Endocrine Disruption

	 Endocrine Disruption
The endocrine system is very dynamic and has ties to most, if not all of the other major systems of the body. It is responsible for production of hormones and the regulation of them as well. These hormones act as chemical messengers within the body. Through several differing mechanisms, they are able to trigger very specific responses in target cells or organs. This is what enables the endocrine system to guide growth, development, reproduction, and behavior, among many others as well.
The hormones produced from the endocrine system come from a wide range of different places. Among those responsible for hormone production are the glands and a few organs as well. The glands that are involved are the pituitary, thyroid, thymus, parathyroid, and adrenal. The organs, which also play a vital part, are the pancreas, gonads, kidneys, heart, and parts of the digestive tract. All these different glands or organs work together in the production of certain hormones. Those produced in one location will almost always have an effect on many other areas of the body, not just the surrounding tissues.

An analogy that fits very well with the study of the endocrine system is that of a message in a bottle. We can think of the body as a river, and a specific hormone may be a bottle containing a message. The organs or glands mentioned above would manufacture the ?bottles?; (hormones) that would be released into the river (blood stream). If there were no receptor sites for the hormones in the body, then they would continue to flow along the river and probably not make their destination. However, there are systems of receptor sites that enable specific hormones to bind in specific places. Structure also plays a major role in determining which hormones are able to bind to which receptors.
When these ?messages in bottles?; reach their appointed destination, the binding into the receptor site causes a cascade of reactions to occur. It is these reactions that are vital in maintaining our homeostasis. Many times the binding of the receptor site causes a direct expression of a certain gene. This is where endocrine disrupters can exert major damage. In addition to gene expression, endocrine disrupters cause havoc in many other areas of the body. What exactly are endocrine disrupting chemicals?

Endocrine disrupters are chemical agents that produce reversible or irreversible effects in individuals or populations by interfering with hormone function. This definition covers a very wide range of chemicals, many of which I will give brief descriptions of later. These ?chemical agents?; may exhibit several different mechanisms in their action of producing the endocrine disrupting effects.

The suspected endocrine disrupters themselves may actually mimic the function of the natural hormone. The chemical in question may be so similar in structure to the hormones that they are able to bind in the receptor sites and produce cellular responses. In essence, the endocrine disrupters are competing with the natural hormones for priority in binding in the specified sites. Since these endocrine disrupting chemicals are usually distributed in large quantities, it would produce many more molecules able to bind with the receptor. This can happen even if the cellular levels of the actual hormone are extremely low or even absent. What does this mean? This translates into the initiation of certain cellular responses when they are not needed and could be very harmful.

Another suspected mechanism is that the endocrine disrupting chemicals are just blocking the function of the natural hormone. This is in contrast to the mechanism above, where the disrupters are actually binding in the site the hormones usually would. This mechanism would produce a lower level of cellular responses, opposite of the first mechanism. There are a few other mechanisms that are thought to occur, but the majority of those we have discovered thus far fall under one of the two described above.
We have defined endocrine disrupters and given their two possible modes of action, but why exactly are we concerned with them? Endocrine disrupting chemicals are especially dangerous due their ability to alter hormone function by both binding and non-binding to the receptor site/s.

When the chemical agents bind to the receptor site/s they are able to effect growth, reproduction, development, behavior, among many other body functions. All the items listed in the preceding sentence are strongly related to hormone function. When the hormone molecules are functioning, as they should, they regulate all of the areas that were listed. It is the irregular levels of the endocrine disrupters that are causing abnormal endocrine functions to occur.

On the other end of the spectrum: synthesis, storage, release, secretion, transportation, and elimination are all affected without receptor site binding. Other types of endocrine disrupters inhibit the natural hormones from performing their specified function. When this occurs, it has a more generalized effect on the molecular level of things. The items discussed in the previous paragraph are, for the most part on the macro level, compared to the items listed here, which are more on the micro level.
To re-cap briefly, chemical agents that bind in the specified hormone sites produce effects on a larger scale than chemicals that only block the function of the natural hormones. Depending on which chemical is involved in the exposure, the effects can vary somewhat. These effects can also vary from individual to individual since they may also be muti-factorial.

