Androgenic and Antiandrogenic Effects of Alkylphenols and Parabens Assessed Using the Reporter Gene Assay with Stably Transfected CHO-K1 Cells (AR-EcoScreen System)

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An updated review of environmental estrogen and androgen mimics and antagonists.

Carlos Sonnenschein, Ana Soto (1998)

For the last 40 y, substantial evidence has surfaced on the hormone-like effects of environmental chemicals such as pesticides and industrial chemicals in wildlife and humans. The endocrine and reproductive effects of these chemicals are believed to be due to their ability to: (1) mimic the effect of endogenous hormones, (2) antagonize the effect of endogenous hormones, (3) disrupt the synthesis and metabolism of endogenous hormones, and (4) disrupt the synthesis and metabolism of hormone receptors. The discovery of hormone-like activity of these chemicals occurred long after they were released into the environment. Aviation crop dusters handling DDT were found to have reduced sperm counts, and workers at a plant producing the insecticide kepone were reported to have lost their libido, became impotent and had low sperm counts. Subsequently, experiments conducted in lab animals demonstrated unambiguously the estrogenic activity of these pesticides. Man-made compounds used in the manufacture of plastics were accidentally found to be estrogenic because they fouled experiments conducted in laboratories studying natural estrogens. For example, polystyrene tubes released nonylphenol, and polycarbonate flasks released bisphenol-A. Alkylphenols are used in the synthesis of detergents (alkylphenol polyethoxylates) and as antioxidants. These detergents are not estrogenic; however, upon degradation during sewage treatment they may release estrogenic alkylphenols. The surfactant nonoxynol is used as intravaginal spermicide and condom lubricant. When administered to lab animals it is metabolized to free nonylphenol. Bisphenol-A was found to contaminate the contents of canned foods; these tin cans are lined with lacquers such as polycarbonate. Bisphenol-A is also used in dental sealants and composites. We found that this estrogen leaches from the treated teeth into saliva; up to 950 microg of bisphenol-A were retrieved from saliva collected during the first hour after polymerization. Other xenoestrogens recently identified among chemicals used in large volumes are the plastizicers benzylbutylphthalate, dibutylphthalate, the antioxidant butylhydroxyanisole, the rubber additive p-phenylphenol and the disinfectant o-phenylphenol. These compounds act cumulatively. In fact, feminized male fish were found near sewage outlets in several rivers in the U.K.; a mixture of chemicals including alkyl phenols resulting from degradation of detergents during sewage treatment seemed to be the causal agent. Estrogen mimics are just a class of endocrine disruptors. Recent studies identified antiandrogenic activity in environmental chemicals such as vinclozolin, a fungicide, and DDE, and insecticide. Moreover, a single chemical may produce neurotoxic, estrogenic and antiandrogenic effects. It has been hypothesized that endocrine disruptors may play a role in the decrease in the quantity and quality of human semen during the last 50 y, as well as in the increased incidence of testicular cancer and cryptorchidism in males and breast cancer incidence in both females and males in the industrialized word. To explore this hypothesis it is necessary to identify putative causal agents by the systematic screening of environmental chemicals and chemicals present in human foods to assess their ability to disrupt the endocrine system. In addition, it will be necessary to develop methods to measure cumulative exposure to (a) estrogen mimics, (b) antiandrogens, and (c) other disruptors.

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A novel cell line, MDA-kb2, that stably expresses an androgen- and glucocorticoid-responsive reporter for the detection of hormone receptor agonists and antagonists.

