Endocrine Disruption

Actions : Docking :: Receptor Binding
  1. Water Loving/Fat Loving?
  2. Hormone Receptors
  3. Inside the Cell
  4. On the Cell Surface
  5. Endocrine Disruption
  6. References

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.

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.

Inside the Cell
Fast Signaling Pathway

CAPTION: One way steroid hormones function is by binding to specific hormone receptors inside a cell. CREDIT: Tulane University

When steroid and thyroid hormones bind with hormone receptors inside the cell, they trigger the gene expression that ultimately leads to protein production. But first, the hormones must get to the cell, enter it, and bind to a receptor to produce an effect. How it happens goes something like this:

  1. Natural hormones, such as the estrogen called 17-beta-estradiol (pink), travel through the bloodstream and enter cells (cyan), where they may find matching hormone receptors, such as estrogen receptors (purple). Not all cells have a hormone’s compatible receptor. The ones that do are called target cells.
  2. Once inside a target cell, the hormone (pink) binds to a receptor (purple)  - similar to a hand sliding in a glove or mitten - and forms what is known as a hormone-receptor complex between the ligand and receptor. A ligand is any molecule that binds to a specific site on a protein or other molecule. In this case, the estrogen hormone 17-beta-estradiol is the ligand, and the estrogen receptor is the protein.
  3. Binding turns on, or activates, a hormone receptor. Activation sets in motion cell signaling systems that trigger gene expression and lead to responses typical of a particular hormone. First, the activated receptor attaches to a specific region of the DNA in the nucleus where it interacts with other activating molecules to turn on a specific gene or suite of genes. Then, the DNA’s genetic code is copied to make a complimentary messenger RNA (mRNA) through a process called gene transcription. The mRNA moves from the nucleus to the cytoplasm, where it is transcribed by ribosomes to make the proteins (enzymes, other receptors, etc.) that directly guide cell and body responses. In the case of estrogen hormones, these responses can include uterine growth to prepare for pregnancy or maintaining systems to prevent bone loss.

On 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:

Fast Signaling Pathway

CAPTION: Estrogen activates membrane receptor initiating a protein signaling cascade. CREDIT: Tulane University

  1. Natural hormones travel through the bloodstream and bind to receptors on the outside surface membrane of certain cells. For example, on immature fish oocytes (eggs), the progestin hormone progesterone (yellow) attaches to progestin receptors (blue barrel-loop structure). A similar kind of membrane progesterone receptor found in the mature eggs of fish and humans activates sperm, making the sperm cells fully competent to fertilize the egg.
  2. Binding activates the hormone receptor and sets in motion a rapid fire information exchange among a number of different kinds of signaling molecules. The process is akin to turning a car key to begin the almost instantaneous exchange of electrical signals from the ignition to the battery to the distributor to the spark plugs, which ignite the fuel in the cylinder producing the energy that starts the engine.

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.

Endocrine 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.

Fast Signaling Pathway

CAPTION: Foreign substances can interfere with hormones by binding to receptors inside the cell. CREDIT: Tulane University

Generally, these, and other plant and fungal compounds, drugs, pesticides, industrial agents, and metals known to interfere with natural hormones are collectively called endocrine disrupters (EDs). More is understood about how EDs interfere with receptor binding than with the other ways, or mechanisms, that these foreigners employ to disrupt endocrine-related functions. But whether the binding causes any long-term, adverse health conditions in humans is still debated.

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.

Hormone Mimic
CAPTION: Foreign substances can mimic with hormones by binding to receptors inside the cell. CREDIT: Tulane University

Like natural hormones, an array of foreign compounds (green), although different in shape and structure, can travel in the bloodstream, contact or enter a cell, and bind with a nuclear receptor. It is as if the imposters pick the lock, open the door, and fool the receptor into letting them dock.

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.

Fast Signaling Pathway

CAPTION: Foreign substances can block hormones by binding to receptors inside the cell. CREDIT: Tulane University

Hormone blockers include drugs like tamoxifen, a specific antiestrogen used to help treat certain types of breast cancers that need estrogen to grow. o,p’-DDE, a breakdown product of the insecticide DDT, blocks androgen receptors. This ties up the receptors so hormones such as testosterone cannot bind.

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.

  • Bassett J, Harvey C, and Williams G. 2003. Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol. Cell. Endocrinology 213:1-11.
  • Cato A, Nestl A, and Mink S. 2002. Rapid actions of steroid receptors in cellular signaling pathways. Science's STKE 2002: re9; doi: 10.1126/stke.2002.138.re9; Available: http://stke.sciencemag.org/cgi/content/full/sigtrans%3b2002/138/re9.
  • Drummond A, Britt K, Dyson M, Jones M, Kerr J, O'Donnell L, Simpson E, and Findlay J. 2002. Ovarian steroid receptors and their role in ovarian function. Mol Cell Endocrinol 191:27-33.
  • Hammes S. 2003. The further redefining of steroid-mediated signaling. Proceeding of the National Academy of Science 100:2168-2170.
  • Ikeuchi T, Todo T, Kobayashi T, and Nagahama Y. 2001. Two subtypes of androgen and progesterone receptors in fish testes. Comp. Biochem. Physiol. B 129:449-455.
  • Lee D and Chang C. 2003. Expression and degradation of androgen receptor: Mechanism and clinical implication. J Clin Endocrinol Metab 88:4043-4054.
  • Mangelsdorf D, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, and Evans R. 1995. The nuclear receptor superfamily: The second decade. Cell 83:835-839.
  • McDonnell D and Norris J. 2002. Connections and regulation of the human estrogen receptor. Science 296:642-1644.
  • Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, and Gustafsson J-A. 2001. Mechanisms of estrogen action. Physiol. Rev. 81:1535-1565.
  • Segars J and Driggers P. 2002. Estrogen action and cytoplasmic signaling cascades. Part I. Membrane-associated signaling complexes. Trends Endocrinol Metab 13:349-354.
  • Sperry T and Thomas P. 1999a. Characterization of two nuclear androgen receptors in Atlantic croaker: Comparison of their biochemical properties and binding specificities. Endocrinology 140:1602-1611.
  • Sperry T and Thomas P. 1999b. Identification of two nuclear androgen receptors in kelp bass (Paralabrax clathratus) and their binding affinities for xenobiotics: Comparison with Atlantic croaker (Micropogonias undulatus) androgen receptors. Biology of Reproduction 61:1152-1161.
  • Toran-Allerand C, 2004. Minireview: A plethora of estrogen receptors in the brain: Where will it end? Endocrinology 145:1069-1074.
  • Zhu Y, Bond J, and Thomas P, 2003a. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proceedings of the National Academy of Science 100:2237-2242.
  • Zhu Y, Rice C, Pang Y, Pace M, and Thomas P, 2003b. Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proceedings of the National Academy of Science 100:2231-2236.