Effects of triazole fungicides on androgenic disruption and CYP3A4 enzyme activity. (March 2017)

• Record Type: Journal Article
• Authors: Lv, Xuan; Pan, Liumeng; Wang, Jiaying; Lu, Liping; Yan, Weilin; Zhu, Yanye; Xu, Yiwen; Guo, Ming; Zhuang, Shulin
• Is Part Of: Environmental pollution. Volume 222(2017)
• Page Start: 504
• Page End: 512
• Publication Date: 2017-03
• Subjects: Triazole -- Androgen receptor -- Metabolism -- CYP450 -- Steroid hormone; Pollution -- Periodicals; Pollution -- Environmental aspects -- Periodicals; Environmental Pollution -- Periodicals; Pollution -- Périodiques; Pollution -- Aspect de l'environnement -- Périodiques; Pollution -- Effets physiologiques -- Périodiques; Pollution; Pollution -- Environmental aspects; Periodicals; Electronic journals; 363.73
• DOI: 10.1016/j.envpol.2016.11.051
• Languages: English
• ISSNs: 0269-7491

Abstract

Abstract: Triazole fungicides are widely used as broad-spectrum fungicides, non-steroidal antiestrogens and for various industrial applications. Their residues have been frequently detected in multiple environmental and human matrices. The increasingly reported toxicity incidents have led triazole fungicides as emerging contaminants of environmental and public health concern. However, whether triazole fungicides behave as endocrine disruptors by directly mimicking environmental androgens/antiandrogens or exerting potential androgenic disruption indirectly through the inhibition of cytochrome P450 (CYP450) enzyme activity is yet an unresolved question. We herein evaluated five commonly used triazole fungicides including bitertanol, hexaconazole, penconazole, tebuconazole and uniconazole for the androgenic and anti-androgenic activity using two-hybrid recombinant human androgen receptor (AR) yeast bioassay and comparatively evaluated their effects on enzymatic activity of CYP3A4 by P450-Glo™ CYP3A4 bioassay. All five fungicides showed moderate anti-androgenic activity toward human AR with the IC50 ranging from 9.34 μM to 79.85 μM. The anti-androgenic activity remained no significant change after the metabolism mediated by human liver microsomes. These fungicides significantly inhibited the activity of CYP3A4 at the environmental relevant concentrations and the potency ranks as tebuconazole > uniconazole > hexaconazole > penconazole > bitertanol with the corresponding IC50 of 0.81 μM, 0.93 μM, 1.27 μM, 2.22 μM, and 2.74 μM, respectively. We found that their anti-androgenic activity and the inhibition potency toward CYP3A4 inhibition was significantly correlated ( R 2 between 0.83 and 0.97, p < 0.001). Our results indicated that the risk assessment of triazole pesticides and structurally similar chemicals should fully consider potential androgenic disrupting effects and the influences on the activity of CYP450s. Graphical abstract: Highlights: The anti-androgenic activity of five triazole fungicides was evaluated. No significant changes of anti-androgenic activity occur prior and after the metabolism. Tebuconazole, uniconazole, hexaconazole, penconazole, bitertanol potently inhibit CYP3A4. The anti-androgenic activity is highly correlated with the inhibition potency toward CYP3A4. Our study is helpful to the health risk assessment of triazole fungicides. Abstract : Five commonly used triazole fungicides have a significant correlation between their anti-androgenic activity and the potent inhibition to CYP3A4.