We show that a number of alkylphenolic compounds, used in a variety of commercial products and found in river water, are estrogenic in fish, birds, and mammals.
4-Octylphenol (OP),
4-nonylphenol, 4-nonylphenoxycarboxylic
acid, and 4-nonylphenoldiethoxylate were each capable of stimulating
vitellogenin gene expression in trout hepatocytes, gene transcription in transfected cells, and the growth of
breast cancer cell lines. The most potent of the chemicals is OP, which was able to stimulate these
biological responses to a similar extent as
17 beta-estradiol itself, albeit at a 1000-fold greater concentration. The action of alkylphenols is mediated by the
estrogen receptor, as their effects depended on its presence and was blocked by
estrogen antagonists. OP,
4-nonylphenol, and 4-nonylphenoxycarboxylic
acid appear to possess intrinsic estrogenic activity, because they compete for binding to the
estrogen receptor. Moreover, it is likely that they interact with a similar region of the
hormone-binding domain as
17 beta-estradiol, because the mutant receptor G-525R, which is defective in
estrogen binding, is also insensitive to OP. Like
17 beta-estradiol, OP is capable of stimulating the activity of both transcriptional activation functions, TAF-1 and TAF-2, in the receptor, as judged by analyzing the activity of the wild-type and mutant receptors in transiently transfected cells. The significance of our results will depend to a large extent on the degree of exposure of wildlife and humans to these estrogenic alkylphenolic compounds.