Endocrine disrupters can produce several effects within the body. These effects can include, but are not limited to androgenic, estrogenic, thyroid problems, and neurological problems. Androgenic problems would involve those related to the male reproductive system, while the female reproductive system is associated with estrogenic effects. The last two problems listed could possibly be grouped together. The thyroid problems associated with endocrine disruption are also closely related to thyroid function. In a later part of the paper I will give some research examples of all four of these effects. Next I would like to discuss the different chemicals that are either known as endocrine disrupters, or highly suspected.

There are approximately 15,000 chemicals that are used commercially today. To test this many substances for endocrine disruption activity would take billions of dollars and an extremely large amount of time. However, even as early as 1938 we have known that certain chemicals were able to exert estrogenic effects on organisms. We by no means have a complete list, but the one we possess is becoming more complete as additional research is conducted. The majority of endocrine disrupting chemicals (edc) fall into two broad categories of pesticides (including herbicides, insecticides, and fungicides) and industrial chemicals. In the following paragraphs a description of several of these chemicals will be given in addition to their chemicals structures.

Industrial chemicals are widely used throughout the world. They constitute a majority of the 15,000 substances used for commercial use. In addition to the high number of substances used, there are also exists high diversity in the methods the chemicals are disposed of. This is a major contributing factor in why we are examining these chemicals to begin with.

The first chemicals I will describe are dioxins and furans. Their chemical structures are as follows:


Dioxin Furan
These two substances are chemically different from one another, but are both produced in similar ways. The are left as unwanted byproducts from industrial activity such as medical and municipal waste incineration, pulp and paper bleaching, fuel combustion, and pvc manufacturing. Both of these chemicals are considered very dangerous by the epa not only due to damage they may cause themselves, but also do to reactions they undergo with other substances.

An example of dioxins and furans reacting with other chemicals would be their reaction with polychlorinated biphenyls. Both dioxins and furans are fairly reactive to begin with, but adding heat and PCB?s can produce some fairly nasty mixtures. The substances formed in these reactions are polychlorinated dibenzofurans (pcdf) and polychlorinated dibenzodioxins (pcdd) respectively. The PCDF?s and PCDD?s that were formed in the reactions have been linked to a few very large disease outbreaks. One of the incidents occurred in Japan, while the other occurred in Taiwan. The people who were exposed to these chemicals experienced severe side effects that were also passed on to their young.
Continuing from the previous group of chemicals, I will now briefly look at PCB?s (polychlorinated biphenyls). One of the chemical structures is as follows:

This picture represents one of over 206 possible congeners, which
are similar to isomers. These chemicals were first used
commercially around 1930. At first glance, they were almost considered a miracle substance. They were used in electrical capacitors, adhesives, oils, and paints, among several other things due to their flame-retardant capabilities. This was all found irrelevant in the 1960?s when the U.S. began testing the substance. It was shown to have carcinogenic effects in mice, so its production was eventually banned in the United States in the late 70?s. We have now discovered it has estrogenic effects and impairs neurological development as well. In a later section, I will discuss how PCB?s inhibit thyroid function in the developing fetus thereby causing neurological problems.
The next chemical I will describe is bisphenol-A with its chemical structure:

Looking at all the structures I have discussed
thus far, there is commonality between them.
All of them up to this point have exhibited some sort of ring structure, and bisphenol-A continues with that trend. This substance is a major component in polycarbonate plastics, epoxy resins, and flame retardants. There are over one billion pounds of this chemical produced annually in the United States, Europe, Japan, Taiwan, and Korea. The epoxy resins that contain bisphenol-A are used to coat the inside of food cans and also as dental sealants. This chemical is one I mentioned on page five, that we have known that it exhibits estrogenic effects since 1938. Why is this a large concern? This is important because lab test show that the bisphenol-A leaches out of the epoxy coatings and sealants into our food and saliva. We do not know exactly how detrimental this is to us, but we have known that it is estrogenic for over 60 years now.

