title: Atrazine-induced aromatase expression is SF-1 dependent: implications for endocrine disruption in wildlife and reproductive cancers in humans.
abstract: BACKGROUND
  Atrazine is a potent endocrine disruptor that increases aromatase expression in some human cancer cell lines. The mechanism involves the inhibition of phosphodiesterase and subsequent elevation of cAMP.
  
  
  METHODS
  We compared steroidogenic factor 1 (SF-1) expression in atrazine responsive and non-responsive cell lines and transfected SF-1 into nonresponsive cell lines to assess SF-1's role in atrazine-induced aromatase. We used a luciferase reporter driven by the SF-1-dependent aromatase promoter (ArPII) to examine activation of this promoter by atrazine and the related simazine. We mutated the SF-1 binding site to confirm the role of SF-1. We also examined effects of 55 other chemicals. Finally, we examined the ability of atrazine and simazine to bind to SF-1 and enhance SF-1 binding to ArPII.
  
  
  RESULTS
  Atrazine-responsive adrenal carcinoma cells (H295R) expressed 54 times more SF-1 than nonresponsive ovarian granulosa KGN cells. Exogenous SF-1 conveyed atrazine-responsiveness to otherwise nonresponsive KGN and NIH/3T3 cells. Atrazine induced binding of SF-1 to chromatin and mutation of the SF-1 binding site in ArPII eliminated SF-1 binding and atrazine-responsiveness in H295R cells. Out of 55 chemicals examined, only atrazine, simazine, and benzopyrene induced luciferase via ArPII. Atrazine bound directly to SF-1, showing that atrazine is a ligand for this "orphan" receptor.
  
  
  CONCLUSIONS
  The current findings are consistent with atrazine's endocrine-disrupting effects in fish, amphibians, and reptiles; the induction of mammary and prostate cancer in laboratory rodents; and correlations between atrazine and similar reproductive cancers in humans. This study highlights the importance of atrazine as a risk factor in endocrine disruption in wildlife and reproductive cancers in laboratory rodents and humans.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
authors.forename: WuQiang
authors.initials: W
authors.lastname: Fan
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanase
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Morinaga
authors.forename: Shigeki
authors.initials: S
authors.lastname: Gondo
authors.forename: Taijiro
authors.initials: T
authors.lastname: Okabe
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Komatsu
authors.forename: Ken-Ichirou
authors.initials: K
authors.lastname: Morohashi
authors.forename: Tyrone B
authors.initials: TB
authors.lastname: Hayes
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
authors.forename: Hajime
authors.initials: H
authors.lastname: Nawata
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D001280:Atrazine / Q000633:toxicity*; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D052244:Endocrine Disruptors / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012839:Simazine / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D008024:Ligands; D054339:Steroidogenic Factor 1; D008156:Luciferases; D001141:Aromatase; D001280:Atrazine; D012839:Simazine