title: Effects of Common Pesticides on Prostaglandin D2 (PGD2) Inhibition in SC5 Mouse Sertoli Cells, Evidence of Binding at the COX-2 Active Site, and Implications for Endocrine Disruption.
abstract: BACKGROUND
  There are concerns that diminished prostaglandin action in fetal life could increase the risk of congenital malformations. Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects.
  
  
  OBJECTIVE
  We assessed the ability of pesticides that are commonly used in the European Union to suppress prostaglandin D2 (PGD2) synthesis.
  
  
  METHODS
  Changes in PGD2 secretion in juvenile mouse Sertoli cells (SC5 cells) were measured using an ELISA. Coincubation with arachidonic acid (AA) was conducted to determine the site of action in the PGD2 synthetic pathway. Molecular modeling studies were performed to assess whether pesticides identified as PGD2-active could serve as ligands of the cyclooxygenase-2 (COX-2) binding pocket.
  
  
  RESULTS
  The pesticides boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, o-phenylphenol, pirimiphos-methyl, pyrimethanil, and tebuconazole suppressed PGD2 production. Strikingly, some of these substances-o-phenylphenol, cypermethrin, cyprodinil, linuron, and imazalil (enilconazole)-showed potencies (IC50) in the range between 175 and 1,500 nM, similar to those of analgesics intended to block COX enzymes. Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes. The molecular modeling studies revealed that the COX-2 binding pocket can accommodate most of the pesticides shown to suppress PGD2 synthesis. Some of these pesticides are also capable of antagonizing the androgen receptor.
  
  
  CONCLUSIONS
  Chemicals with structural features more varied than previously thought can suppress PGD2 synthesis. Our findings signal a need for in vivo studies to establish the extent of endocrine-disrupting effects that might arise from simultaneous interference with PGD2 signaling and androgen action.
  
  
  BACKGROUND
  Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A. 2016. Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse Sertoli cells, evidence of binding at the COX-2 active site, and implications for endocrine disruption. Environ Health Perspect 124:452-459; http://dx.doi.org/10.1289/ehp.1409544.
authors.affiliation: Institute of Environment, Health and Societies, Brunel University London, Uxbridge, United Kingdom.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Kugathas
authors.forename: Karine
authors.initials: K
authors.lastname: Audouze
authors.forename: Sibylle
authors.initials: S
authors.lastname: Ermler
authors.forename: Frances
authors.initials: F
authors.lastname: Orton
authors.forename: Erika
authors.initials: E
authors.lastname: Rosivatz
authors.forename: Martin
authors.initials: M
authors.lastname: Scholze
authors.forename: Andreas
authors.initials: A
authors.lastname: Kortenkamp
mesh_terms: D059002:Androgen Receptor Antagonists; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D020134:Catalytic Domain; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052244:Endocrine Disruptors / Q000633:toxicity*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010575:Pesticides / Q000633:toxicity*; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D012708:Sertoli Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D059002:Androgen Receptor Antagonists; D052244:Endocrine Disruptors; D010575:Pesticides; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D015230:Prostaglandin D2