The final substances I will discuss under the industrial chemical category are phthalates. Their chemical structure is as follows:

This is the most abundant manmade chemical in our environment and found virtually everywhere in the world. Phthalates have been shown to produce weak estrogenic effects. This was demonstrated in an experiment in which
rats were given drinking water contaminated with benzyl butyl phthalate during their gestation period. It was linked to decreased sperm counts and smaller testis size.
Now that I have discussed a handful of the chemicals from the industrial category, now I will describe a few from the pesticides, herbicides, insecticides, and fungicides. The first one I will mention is vinclozolin. Here is a view of its chemical structure:

This substance is a fungicide used on fruits, vegetables,
ornamentals, and turf grass. In soil, plants, and animals, this
is transformed into by-products that block the androgen
receptor or displace testosterone from sex hormone binding
globulin. This globulin molecule is the carrier protein for steroid sex hormones in the blood. The effects from this are evident. It can cause feminization of male?s (wildlife) and cause male characteristics to develop in females.

The next substance is ddt (dichlorodiphenyltrichloroethane) with its structure as follows:

This substance is no longer registered for use in the
United States, but over one ton passes through
our ports each day. It is an organochlorine pesticide that was primarily used to control mosquitoes carrying the malaria virus. There are less persistent pesticides used now, but ddt is still used in many parts of the world. It has been shown to have weak estrogenic effects, but its major metabolite (dde) has been shown to exert a much stronger effect. This dde blocks the androgen receptor molecule from binding testosterone, and does this with extreme strength.

The final substance I will discuss is chlordane with the chemical structure as follows:
Chlordane is another organochlorine pesticide that has also been stopped from usage in the U.S. It has been strongly linked to endocrine disruption via its action in androgen antagonism and estrogenic effects as well.

After giving a brief history of some of the substance involved in endocrine disruption, a clear correlation can be drawn. There seems to be a definite link between the structure and function of these chemicals. Every one of the substances shown in this paper involves ring structures, and many also incorporate halogen atoms as well. Here is a basic pathway that helps in the understanding of how these chemicals may be exerting their effects in the endocrine system.



Cholesterol Estradiol
This pathway shows the relationship between cholesterol,
testosterone, and estradiol. The cholesterol molecule is a
precursor for the formation of many of the important
hormones involved with the endocrine system. It is also
Testosterone highly indicative of the structures of the other hormones that are not derived from cholesterol. The main point is that ring structures are highly conserved within a majority of the natural hormones within the body. This plays right in with the structures of the substances we suspect in endocrine disruption.
Now that there is enough general information to build upon, I will discuss some of the research that has been completed and how it is related to the study of endocrine disruption. There have been two major areas of research conducted thus far. The first area involves wildlife studies while the second area is human epidemiological studies.
Most of the information that we have obtained up to this point, has been from wildlife research. It is much easier to obtain results this way, but also makes it more difficult to draw a correlation to humans. We are able to acquire a large amount of data in this area, but it does not always help us when we are trying to look at the effects it may have on humans. A chemical that might cause cancer in one animal, does not necessarily exert the same effect in us. In the following paragraphs I will discuss some of the examples that have been completed.

In the Great Lakes region, it has been discovered that almost all birds and fish have abnormal thyroids. Their glands are enlarged and abnormal on microscopic examination as well. It has been suggested that this malformation among species might be due to lack of iodine levels. There are also others that firmly believe it is due totally to persistent organic pollutants such as those listed in earlier parts of the paper.

It has also been found that several species of female fish downstream from pulp and paper mills have developed male sex organs and exhibit altered behavior patterns. The females that have been ?masculinized?; have tried to mate with other females or with each other. The males in this same area were hypermasculinized, showing very aggressive behavior. The possible cause of these conditions are thought to be related to chemicals relased from the pulp factories (such as dioxins, furans, and PCB?s). These substances are acting very similar to androgenic steroids.

Another example of wildlife studies which have been done are the cases of abnormal alligators in Florida. Male alligators from Lake Apopka in Fl., which were exposed to an insecticide dicofol (ring structure with chlorines or bromines) showed permanent alteration in hormone levels, diminished reproductive success, small penises, and feminization of other reproductive structures.

There seems to be a common theme that runs through many, if not all, of the wildlife studies. They do not show any accurate exposure assesments or data showing effects of mixtures with co-occuring pollutants. When more laboratory work can be incorporated with the field studies that have been conducted.

Endocrine Disruption 7 of 10 on the basis of 3412 Review.