDT, and alkylphenols can cause an estrogen-like response at the wrong time or in the wrong amounts in both sexes. These kinds of estrogen mishaps can enhance female traits in males (feminize) or cause permanent birth defects that jeopardize survival and reproduction . In addition, kepone and o,p’-DDD can block progesterone receptors on the outside membrane layer of sperm cells, preventing them from becoming competent to fertilize eggs.
All in all, much still needs to be learned about how membrane and nuclear hormone receptors function to control cell processes. Discovering more about these mechanisms will lead to a greater understanding of how ubiquitous environmental chemicals interfere with hormones and what, if any, harmful health problems may ensue. back to topReferences
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