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WuQiang Fan,¹ Toshihiko Yanase,¹ Hidetaka Morinaga,¹ Shigeki Gondo,¹ Taijiro Okabe,¹ Masatoshi Nomura,¹ Tomoko Komatsu,² Ken-Ichirou Morohashi,² Tyrone B. Hayes,³ Ryoichi Takayanagi,¹ and Hajime Nawata⁴

¹Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan; ²Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan; ³Laboratory for Integrative Studies in Amphibian Biology, Group in Endocrinology, Museum of Vertebrate Zoology, Energy and Resources Group, and Department of Integrative Biology, University of California, Berkeley, California, USA;⁴Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

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 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.

Key words: aromatase, atrazine, breast cancer, cAMP, CYP19, endocrine disruptor, hermaphroditism, prostate cancer, SF-1. Environ Health Perspect 115:720–727 (2007) . doi:10.1289/ehp.9758 available via http://dx.doi.org/ [Online 5 February 2007]

Address correspondence to T.B. Hayes, Department of Integrative Biology, University of California, Berkeley, CA 94720-3104 USA. Telephone: (510) 643-1054. Fax: (510) 643-6264. E-mail: tyrone@berkeley.edu

We thank E.R. Simpson for the generous gift of the luciferase reporter plasmids of ArPII-516 and ArPII-516-SF1-M ; and K.-I. Morohashi for the anti-SF-1 antibody and the baculo-virus vector for mouse SF-1.

The study was supported by a grant-in-aid for "Mechanisms of Sex Differentiation" and a grant for the 21st Century COE program from the Ministry of Education, Culture, Sports, Science and Technology of Japan. No U.S. federal funds were used in these studies. T.B.H. was funded by the University of California, Berkeley.

The authors declare they have no competing financial interests.

Received 22 September 2006 ; accepted 5 February 2007.