title: Modelling inhibition of avian aromatase by azole pesticides.
abstract: The potential effects of pesticides and their metabolites on the endocrine system are of major concern to wildlife and human health. In this context, the azole pesticides have earned special attention due to their cytochrome P450 aromatase inhibition potential. Cytochrome P450 aromatase (CYP19) catalyses the conversion of androstenedione and testosterone into oestrone and oestradiol, respectively. Thus, aromatase modulates the oestrogenic balance essential not only for females, but also for male physiology, including gonadal function. Its inhibition affects reproductive organs, fertility and sexual behaviour in humans and wildlife species. Several studies have shown that azole pesticides are able to inhibit human and fish aromatases but the information on birds is lacking. Consequently, it appeared to be of interest to estimate the aromatase inhibition of azoles in three different avian species, namely Gallus gallus, Coturnix coturnix japonica and Taeniopygia guttata. In the absence of the crystal structure of the aromatase enzyme in these bird species, homology models for the individual avian species were constructed using the crystal structure of human aromatase (hAr) (pdb: 3EQM) that showed high sequence similarity for G. gallus (82.0%), T. guttata (81.9%) and C. japonica (81.2%). A homology model with Oncorhynchus mykiss (81.9%) was also designed for comparison purpose. The homology-modelled aromatase for each avian and fish species and crystal structure of human aromatase were selected for docking 46 structurally diverse azoles and related compounds. We showed that the docking behaviour of the chemicals on the different aromatases was broadly the same. We also demonstrated that there was an acceptable level of correlation between the binding score values and the available aromatase inhibition data. This means that the homology models derived on bird and fish species can be used to approximate the potential inhibitory effects of azoles on their aromatase.
authors.affiliation: a CSIR-CDRI , Lucknow , India.
authors.forename: A K
authors.initials: AK
authors.lastname: Saxena
authors.affiliation: b CTIS , Rillieux La Pape , France.
authors.forename: J
authors.initials: J
authors.lastname: Devillers
authors.affiliation: c Global Institute of Pharmaceutical Education and Research , Kashipur , India.
authors.forename: S S
authors.initials: SS
authors.lastname: Bhunia
authors.affiliation: d Research Department , National Game and Wildlife Institute (ONCFS) , Le Perray en Yvelines, France.
authors.forename: E
authors.initials: E
authors.lastname: Bro
mesh_terms: D000818:Animals; D001141:Aromatase / Q000737:chemistry*; D047072:Aromatase Inhibitors / Q000737:chemistry* / Q000633:toxicity; D001393:Azoles / Q000737:chemistry* / Q000633:toxicity; D001717:Birds; D003198:Computer Simulation; D052244:Endocrine Disruptors / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D062105:Molecular Docking Simulation; D017686:Oncorhynchus mykiss; D010575:Pesticides / Q000737:chemistry* / Q000633:toxicity; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D001393:Azoles; D052244:Endocrine Disruptors; D010575:Pesticides; D001141:Aromatase; C561410:CYP19A1 protein, human
keywords: Homology modelling; aromatase; azole pesticides; bird; endocrine disruptors; fish; human