title: Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity.
abstract: The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [(3)H](2)O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks.
authors.affiliation: Centre for Arctic Health, Department of Public Health, Aarhus University, Aarhus, Denmark.
authors.forename: Lisbeth Stigaard
authors.initials: LS
authors.lastname: Kjeldsen
authors.forename: Mandana
authors.initials: M
authors.lastname: Ghisari
authors.forename: Eva Cecilie
authors.initials: EC
authors.lastname: Bonefeld-Jørgensen
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045424:Complex Mixtures / Q000737:chemistry / Q000633:toxicity*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D010575:Pesticides / Q000737:chemistry / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D045424:Complex Mixtures; D052244:Endocrine Disruptors; D010575:Pesticides; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D001141:Aromatase
keywords: 17β-estradiol; 2-methyl-4-chlorophenoxyacetic acid; 4-AOD; 4-Androsten-4-ol-3,17-dione; AR; Antiandrogenic; Aromatase; CA; CV; CYP; DDE; DDT; DHT; DMSO; E2; ED; EDC; ER; ETU; Endocrine disruptor; Estrogenic; HF; Luciferase reporter gene assay; MCPA; Pesticide; QSAR; R1881; SC; SD; Solvent control; Standard deviation; androgen receptor; coefficient of variation; concentration addition; cytochrome P450; dichlorodiphenyldichloroethylene; dichlorodiphenyltrichloroethane; dihydrotestosterone; dimethyl sulfoxide; endocrine-disrupting chemical; endocrine-disrupting/endocrine disruption; estrogen receptor; ethylene thiourea; hydroxyflutamide; methyltrienolone; quantitative structure–activity relationship