Assessment of combined antiandrogenic effects of binary parabens mixtures in a yeast-based reporter assay

Abstract

To date, toxicological studies of endocrine disrupting chemicals (EDCs) have typically focused on single chemical exposures and associated effects. However, exposure to EDCs mixtures in the environment is common. Antiandrogens represent a group of EDCs, which draw increasing attention due to their resultant demasculinization and sexual disruption of aquatic organisms. Although there are a number of in vivo and in vitro studies investigating the combined effects of antiandrogen mixtures, these studies are mainly on selected model compounds such as flutamide, procymidone, and vinclozolin. The aim of the present study is to investigate the combined antiandrogenic effects of parabens, which are widely used antiandrogens in industrial and domestic commodities. A yeast-based human androgen receptor (hAR) assay (YAS) was applied to assess the antiandrogenic activities of n-propylparaben (nPrP), iso-propylparaben (iPrP), methylparaben (MeP), and 4-n-pentylphenol (PeP), as well as the binary mixtures of nPrP with each of the other three antiandrogens. All of the four compounds could exhibit antiandrogenic activity via the hAR. A linear interaction model was applied to quantitatively analyze the interaction between nPrP and each of the other three antiandrogens. The isoboles method was modified to show the variation of combined effects as the concentrations of mixed antiandrogens were changed. Graphs were constructed to show isoeffective curves of three binary mixtures based on the fitted linear interaction model and to evaluate the interaction of the mixed antiandrogens (synergism or antagonism). The combined effect of equimolar combinations of the three mixtures was also considered with the nonlinear isoboles method. The main effect parameters and interaction effect parameters in the linear interaction models of the three mixtures were different from zero. The results showed that any two antiandrogens in their binary mixtures tended to exert equal antiandrogenic activity in the linear concentration ranges. The antiandrogenicity of the binary mixture and the concentration of nPrP were fitted to a sigmoidal model if the concentrations of the other antiandrogens (iPrP, MeP, and PeP) in the mixture were lower than the AR saturation concentrations. Some concave isoboles above the additivity line appeared in all the three mixtures. There were some synergistic effects of the binary mixture of nPrP and MeP at low concentrations in the linear concentration ranges. Interesting, when the antiandrogens concentrations approached the saturation, the interaction between chemicals were antagonistic for all the three mixtures tested. When the toxicity of the three mixtures was assessed using nonlinear isoboles, only antagonism was observed for equimolar combinations of nPrP and iPrP as the concentrations were increased from the no-observed-effect-concentration (NOEC) to effective concentration of 80%. In addition, the interactions were changed from synergistic to antagonistic as effective concentrations were increased in the equimolar co...

Side Chains of Parabens Modulate Antiandrogenic Activity: In Vitro and Molecular Docking Studies

“…The ubiquitous presence of parabens in the environment has raised public concern about whether they potentially cause adverse reproductive effects and their safety has been widely discussed. − Exposure to parabens was reported to cause estrogenic disrupting effects. − Ethyl- and butyl parabens caused a significant increase in progesterone formation in the adrenal H295R steroidogenesis assay and interfered with the transport of cholesterol to the mitochondria . There has been a growing concern in recent years about the health risk of parabens to the androgen hormone system. − Parabens induced an adverse effect on the male reproductive system through reduced testosterone concentrations and sperm production in rats, potentially by influencing the biosynthesis, transport, and metabolism of steroid hormone . Evaluation of the androgen receptor (AR) disruption is thus of significance for better risk assessment of various paraben analogues.…”

Endocrine‐disrupting effects of methylparaben on the adult gerbil prostate

“…In this study, the higher AR activation was not directly related with cell proliferation increase and enhancement of the prostate secretory activity. Recent studies have demonstrated that parabens can bind to AR, resulting in antiandrogenic effects . Thus, we suggest that morphophysiological changes found in gerbil prostate result from the estrogenic and antiandrogenic effects of methylparaben.…”

“…Recent studies have demonstrated that parabens can bind to AR, resulting in antiandrogenic effects. 36,38,39 Thus, we suggest that morphophysiological changes found in gerbil prostate result from the estrogenic and antiandrogenic effects of methylparaben.…”

Biological removal of antiandrogenic activity in gray wastewater and coking wastewater by membrane reactor process

“…Differences between the sum of the fractions and the total samples could be due to a number of factors; that either there were combined effects between different antiandrogens in different fractions or that androgens in different fractions together could mask the detection of antiandrogenic activity. The combined effects of mixed antiandrogens are complicated, including synergistic effects, antagonistic effects, and interaction (Ma et al, 2014). The sums of activities of different fractions were slightly higher than that of the total samples, as shown in Fig.…”