The suitability of concentration addition for predicting the effects of multi-component mixtures of up to 17 anti-androgens with varied structural features in an in vitro AR antagonist assay

Ermler, Sibylle; Scholze, Martin; Kortenkamp, Andreas

doi:10.1016/j.taap.2011.09.005

Cited by 67 publications

(56 citation statements)

References 22 publications

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“…Both of these mechanisms have the same MOA, but act in a dissimilar manner, which can cause complex mixture interactions. This complexity in mixture interactions has been highlighted in several studies (Kjaerstad et al 2010;Ermler et al, 2011;Archer and Van Wyk, 2015). Therefore, recent mixture interaction studies refer not to the general outcome of the MOAs (oestrogenic, androgenic, etc.…”

Section: Mixture Interactions Of Environmental Pollutantsmentioning

confidence: 99%

Review: <i>Pharmaceutical and personal care products (PPCPs) as endocrine disrupting contaminants (EDCs) in South African surface waters</i>

Archer

Wolfaardt

Wyk

2017

WSA

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Globally, water resources are under constant threat of being polluted by a diverse range of man-made chemicals, and South Africa is no exception. These contaminants can have detrimental effects on both human and wildlife health. It is increasingly evident that several chemicals may modulate endocrine system pathways in vertebrate species, and these are collectively referred to as endocrine disrupting contaminants (EDCs). Although the endocrine-disrupting effect of water pollutants has been mainly linked to agricultural pesticides and industrial effluents, other pollutants such as pharmaceuticals and personal care products (PPCPs) are largely unnoticed, but also pose a potentially significant threat. Here we present for the first time in a South African context, a summarised list of PPCPs and other EDCs detected to date within South African water systems, as well as their possible endocrine-disrupting effect in-vitro and in-vivo. This review addresses other factors which should be investigated in future studies, including endocrine disruption, PPCP metabolites, environmental toxicology, and antibiotic resistance. The challenges of removing EDCs and other pollutants at South African wastewater treatment works (WWTWs) are also highlighted. The need for focused research involving both in-vitro and in-vivo studies to detect PPCPs in water systems, and to delineate adverse outcome pathways (AOPs) of priority PPCPs to aid in environmental impact assessment (EIA), are discussed.

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Section: Mixture Interactions Of Environmental Pollutantsmentioning

confidence: 99%

Review: <i>Pharmaceutical and personal care products (PPCPs) as endocrine disrupting contaminants (EDCs) in South African surface waters</i>

Archer

Wolfaardt

Wyk

2017

WSA

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“…The day the vaginal plug was detected was designated as GD 1 and the expected day of delivery (GD 23) was designated as pup day (PD) 1. (Kang et al 2002), in vitro AR antagonist (Ermler et al 2011) Decreased sperm count and motility (Kang et al 2002) --100 (Kang et al 2002) Paracetamol Analgesic and antipyretic Inhibitor of prostaglandin synthesis (Kristensen et al 2011(Kristensen et al , 2012 Positive association between ingestion during first and second trimester and cryptorchidism in humans (Kristensen et al 2011) AGD Y (Kristensen et al In the gestation period, only PM was added to the mixture groups and dosed to the PM group from GD 13 to GD 19. The later initiation of PM exposure during pregnancy, i.e.…”

Section: Animals and Exposurementioning

confidence: 99%

Mixtures of endocrine-disrupting contaminants induce adverse developmental effects in preweaning rats

et al. 2014

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Reproductive toxicity was investigated in rats after developmental exposure to a mixture of 13 endocrine-disrupting contaminants, including pesticides, plastic and cosmetic ingredients, and paracetamol. The mixture was composed on the basis of information about high-end human exposures, and the dose levels reflecting 100, 200, and 450 times this exposure were tested. The compounds were also grouped according to their estrogenicity or anti-androgenicity, and their joint effects were tested at two different doses, with each group reflecting 200 or 450 times human exposure. In addition, a single paracetamol dose was tested (350 mg/kg per day). All exposures and a vehicle were administered by oral gavage to time-mated Wistar dams rats throughout gestation and lactation, and their offspring were assessed for reproductive effects at birth and in prepuberty. The mixture doses, which included the anti-androgenic compounds, affected the male offspring by causing decreased anogenital distance, increased nipple retention (NR), and reduced ventral prostate weights, at both medium and high doses. In addition, the weights of the levator ani/bulbocavernosus muscle (LABC) were decreased at the high dose of anti-androgen mixture. No effects were seen after exposure to the estrogenic chemicals alone, whereas males exposed solely to paracetamol showed decreased LABC weights and increased NR. Thus adverse reproductive effects were observed at mixtures reflecting 200 times high-end human exposure, which is relatively close to the safety margin covered by the regulatory uncertainty factor of 100. This suggests that highly exposed human population groups may not be sufficiently protected against mixtures of endocrine-disrupting chemicals.

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“…Chemicals modulating the androgen receptor (AR), resulting in an anti-androgenic response, have been shown to adversely affect male reproductive health, causing testicular dysgenesis syndrome, cryptorchydism, testicular cancer and altered semen quality (Skakkebaek et al, 2001;Kortenkamp and Faust, 2010). Although modulation of the androgenic system may not be limited to interaction with the AR, competitive binding at the AR level seems to have been the focus of most previous studies (Kelce et al, 1998;Ermler et al, 2010Ermler et al, , 2011Orton et al, 2011). Chemicals having AR antagonistic ED properties are of specific concern, as these contaminants can compete with androgens to bind to the AR, resulting in decreased transcription of target genes (Birkøj et al, 2004;Ermler et al, 2010Ermler et al, , 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Although modulation of the androgenic system may not be limited to interaction with the AR, competitive binding at the AR level seems to have been the focus of most previous studies (Kelce et al, 1998;Ermler et al, 2010Ermler et al, , 2011Orton et al, 2011). Chemicals having AR antagonistic ED properties are of specific concern, as these contaminants can compete with androgens to bind to the AR, resulting in decreased transcription of target genes (Birkøj et al, 2004;Ermler et al, 2010Ermler et al, , 2011). An example of a direct AR antagonist is flutamide, a clinical drug used to treat prostate cancer (Behrends et al, 2010;Hoffmann and Kloas, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…AR antagonism) will be expected to have an additive mixture response (e.g. elevated anti-androgenic activity) while EDCs having dissimilar mechanisms of action will be expected to have independent mixture responses (no increased or reduced endocrine activity) (Birkhøj et al, 2004;Blake et al, 2010;Ermler et al, 2011). However, there are few in-vitro studies reporting on the anti-androgenic effects of commonly-used pesticides in South African agriculture, alone or as mixtures.…”

Section: Introductionmentioning

confidence: 99%

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

Archer¹,

Wyk²

2015

WSA

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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.

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The suitability of concentration addition for predicting the effects of multi-component mixtures of up to 17 anti-androgens with varied structural features in an in vitro AR antagonist assay

Cited by 67 publications

References 22 publications

Review: <i>Pharmaceutical and personal care products (PPCPs) as endocrine disrupting contaminants (EDCs) in South African surface waters</i>

Review: <i>Pharmaceutical and personal care products (PPCPs) as endocrine disrupting contaminants (EDCs) in South African surface waters</i>

Mixtures of endocrine-disrupting contaminants induce adverse developmental effects in preweaning rats

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

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