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

被引:182
作者
Fan, WuQiang
Yanase, Toshihiko
Morinaga, Hidetaka
Ondo, Shigeki
Okabe, Taijiro
Nomura, Masatoshi
Komatsu, Tomoko
Morohashi, Ken-Ichirou
Hayes, Tyrone B. [1 ]
Takayanagi, Ryoichi
Nawata, Hajime
机构
[1] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA
[2] Univ Calif Berkeley, Museum Vertebrate Zool, Energy & Resources Grp, Lab Integrat Studies Amphibian Biol,Grp Endocrino, Berkeley, CA 94720 USA
[3] Natl Inst Basic Biol, Dept Dev Biol, Okazaki, Aichi, Japan
[4] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka, Japan
关键词
aromatase; atrazine; breast cancer; cAMP; CYP19; endocrine disruptor; hermaphroditism; prostate cancer; SF-1;
D O I
10.1289/ehp.9758
中图分类号
X [环境科学、安全科学];
学科分类号
08 ; 0830 ;
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.
引用
收藏
页码:720 / 727
页数:8
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