Environmental Health Perspectives 103, Supplement 7, October 1995
[Citation in PubMed]
Symposium on Estrogens in the Environment, III
John A. McLachlan1 and Kenneth S. Korach2
1Tulane/Xavier Center for Bioenvironmental Research, Tulane University, New Orleans, Louisiana;
2Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
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Environ Health Perspect 103(Suppl 7):3-4 (1995)
This paper was presented at the Symposium on Estrogens in the Environment, III: Global Health Implications held 9-11 January 1994 in Washington, DC.
Address correspondence to Dr. John A. McLachlan,Tulane/Xavier Center for Bioenvironmental Research, Tulane University, 1430 Tulane Avenue, New Orleans, LA 70112-2699. Telephone (504) 585-6910. Fax (504) 585-6428. e-mail jmclach@mailhost.tcs.tulane.edu
Hormonally active xenobiotics are a group of exogenous chemicals that exhibit biological hormonal activity. Because of this activity, the chemicals have received a great deal of attention in the past decade as possible sources of certain disease states. Some of these chemicals display estrogenlike activities that have both developmental influences and physiological actions most clearly related to controlling reproduction in females. These xenobiotics can come from the diet, such as the phytoestrogens coumestrol and genestein, or from the environment (e.g., o,p´-DDT, and PCBs), where they are produced as pesticides and wastes from manufacturing processes. Besides a relative requirement for a phenolic ring, the array of chemical structures and substitutions found in environmental compounds makes prediction of estrogenic potency difficult. An emphasis of the first "Estrogens in the Environment" conference in 1979 was to evaluate the chemical properties and structural diversity among environmental estrogens.
Natural estrogens elicit their biological actions by a nuclear receptor protein-mediated mechanism. These proteins act as ligand-inducible transcription factors by stimulating gene regulation in responsive cells. For a number of years, it was believed that receptor binding of the estrogen ligand resulted in biological activity. The level of activity was dependent on the binding affinity of the receptor for a particular compound. Analyses of the receptor binding activities of environmental estrogenic compounds have indicated that they too may work through the same mechanism. More recent findings have shown that receptor mediated estrogen action also can be stimulated by other signaling mechanisms, such as growth factors. This could broaden the mechanistic possibilities to include action of xenobiotics on other signaling pathways in addition to direct interactions with the estrogen receptor.
An association or link between estrogen exposure and breast cancer has been a topic of debate for a number of years. Questions of whether estrogens act as initiators, promoters, or both in regards to breast cancer is under current study. Many breast cancers, as well as nonmalignant reproductive tract conditions such as endometriosis, are hormonally responsive, which makes estrogenic exposure an important component of their etiology. Therefore, the possibility of human exposure to environmental chemicals possessing estrogenic activity is a situation that may raise concern. The second "Estrogens in the Environment" conference in 1985 dealt with discussions of the many biological and potential toxicological actions of estrogenic exposure. Experimental animal studies involving prenatal estrogen exposure were shown to produce hypospadias and cryptorchidism. Recent reports have hypothesized a link between the observed increase in testicular tumors and lower sperm counts in humans and possible prenatal and neonatal estrogen exposure. Part of the difficulty in evaluating a possible link is the lack of understanding of the role(s) for estrogen in males.
Besides possible human-associated cancer and noncancer effects of environmental estrogens, there are reported estrogenic effects on wildlife populations related to fertility and sexual development. Detrimental effects of wildlife became an important topic and also became the focus of the third "Estrogens in the Environment" conference. There are reports of wildlife being exposed to the pesticide DDT, which produced male infertility resulting from low sperm counts and hypospadias. Experimental studies in rats and mice with o,p´-DDT have shown in vivo estrogenic activity. Other types of simple alkyl substituted phenols (e.g., 4-octylphenol, 4-nonylphenol), which are nonionic surfactants present in detergents, were shown to be environmentally persistent and to affect fish populations in contaminated waters.
A most surprising finding was that estrogenic xenobiotics are not only found in the environment but are also contaminants (e.g., nonylphenol, bisphenol A) of laboratory plasticware, such as flasks and petri dishes. In these cases, materials used in the plastic-manufacturing process were found to alter growth of MCF-7 breast cancer cells due to their estrogenic activity. The biological activities are weak, but when it is considered that 300,000 tons of alkyl phenol polyethoxylates are introduced into the environment each year, the magnitude of the problem becomes potentially more significant.
The meeting highlighted several major questions regarding environmental estrogens, to their impact on human disease, and the associated link between estrogens and cancer. Presentations in the program provided ideas and thoughts regarding some immediate approaches toward analyzing the effects of environmental estrogens. Currently, it is unclear what relationship environmental exposure to these types of compounds may have to either the initiation or progression of certain diseases. Although wildlife populations have been affected, there is no analysis of tumors or cancers in the exposed populations. Additionally, identifying and evaluating exposed human populations is much more difficult. Epidemiological studies will be required to critically evaluate and establish the relevance of these exposures. Both human and experimental studies must be done before any clear assessment can be drawn regarding the causative role for environmental estrogens and various hormonally dependent cancers. It should at least be considered, however, that the wildlife effects that are seen may be an early indication of the consequences of human exposures.
Evaluation of the hormonal activities of these environmental xenoestrogens requires consideration of their bioavailability, lipophobicity, metabolism, and pharmacokinetics; these characteristics are not totally understood for these compounds and are most likely quite different from that of steroidal estrogens. Studies need to be conducted to evaluate the parameters that are relevant to established estrogenic agents. In addition to the chemical and pharmacological properties of the xenoestrogens, the hormonal activities of compound mixtures and the effect of persistent dosing need to be determined. A single agent or chemical may be weak and have a low threshold of activity; however, mixtures of compounds found environmentally could produce a noticeable effect by synergism. In fact, it has been reported that some drinking-water sources have as many as 20 chemically related alkyl phenolic compounds.
It is clear that a number of questions still exist regarding chemicals that exhibit hormonal activity and their potential relationship to human disease; this requires further studies at the basic, clinical, and epidemiological levels. We feel that an attempt to bring together investigators from the varied scientific disciplines aided and broadened both the experience and acknowledgment of the environmental estrogen problem.
Finally, we would like to express our thanks to all those individuals in Research Triangle Park, North Carolina, and Washington, DC, involved in helping to conduct the meeting. We especially would like to express our gratitude to Vickie Englebright and Cindy Garrard whose planning, suggestions, and organization were instrumental in making the meeting a success. We are also deeply indebted to the hard work of Vickie Englebright in managing the organization of the contents of these proceedings.
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