C Lambright, L. Gray, Kathy Bobseine … (2002)

The U.S. Environmental Protection Agency has proposed that in vitro assays for estrogen receptor (ER)- and androgen receptor (AR)-mediated actions be included in a Tier-I screening battery to detect hormonally active chemicals. Herein we describe the development of a novel stable cell line, MDA-kb2, for screening of androgen agonist and antagonists and to characterize its specificity and sensitivity to endocrine-disrupting chemicals. The breast cancer cell line, MDA-MB-453, was stably transformed with the MMTV.luciferase.neo reporter gene construct. Since both GR and AR are present in the MDA-MB-453 cells, and both receptors can act through the MMTV promoter, compounds that act through either AR or GR activate the MMTV luciferase reporter. As expected, AR agonists such as dihydrotestosterone (DHT), and GR agonists such as dexamethasone (DEX), corticosterone, and aldosterone induce luciferase expression at appropriate concentrations. DHT consistently produced 3-9-fold induction at concentrations from 0.1 to 10 nM. At 1 to 1000 nM, DEX induced luciferase activity 1.3-19.5-fold. To distinguish AR- from GR-mediated ligands, chemicals were assayed concurrently with the antiandrogen, hydroxyflutamide (OHF), which blocks AR- but not GR-mediated responses. In addition, known AR antagonists, including hydroxyflutamide, vinclozolin, vinclozolin metabolites M1 and M2, p,p'-DDE, and linuron inhibited DHT-induced luciferase gene expression at appropriate concentrations in this system. We have found that these cells are relatively easy to culture and maintain. Responsiveness was monitored over time and was stable for more than 80 passages. Some advantages of this assay are that it is relatively rapid (2 days), eliminates the need for transfection, can be conducted in a 96-well plate format, and produces consistent reproducible results. In summary, we have developed a cell line that can be used to screen chemicals, not just for AR- but for GR-mediated activities as well.

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Comparison of vitellogenin responses in zebrafish and rainbow trout following exposure to environmental estrogens.

K Van den Belt, R Verheyen, H Witters (2003)

In this comparative study, the suitability of the commonly used in vivo biomarker for estrogenicity, vitellogenin (VTG), upon waterborne exposure to known environmental estrogens is evaluated in both male zebrafish (Danio rerio) and juvenile rainbow trout (Oncorhynchus mykiss). The results from initial experiments in which both species were exposed to 4-tert-octylphenol (OP) or 17 alpha-ethynylestradiol under semistatic conditions for 3 weeks demonstrated a difference in species sensitivity for OP exposure. Additional dose-response studies (semistatic, 3 weeks) with 4-nonylphenol (20, 100, and 500 microg/L), bisphenol A (40, 200, and 1000 microg/L), dibutylphthalate (40, 200, and 1000 microg/L DBP), and 17beta-estradiol (20 and 100 ng/L E2) were conducted. All these compounds, except for DBP, were found to be estrogenic to both fish species. The results demonstrated a difference in species sensitivity for NP with the zebrafish being about 5 times less sensitive. For the other compounds tested, no indications for a difference in species sensitivity was found. The results from this study demonstrated that both fish species can be used for the detection of VTG as biomarker for estrogenicity, taken into the potential interspecies differences in sensitivity which might be important for the evaluation of fish population effects.

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Journal

Journal ID (publisher-id): JHSCFD

Title: JOURNAL OF HEALTH SCIENCE

Abbreviated Title: J. Health Sci.

Publisher: Pharmaceutical Society of Japan

ISSN (Print): 1344-9702

ISSN (Electronic): 1347-5207

Publication date Created: 2005

Publication date (Print): 2005

Volume: 51

Issue: 5

Pages: 557-568

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DOI: 10.1248/jhs.51.557

SO-VID: 2912dabb-b35c-4a94-9899-0ec42962a443

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Androgenic and Antiandrogenic Effects of Alkylphenols and Parabens Assessed Using the Reporter Gene Assay with Stably Transfected CHO-K1 Cells (AR-EcoScreen System)

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Abstract

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Most cited references 11

An updated review of environmental estrogen and androgen mimics and antagonists.

A novel cell line, MDA-kb2, that stably expresses an androgen- and glucocorticoid-responsive reporter for the detection of hormone receptor agonists and antagonists.

Comparison of vitellogenin responses in zebrafish and rainbow trout following exposure to environmental estrogens.

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