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

作者:Fan WuQiang; Yanase Toshihiko; Morinaga Hidetaka; Ondo Shigeki; Okabe Taijiro; Nomura Masatoshi; Komatsu Tomoko; Morohashi Ken Ichirou; Hayes Tyrone B*; Takayanagi Ryoichi; Nawata Hajime
来源:Environmental Health Perspectives, 2007, 115(5): 720-727.
DOI:10.1289/ehp.9758

摘要

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 (ST-1) expression in atrazine responsive and non-responsive cell lines and transfected SF-1 into non-responsive 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 (ArPlI) 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-I conveyed atrazine-responsiveness to otherwise nonresponsive KGN and NIH/3T3 cells. Atrazine induced binding of SF-I to chromatin and mutation of the SF-1 binding site in ArPll eliminated SF-1 binding and atrazine-responsiveness in H295R cells. Out of 55 chemicals examined, only atrazine, simazine, and benzopyrene induced luciferase via ArPll. 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 a,, a risk factor in endocrine disruption in wildlife and reproductive cancers in laboratory rodents and humans.

  • 出版日期2007-5