CARCINOGENIC POLYCYCLIC AROMATIC-HYDROCARBONS INCREASE INTRACELLULAR CA2-PROLIFERATION IN PRIMARY HUMAN MAMMARY EPITHELIAL-CELLS( AND CELL)

Previous studies have shown that polycyclic aromatic hydrocarbons (PAH s) mobilize intracellular Ca2+ in human T cells by inositol trisphosph ate - dependent mechanisms resulting from activation of phospholipase C-gamma by SRC-related protein tyrosine kinases, thereby mimicking ant igen-receptor activation, Ca2+ appears to play an important second mes senger role in growth factor control of cell proliferation in human ma mmary epithelial cells (HMEC), such as the epidermal growth factor rec eptor pathway, The purpose of the present studies was to determine if PAHs are able to increase intracellular Ca2+ in primary cultures of HM EC and increase cell proliferation, Two carcinogenic and two non-carci nogenic PAHs mere tested for their ability to increase intracellular C a2+ in HMEC. The carcinogenic PAHs dimethylbenz[a]anthracene (DR IBA) and benzo[a] pyrene (BaP) were able to cause Ca2+ elevation in HR-IEC at early time points (2 h) and caused sustained alterations in Ca2+ ho meostasis (18 h), DMBA showed maximal effects at early time points (2 h), while BaP showed maximal effects on sustained Ca2+ (18 h), 2,3,7,8 -Tetrachlorodibenzo-p-dioxin (TCDD), a potent dioxin and tumor promote r, produced maximal Ca2+ elevation at 2 h, with a return to near basel ine levels by 6 h, The non-carcinogenic PAHs benzo[e]pyrene and anthra cene did not significantly alter intracellular Ca2+ at any time point, alpha-Naphthoflavone significantly reduced the Ca2+ response induced by BaP treatment, but not by DMBA or TCDD, suggesting that P450 1A or 1B metabolism of BaP may be important in the sustained Ca2+ elevating response, In evaluating the effects of BaP on HMEC proliferation, BaP was found to increase the number of cells recovered after 4 days in cu lture in the absence or presence of various concentrations of epiderma l growth factor, These studies provide initial evidence that Ca2+ sign aling may be associated with mitogenesis in HR-IEC, which may play a r ole in tumor promotion and progression produced by PAHs.