Atrazine-induced aromatase expression is SF-1 dependent: Implications for endocrine disruption in wildlife and reproductive cancers in humans

Wu Qiang Fan, Toshihiko Yanase, Hidetaka Morinaga, Shigeki Gondo, Taijiro Okabe, Masatoshi Nomura, Tomoko Komatsu, Ken Ichirou Morohashi, Tyrone B. Hayes, Ryoichi Takayanagi, Hajime Nawata

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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 nonresponsive 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 tole 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.

Original languageEnglish
Pages (from-to)720-727
Number of pages8
JournalEnvironmental Health Perspectives
Volume115
Issue number5
DOIs
Publication statusPublished - May 2007

All Science Journal Classification (ASJC) codes

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

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    Fan, W. Q., Yanase, T., Morinaga, H., Gondo, S., Okabe, T., Nomura, M., Komatsu, T., Morohashi, K. I., Hayes, T. B., Takayanagi, R., & Nawata, H. (2007). Atrazine-induced aromatase expression is SF-1 dependent: Implications for endocrine disruption in wildlife and reproductive cancers in humans. Environmental Health Perspectives, 115(5), 720-727. https://doi.org/10.1289/ehp.9758