Academic journal article Environmental Health Perspectives

G-Protein-Coupled Receptor 30 and Estrogen Receptor-[Alpha] Are Involved in the Proliferative Effects Induced by Atrazine in Ovarian Cancer Cells

Academic journal article Environmental Health Perspectives

G-Protein-Coupled Receptor 30 and Estrogen Receptor-[Alpha] Are Involved in the Proliferative Effects Induced by Atrazine in Ovarian Cancer Cells

Article excerpt

BACKGROUND: Atrazine, one of the most common pesticide contaminants, has been shown to up-regulate aromatase activity in certain estrogen-sensitive tumors without binding or activating the estrogen receptor (ER). Recent investigations have demonstrated that the orphan G-proteincoupled receptor 30 (GPR30), which is structurally unrelated to the ER, mediates rapid actions of 17-estradiol and environmental estrogens.

OBJECTIVES: Given the ability of atrazine to exert estrogen-like activity in cancer cells, we evaluated the potential of atrazine to signal through GPR30 in stimulating biological responses in cancer cells.

METHODS AND RESULTS: Atrazine did not transactivate the endogenous ER [alpha] in different cancer cell contexts or chimeric proteins encoding the ER [alpha] and ER [BETA] hormone-binding domain in gene reporter assays. Moreover, atrazine neither regulated the expression of ER [alpha] nor stimulated aromatase activity. Interestingly, atrazine induced extracellular signal-regulated kinase (ERK) phosphorylation and the expression of estrogen traget genes. Using specific signalicg inhibitors and gene silecing, we demonstrated that atrazine stimulated the proliferation of ovarian cancer cells through the GPR30-epidermal growth factor receptor transduction pathway and the involvement of ER[alpha].

CONCLUSIONS: Our results indicate a novel mechanism through which atrazing may exert relevant biological effects in cancer cells. On the basis of the present data, atrazine should be included among the environmental contaminants potentially able to signal via GPR30 in eliciting estrogenic action.

KEY WORDS: 17[BETA]-estradiol, atrazine, estrogen receptor, GPR30, ovarian cancer cells. Environ Health Perspect 116:1648-1655 (2008). doi:10.1289/ehp.11297 available via http:lldx.doi.orgl [Online 22 July 2008]

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Atrazine belongs to the 2-chloro-s-triazine family of herbicides (Figure 1) and is the most common pesticide contaminant of groundwater and surface water (Fenelon and Moore 1998; Kolpin et al. 1998; Lode et al. 1997; Solomon et al. 1996; Thurman and Cromwell 2000). Among the endocrine-disrupting effects, atrazine interferes with androgen-and estrogen-mediated processe (Babic-Gojmerac et al. 1989; Cooper et al. 1999, 2000; Cummings et al. 2000; Friedmann 2002; Kniewald et al. 1979, 1995; Narotsky et al. 2001; Shafer et al. 1999; Simic et al. 1991; Stoker et al. 1999, 2000). The interference of attazine with androgen and estrogen action does not occur by direct agonism or antagonism of cognate receptors for these steroids as shown by binding affinity studies (Roberge et al. 2004; Tennant et al. 1994a, 1994b)., In this respect, previous investigations have suggested that atrazine reduces androgen synthesis and action (Babic-Gojmerac et al. 1989; Kniewald et al. 1979, 1980, 1995; Simic et al. 1991) and stimulates estrogen production (Crain et al. 1997; Heneweer et al. 2004; Keller and McClellan-Green 2004; Sanderson et al. 2000, 2001,.2002; Spano et al, 2004). The latter ability is exerted through at least two meachanisms that converge on increasing aromatase expression and activity. First, inhibiting phosphodiesterase, atrazing upregulates cAMP, which induces the expression of SF-1, an important regulator of the P II promoter of aromatase gene CYP 19. The enhanced transcription of the aromatase gene increases both enzymatic activity of aromatase and estrogen production(Heneweer et al. 2004; Lehmann et al. 2005; Morinaga et al. 2004; Reberge et al. 2004; Sanderson et al. 2000, 2001). Next, atrazine binds to SF-1 and facilitates the recruitment of this factor to the PII promoter of the aromatase gene, further stimulating the biological effects described above (Fan et al. 2007a, 2007b).

Epidemiologic studies have associated long-term exposure to triazine herbicides with increased risk of ovarian cancer in female farm workers in Italy (Donna et al. 1989) and breast cancer in the general population of Kentucky in the United States (Kettles et al. …

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