title: Many putative endocrine disruptors inhibit prostaglandin synthesis.
abstract: BACKGROUND
  Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine-disrupting compounds (EDCs) share a high degree of structural similarity with mild analgesics.
  
  
  OBJECTIVE
  Using cell-based transfection and transduction experiments, mass spectrometry, and organotypic assays together with molecular modeling, we investigated whether inhibition of the PG pathway by known EDCs could be a novel point of endocrine disruption.
  
  
  RESULTS
  We found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis, and this reduction was correlated with a reduced testosterone production. The inhibition of PG synthesis occurred without involvement of canonical PG receptors or the peroxisome proliferator-activated receptors (PPARs), which have previously been described as targets of EDCs. Instead, our results suggest that the compounds may bind directly into the active site of the cyclooxygenase (COX) enzymes, thereby obstructing the conversion of arachidonic acid to PG precursors without interfering with the expression of the COX enzymes. A common feature of the PG inhibitory EDCs is the presence of aromatic groups that may stabilize binding in the hydrophobic active site of the COX enzymes.
  
  
  CONCLUSIONS
  Our findings suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades.
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. david@moebjerg.com
authors.forename: David M
authors.initials: DM
authors.lastname: Kristensen
authors.forename: Maria L
authors.initials: ML
authors.lastname: Skalkam
authors.forename: Karine
authors.initials: K
authors.lastname: Audouze
authors.forename: Laurianne
authors.initials: L
authors.lastname: Lesné
authors.forename: Christele
authors.initials: C
authors.lastname: Desdoits-Lethimonier
authors.forename: Hanne
authors.initials: H
authors.lastname: Frederiksen
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.forename: Niels E
authors.initials: NE
authors.lastname: Skakkebæk
authors.forename: Bernard
authors.initials: B
authors.lastname: Jégou
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Hansen
authors.forename: Steffen
authors.initials: S
authors.lastname: Junker
authors.forename: Henrik
authors.initials: H
authors.lastname: Leffers
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D054872:Fatty Acid Synthesis Inhibitors / Q000633:toxicity; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D013737:Testis / Q000187:drug effects* / Q000378:metabolism
chemical_list: D052244:Endocrine Disruptors; D054872:Fatty Acid Synthesis Inhibitors; D011453:Prostaglandins; D051546:Cyclooxygenase 2