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Can Environmental Chemicals Confuse Our Hormones?

Katrina Brown
Physics
Vanderbilt University
August 2001

There are some chemicals in our environment that adversely affect our health by mimicking the natural hormones present in animals and people. We are using computer simulations to determine how easy it is for a group of chemicals to bind to the estrogen hormone such that these chemicals may disrupt the way the hormone normally functions. We hope that our studies will help experimental chemists and environmental researchers narrow down which of these thousands of chemicals may be potentially dangerous and should be monitored or regulated in the environment.

During the 1700's young boys were used as chimney sweeps; due to their small size, they could fit into the narrow chimneys to clean the coal tar and soot out of the flues. Around 1775 a British surgeon noticed that many chimney sweeps were afflicted with scrotal cancer later in life and he deduced that their cancer was caused by a prolonged contact with the soot. In the early 1900's scientists determined that some of the chemicals in the soot and tar which cause cancer belong to a class known as polycyclic aromatic hydrocarbons, or PAHs. Today we know that there are many chemicals in this class, some of which are carcinogens (cancer-causing) and others which are not. They are ubiquitous and are produced in processes such as vehicle emissions and cigarette smoke.

Several PAHs can cause breast tumors and we do not yet entirely understand the cellular and molecular interactions responsible for this. Since the hormone estrogen is very important in the development of breast tissue it is possible that these PAHs interact with the estrogen itself and subsequently effect its ability to carry out its normal functions, resulting in the tumor growth. On the molecular level, a PAH could interact with the estrogen by binding to it. In our computational chemistry laboratory, we are using computer simulations to determine how easy it is for different PAHs to do this binding.

Estrogen is a large protein that has a pocket in it where a small chemical can bind. This bound chemical is known as a 'ligand'. In humans and animals the natural ligand is a chemical called estradiol. Once estradiol is bound to the estrogen, the estrogen binds to DNA and a series of molecular events follow that constitute the hormonal activity of estrogen. Unfortunately, there are many chemicals that are similar in shape and size to estradiol and they can compete with the estradiol to bind to the estrogen. In fact, there are several PAHs that are quite similar in structure to the estradiol molecule. If these chemicals manage to bind to the estrogen, they can change its shape such that it can no longer bind to the DNA and the hormonal cycle is interrupted. Alternatively, it is possible that these bound, non-natural ligands can cause the estrogen to behave as it normally would, thus starting the hormonal cycle when the animal's body didn't need it started.

In my research, I am using computer simulations to examine how easily some PAHs will fit into estrogen's binding pocket. The methods we use determine the position of the ligand in the binding site based on the structures of the ligand and protein. The process is roughly analogous to trying to fit two puzzle pieces together. The programs move and rotate the ligand around in various positions inside the pocket trying to find the best fit. If the ligand is very similar to estradiol then it may fit well, but if the ligand is too big or shaped wrong then there won't be a good match.

Once a PAH is placed in the binding pocket, we can calculate the energy that would be required to put it there (the binding energy); the less energy required, the more stable the complex. For example, if a negative charge on a ligand is close to a positive charge on the protein it is an energetically favorable interaction (since opposite charges attract). If a negative charge on a ligand is close to a negative charge on the protein, however, it is an energetically unfavorable interaction (since like charges repel).

We can compare the binding energies of ligands and determine which ones are more likely to bind to the receptor. We have found that there are several PAHs that have favorable binding energies. This indicates that they have the potential to compete with estradiol in biological systems and if they succeed they may disrupt the functioning of the hormone. We will share our results with other scientists who can further test the chemicals in animals. Eventually, all of the studies on these chemicals will help determine if the government should regulate the chemicals in the environment as potential disrupters in the hormonal cycles of animals.