title: Effects of triazole fungicides on androgenic disruption and CYP3A4 enzyme activity.
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 IC50ranging 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 IC50of 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 (R2between 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.
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Health Risk Factors for Seafood of Zhejiang Province, Zhoushan 316022, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Lv
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Liumeng
authors.initials: L
authors.lastname: Pan
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Health Risk Factors for Seafood of Zhejiang Province, Zhoushan 316022, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Lu
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China; Guangzhou Key Laboratory of Environmental Exposure and Health, School of Environment, Jinan University, Guangzhou 510632, China.
authors.forename: Weilin
authors.initials: W
authors.lastname: Yan
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yanye
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: School of Science, Zhejiang Agriculture & Forestry University, Lin'an 311300, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Health Risk Factors for Seafood of Zhejiang Province, Zhoushan 316022, China. Electronic address: shulin@zju.edu.cn.
authors.forename: Shulin
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D001681:Biological Assay; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D052244:Endocrine Disruptors / Q000737:chemistry* / Q000494:pharmacology; D005659:Fungicides, Industrial / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry* / Q000502:physiology; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D001713:Biphenyl Compounds; D065692:Cytochrome P-450 CYP3A Inhibitors; D052244:Endocrine Disruptors; D005659:Fungicides, Industrial; D011944:Receptors, Androgen; D014230:Triazoles; C087058:penconazole; C087114:tebuconazole; D051544:Cytochrome P-450 CYP3A; C083642:bitertanol; C092705:uniconazole; C409722:hexaconazole
keywords: Androgen receptor; CYP450; Metabolism; Steroid hormone; Triazole