The potential anti-androgenic effect of agricultural pesticides used in the Western Cape: In vitro investigation of mixture effects

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 IC50 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 IC50 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