Abstract
Although it is known that environmental chemicals can affect the oestrogenic system, far less attention has been paid to chemicals interacting with the androgen receptor (AR). Pesticides, particularly fungicides, have been shown to competitively bind or affect expression of the AR in an inhibiting manner. Few studies have addressed anti-androgenic effects of agrochemical use in South Africa. The aim of this study was to screen for the ability of commonly-used pesticides (mostly fungicides) in Western Cape agricultural areas to alter the binding of an androgen (DHT) to the human AR (hAR) using a recombinant yeast androgen screen (YAS), and also to test the additivity mixture interaction hypothesis when commonly-used pesticides with similar modes of action (MOAs) are exposed in mixture. Fungicides vinclozolin, folpet, procymidone, dimethomorph, fenarimol, mancozeb, and the insecticide chlorpyrifos, all independently antagonised the binding of the androgen dihydrotestosterone (DHT) to the AR in a dose-dependent manner. The fungicide mancozeb was found to be the most potent anti-androgen in the assay. Binary, equimolar mixtures of the pesticides also antagonised the binding of DHT to the AR, but at lower IC 50 concentration potencies relative to their individual counterparts. The mixtures of the majority of the selected pesticides did not conform to the expected additive mixture interaction. Only the mixture between dimethomorph and mancozeb showed an additive mixture response at IC 50 concentrations, and, therefore, revealed a more severe AR antagonistic effect compared to their individual counterparts. This study confirmed that pesticides regularly used in agriculture inhibit the binding of androgens to the AR, but when in mixture do not always conform to the predictive addition mixture response model. Also, high relative potencies of individual chemicals in the assay were suppressed when combined with less potent chemicals, showing that the potent chemicals may not be granted access to bind with the AR when exposed in mixture. Keywords : androgen receptor, anti-androgen, fungicides, mixtures
Highlights
Several natural and man-made compounds have been shown to modulate endocrine activity in vertebrates (Heath and Claassen, 1999; Urbatzka et al, 2007a; Blake et al, 2010)
The aim of this study was to screen selected pesticides, mostly fungicides, which are commonly used in Western Cape agricultural areas of South Africa, for their ability to alter the binding of an androgen (DHT) to the human androgen receptor (AR) using a recombinant yeast anti-androgen screen
In this study 6 fungicides and one insecticide, which are regularly used in agriculture, exerted anti-androgenic activity by decreasing the androgen response expected from the presence of DHT
Summary
Several natural and man-made compounds have been shown to modulate endocrine activity in vertebrates (Heath and Claassen, 1999; Urbatzka et al, 2007a; Blake et al, 2010). Compounds acting in this way are collectively referred to as endocrine-disrupting contaminants (EDCs). The majority of EDC studies conducted to date have focused on EDCs modulating the oestrogenic response system in one way or the other (Sohoni and Sumpter, 1998; Urbatzka et al, 2007a & 2007b; Kloas et al, 2009; Behrends et al, 2010). In contrast to the intensive research focus on manmade chemicals that potentially disrupt normal oestrogenic function, relatively few studies have addressed interaction with the androgenic endocrine systems, either from an agonistic or antagonistic perspective (Urbatzka et al, 2007a)
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