Environmental contaminants have been shown to alter growth-regulating signaling pathways through molecular mechanisms that are mainly unclear. Here we report that within a narrow concentration range (0.5-1 
M) methyl mercury (MeHg) significantly stimulated growth of MCF-7 cells, induced Ca2+ mobilization, and activated extracellular signal-regulated kinase ? (Erk1/2). MeHg modulated E2-dependent stimulation of growth in a dose-dependent manner, although MeHg neither suppresses nor increases constitutive E2 metabolism. MeHg demonstrated weak estrogen receptor (ER)-binding ability.
However, long preincubation with antiestrogens LY156,758 and ICI164,384 decreased MeHg-induced foci formation, Ca2+ mobilization, and Erk1/2 activation, confirming involvement of ERs. The MeHg-induced increase in [Ca2+]i was observed to coincide with enhanced Erk1/2 phosphorylation. These data suggest that MeHg can significantly modulate the intracellular signaling environment in MCF-7 cells, resulting in a dose-dependent alteration of ER-mediated estrogenic capacity and therefore should be considered as a potential estrogen-disrupting compound. © 2005 Wiley Periodicals, Inc. Environ Toxicol 20: 32-44, 2005.