Academic journal article Environmental Health Perspectives

Assaying Estrogenicity by Quantitating the Expression Levels of Endogenous Estrogen-Regulated Genes

Academic journal article Environmental Health Perspectives

Assaying Estrogenicity by Quantitating the Expression Levels of Endogenous Estrogen-Regulated Genes

Article excerpt

Scientific evidence suggests that humans and wildlife species may experience adverse health consequences from exposure to environmental chemicals that interact with the endocrine system. Reliable short-term assays are needed to identify hormone-disrupting chemicals. In this study we demonstrate that the estrogenic activity of a chemical can be evaluated by assaying induction or repression of endogenous estrogen-regulated "marker genes" in human breast cancer MCF-7 cells. We included four marker genes in the assay--pS2, transforming growth factor [Beta]3 (TGF[Beta]3), monoamine oxidase A, and [Alpha]1-antichymotrypsin--and we evaluated estrogenic activity for 17[Beta]-estradiol ([E.sub.2]), diethylstilbestrol, [Alpha]-zearalanol, nonylphenol, genistein, methoxychlor, endosulphan, o,p-DDE, bisphenol A, dibutylphthalate, 4-hydroxy tamoxifen, and ICI 182.780. All four marker genes responded strongly to the three high-potency estrogens ([E.sub.2], diethylstilbestrol, and [Alpha]-zearalanol), whereas the potency of the other chemicals was [10.sup.3]- to [10.sup.6]-fold lower than that of [E.sub.2]. There were some marker gene-dependent differences in the relative potencies of the tested chemicals. TGF[Beta]3 was equally sensitive to the three high-potency estrogens, whereas the sensitivity to [Alpha]-zearalanol was approximately 10-fold lower than the sensitivity to [E.sub.2] and diethylstilbestrol when assayed with the other three marker genes. The potency of nonylphenol was equal to that of genistein when assayed with pS2 and TGF[Beta]3, but 10- to 100-fold higher/lower with monoamine oxidase A and [Alpha]1-antichymotrypsin, respectively. The results are in agreement with results obtained by other methods and suggest that an assay based on endogenous gene expression may offer an attractive alternative to other E-SCREEN methods. Key words: [Alpha]-antichymotrypsin, competitive PCR, differential display, endocrine disruptors, estrogen, estrogenicity assay, gene expression, monoamine oxidase A, pS2, TGF[Beta]3. Environ Health Perspect 108:403-412 (2000). [Online 17 March 2000]

http://ehpnet1.niehs.nih.gov/docs/2000 /108p403-412jorgensen/abstract.html

The presence of endocrine disruptors in our environment has caused an increasing concern of their possible impact on wildlife and human health (1,2). Investigators have focused on a possible decrease in human semen quality and an undisputed increased incidence of testicular cancer over the past few decades (3,4). Although hypothetical, these changes may be caused by intrauterine exposure of the male fetus to estrogens or antiandrogens (5). In addition, significant increases in the incidences of prostate, endometrium, and breast cancer, and malformations of the external and internal genitals have been observed over the past 40-50 years, and may also be associated with increased exposure to estrogens (6-8).

Environmental estrogens include a variety of very different chemicals such as polychlorinated biphenyls (PCBs), organochlorine pesticides, alkylphenols, phthalates, and food antioxidants (2,9-11). In addition, many plants and fungi contain compounds with estrogenic activity--the phytoestrogens and mycoestrogens (2). The chemical structures of these chemicals vary substantially, which makes it difficult to predict their estrogenicity solely on a structural basis.

Hence, there is a strong need for reliable short-term methods that can rapidly detect chemicals with estrogenic properties. This is reflected in the ambitious Endocrine Disruptor Screening and Testing Program (EDSTP), which was recently proposed by the U.S. Environmental Protection Agency (EPA), for which the EPA is concidering more than 87,000 substances as potential candidates for testing. These compounds include pesticides, commercial chemicals, ingredients in cosmetics, food additives, nutritional supplements, and certain mixtures. The EDSTP is available online from the EPA website (12). …

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