title: Widely used pharmaceuticals present in the environment revealed as in vitro antagonists for human estrogen and androgen receptors.
abstract: A considerable amount of scientific evidence indicates that a number of pharmaceuticals that could be detected in the environment can contribute towards the development of problems associated with human reproductive systems, as well as those of wildlife. We investigated the estrogenic and androgenic effects of select pharmaceuticals with high production volume and environmental relevance. We examined the receptor-binding activities of these pharmaceuticals in the T47D human cell line using altered secretion of cytokine CXCL12. Functional yeast-luciferase reporter gene assays were also employed to confirm the mechanism of receptor binding by estrogen and androgen. Non-steroidal anti-inflammatory drugs, namely ibuprofen, diclofenac and antiarrhythmic agent amiodarone showed strong anti-estrogenic effects in the T47D cell line. In the yeast-luciferase assay, these anti-inflammatory drugs also demonstrated anti-estrogenic potency and inhibited the E2 response in a concentration-dependent manner. Amiodarone did not exhibit any response in the yeast-luciferase assay; therefore, the endocrine disruption presumably occurred at a different level without directly involving the receptor. All the anti-inflammatory drugs considered in this study, including ketoprofen, naproxen and clofibrate, exhibited a dose-dependent antagonism towards the androgen receptor in the yeast-luciferase assays. Several other drugs, including the stimulant caffeine, did not show any response in the tests that were employed. A risk assessment analysis using 'Hazard Quotient' suggested a potential risk, especially in the cases of ibuprofen, ketoprofen, diclofenac and clofibrate. The results reveal the intrinsic endocrine disrupting nature of several pharmaceuticals and thus could contribute towards explaining a number of adverse health effects on humans and wildlife.
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i., Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic; Institute for Environmental Studies, Faculty of Science, Charles University, Benátská 2, CZ-128 01 Prague 2, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Ezechiáš
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i., Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Janochová
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i., Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Filipová
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i., Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic; Institute for Environmental Studies, Faculty of Science, Charles University, Benátská 2, CZ-128 01 Prague 2, Czech Republic.
authors.forename: Zdena
authors.initials: Z
authors.lastname: Křesinová
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i., Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic; Institute for Environmental Studies, Faculty of Science, Charles University, Benátská 2, CZ-128 01 Prague 2, Czech Republic. Electronic address: cajthaml@biomed.cas.cz.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Cajthaml
mesh_terms: D000728:Androgens / Q000032:analysis* / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000032:analysis / Q000633:toxicity; D001681:Biological Assay / Q000379:methods; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000032:analysis* / Q000633:toxicity; D004958:Estradiol / Q000633:toxicity; D004965:Estrogen Antagonists / Q000032:analysis* / Q000633:toxicity; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000032:analysis*; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014874:Water Pollutants, Chemical / Q000032:analysis* / Q000633:toxicity
chemical_list: C410798:AR protein, human; D000728:Androgens; D000894:Anti-Inflammatory Agents, Non-Steroidal; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D052244:Endocrine Disruptors; D004965:Estrogen Antagonists; D004364:Pharmaceutical Preparations; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D014874:Water Pollutants, Chemical; D004958:Estradiol; D008156:Luciferases
keywords: Anti-androgenic; Anti-estrogenic; Anti-inflammatory pharmaceuticals; CXCL12; Endocrine disruptor; Recombinant yeast assay