Environmental Chemicals and Estrogens, the Good, the Bad and the Unknown: Lessons From Fish

by Sherilyn J. Sawyer
Today, estrogens are commonly known for their roles in reproduction, hormone replacement therapy, oral contraceptives, and the controversies surrounding breast and other cancers; all focusing on women. Although these “women’s issues” have been in the spotlight lately, estrogen has many important roles in the bodies of both women and men.

Estrogen is Important to Nervous System of Both Sexes

Recently it has become apparent that estrogens have many functions in the nervous system of both sexes, specifically on areas of the brain important for learning and memory, as well as motor coordination and pain sensitivity. Correlations between gender specific estrogen levels and cognition, depression, Alzheimer’s disease, and Parkinson’s disease demonstrate the importance of estrogens in neural health. The understanding of normal and abnormal neural estrogen activities and regulation is vital to understanding connections between estrogen, neural development and the maintenance of the nervous system in adults.

Environmental Chemicals as Hormone Disruptors

In general, our bodies are very good at producing just the right amount of hormones and other regulatory molecules, but what if man-made chemical pollutants found in our environment could enter the body and act as hormones, like estrogen, altering the body’s innate regulatory mechanisms? This process, termed endocrine disruption, can and does happen. For several decades endocrine disruption has been linked to reproductive abnormalities and to some cancers. But what if there were also less obvious, more subtle effects? For example, could exposure to this type of pollution prenatally alter the mental development of a child? Or could endocrine disruption in development or adulthood change susceptibility to neural disease such as depression, Alzheimer’s, Parkinson’s, and macular degeneration in advanced age? Our laboratory at Boston University has demonstrated that some pollutants do have an effect on gene regulation in neural tissues. It is our goal to determine how natural estrogens and endocrine disruptor chemicals (EDC) affect the processes of development and aging of the brain.

Estrogen and Gene Expression

Paradoxically, the “female hormone” estrogen is a derivative of the so-called “male hormone” testosterone. In reality, both hormones are present in males and females, just in differing amounts. A process called aromatization, mediated by the enzyme aromatase, drives the production of estrogen from testosterone.
Normal levels of neural estrogen play a role in signaling cells during development and potentially throughout life. The process by which estrogen acts in cells is mediated by a protein transcription factor, the estrogen receptor, which binds to estrogen and then exerts an effect on gene expression in the cell. By modulating gene expression, estrogen can subsequently influence the amount and types of proteins within the cell, thereby changing the cell’s fate or function.
For example, it is cell signaling that directs the developmental timing and formation of the many different neural tissues. Consequently, disruption of these signaling systems can have a wide variety of effects on the outcome of tissue differentiation and development.

Pollutants Can Mimic or Block Hormones

Environmental exposure to compounds that can mimic or block the activities of hormones (endocrine disruptors) is of growing concern. Several known compounds have activity similar to the body’s own estrogen. Two common EDCs studied specifically in our lab are PCBs and BPA.
Polychlorinated hydroxybiphenyls, or PCBs, are a class of compounds some of which affect estrogen signaling pathways. Until the halt of their U.S. manufacture in 1977, PCB’s were commonly used as lubricants and coolants in a wide variety of electrical equipment including common household items. Due to a very long half-life, PCBs were found to build up in the environment, specifically in soil, sediment, and water, where they still exist today.
Another prevalent environmental estrogen, bis-phenol A or BPA, is a building block of polycarbonate plastics and polystyrene resins. The common plastics made from BPA are found in the lining of metal food cans, in plastic milk, juice and water cartons, in baby bottles, in microwave oven ware, and in other widely used plastic and polystyrene food packages.
PCBs and BPA enter the body through exposure to contaminated material, most commonly through ingestion of contaminated foods and water. Once in the body, these compounds and others like them can be circulated, metabolized, and/or stored by the body tissues where their effects can continue for long periods of time.

Lessons from Zebrafish and Killifish

Our lab is concerned with estrogen and EDC effects on neural endpoints. In order to study this, we use fish as a model system; specifically laboratory raised zebrafish, and the killifish, which is found in the natural environment. These two different fish species allow us to perform both year round controlled zebrafish experiments in the lab, and to provide a direct environmental connection by examining what is happening to populations of killifish living in the EDC polluted waters of New Bedford Harbor Massachusetts.
As a measure of estrogenic effects, our lab is currently studying the regulation of neural aromatase, the gene responsible for estrogen production in the brain, as well as several members of cell signaling pathways, and neural structural components thought to be targets of estrogen and EDC.
To date, our work has demonstrated the ability of estrogen and endocrine disruptors to alter gene regulation during development and adulthood, using both fish as models in the lab, and by studying natural fish populations.
This information is the first step in understanding the normal and abnormal roles of estrogen and EDC in the development and maintenance of neural tissues. In the future, we hope to further elucidate the role of endocrine disruption and estrogen pathways in neural health during development and age.
S. Sawyer is a PhD candidate at Boston University in the laboratory of Dr. Gloria V. Callard. She is training in the field of molecular endocrinology studying neuroendocrine and reproductive effects of environmental endocrine disrupting chemicals using zebrafish as a model system. This research is funded in part by grants to GVC from the EPA and NIEHS.

For More Information:

Sawyer SJ, Gerstner KA, Callard GV. Real-time PCR analysis of cytochrome P450 aromatase expression in zebrafish: gene specific tissue distribution, sex differences, developmental programming, and estrogen regulation. Gen Comp Endocrinol. 2006 Jun;147(2):108-17.

Greytak SR, Champlin D, Callard GV. Isolation and characterization of two cytochrome P450 aromatase forms in killifish (Fundulus heteroclitus): differential expression in fish from polluted and unpolluted environments. Aquat Toxicol. 2005 Mar 4;71(4):371-89.

Sawyer SJ, Gerstner KA, Callard GV. Real-time PCR analysis of cytochrome P450 aromatase expression in zebrafish: gene specific tissue distribution, sex differences, developmental programming, and estrogen regulation. Gen Comp Endocrinol. 2006 Jun;147(2):108-17.
Originally posted in “On Eagles’  Wings” August 1st 2006