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.

CONCLUSION:

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: WuQiang Fan, Toshihiko Yanase, Hidetaka Morinaga, Shigeki Gondo, Taijiro Okabe, Masatoshi Nomura, Tomoko Komatsu, Ken-Ichirou Morohashi, Tyrone B Hayes, Ryoichi Takayanagi, Hajime Nawata
• Journal: Environmental health perspectives (Environ Health Perspect) Vol. 115 Issue 5 Pg. 720-7 (May 2007) ISSN: 0091-6765 [Print] United States
• PMID: 17520059 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Endocrine Disruptors
• Environmental Pollutants
• Ligands
• Steroidogenic Factor 1
• Luciferases
• Aromatase
• Atrazine
• Simazine

Topics

• Analysis of Variance
• Animals
• Aromatase (genetics, metabolism)
• Atrazine (toxicity)
• Binding Sites (genetics)
• Blotting, Western
• Cell Line, Tumor
• DNA Primers
• Endocrine Disruptors (toxicity)
• Environmental Pollutants (toxicity)
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Ligands
• Luciferases (metabolism)
• Mice
• Mutation (genetics)
• Promoter Regions, Genetic (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Simazine (metabolism)
• Steroidogenic Factor 1 (metabolism)