Screening for Estrogen and Androgen Receptor Activities in 200 Pesticides by in Vitro Reporter Gene Assays Using Chinese Hamster Ovary Cells

By Kojima, Hiroyuki; Katsura, Eiji et al. | Environmental Health Perspectives, April 2004 | Go to article overview

Screening for Estrogen and Androgen Receptor Activities in 200 Pesticides by in Vitro Reporter Gene Assays Using Chinese Hamster Ovary Cells


Kojima, Hiroyuki, Katsura, Eiji, Takeuchi, Shinji, Niiyama, Kazuhito, Kobayashi, Kunihiko, Environmental Health Perspectives


We tested 200 pesticides, including some of their isomers and metabolites, for agonism and antagonism to two human estrogen receptor (hER) subtypes, hER[alpha] and hER[beta], and a human androge receptor (hAR) by highly sensitive transactivation assays using Chinese hamster ovary cells. The test compounds were classified into nine groups: urganochlorines, diphenyl ethers, organophosphorus pesticides, pyrethroids, carbamates, acid amides, triazines, ureas, and others. These pesticides wet tested at concentrations < [10.sup.-5] M. Of the 200 pesticides tested, 47 and 33 showed hER[alpha]- and hER[beta]-mediated estrogenic activities, respectively. Among them, 29 pesticides had both hER[alpha] and hER[beta] agonistic activities, and the effects of the organochlorine insecticides [beta]-benzene hexachloride (BHC) and [delta]-BHC and the carbamate insecticide methiocarb were predominantly hER[beta] rather than hER[alpha] agonistic. Weak antagonistic effects toward hER[alpha] and hER[beta] were shown in five and two pesticides, respectively. On the other hand, none of tested pesticides showed hAR-mediated androgenic activity, but 66 of 200 pesticides exhibited inhibitory activity against the transctiptional activity induced by 5[alpha]-dihydrotestosterone. In particular, the antiandrogenic activities of two diphenyl ether herbicides, chlornitrofen and chlomethoxyfen, were higher than those of vinclozolin and p,p'-dichlorodiphenyl dichloroethylene, known AR antagonists. The results of our ER and AR assays show that 34 pesticides possessed both estrogenic and antiandrogenic activities, indicating pleiotropic effects on hER and hAR. We also discussed chemical structures related to these activities. Taken together, our findings suggest that a variety of pesticides have estrogenic and/or antiandrogenic potential via ER and/or AR, and that numerous other manmade chemicals may also possess such estrogenic and antiandrogenic activities. Key words: antiandrogenic activity, Chinese hamster ovary cells, estrogenic activity, human androgen receptor, human estrogen receptor [alpha], human estrogen receptor [beta], pesticide, reporter gene assay.

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It has been well documented that several chemicals from agricultural, industrial, and household sources possess endocrine-disrupting properties, which provide a potential threat to human and wildlife reproduction (Colborn 1995; Colborn et al. 1993; Jensen et al. 1995). A suggested mechanism is that these environmental contaminants alter the normal functioning of the endocrine and reproductive system by mimicking or inhibiting endogenous hormone action, modulating the production of endogenous hormones, or altering hormone receptor populations (Sonnenschein and Soto 1998). A major mechanism of endocrine disruption is the action of chemicals as receptor agonists or antagonists through direct interaction with hormone receptors, thus altering endocrine function. In particular, chemicals mimicking endogenous estrogen via estrogen receptor (ER) have been the focus of research for the last 20 years. Meanwhile, recent studies have shown that several chemicals may exert antiandrogenic effect by interfering with androgen receptor (AR; Sohoni and Sumpter 1998; Vinggaard et al. 1999).

Pesticides commonly used to control agricultural and indoor pests are the most likely suspects as endocrine disruptors. The ubiquitous nature of pesticide usage with minimal precautions has resulted in contamination of food, the workplace, and the environment Recent reports showed that several pesticide exert estrogenic and antiandrogenic activitie through interaction with estrogen and androgen receptors. To date, p,p'-dichlorodiphenyl trichloroethane (DDT) (Welch et al. 1969), methoxychlor (Bulger et al. 1978; Cummings 1997), [beta]-benzene hexachloride (BHC) (Coosen and Velsen 1989), endosulfan, toxaphene, and dieldrin (Soto et al. 1995), and fenvalerate (Garey and Wolff 1998) have been reported as estrogenic pesticides. …

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