Effects of benzo-a-pyrene on oxytocin-induced Ca²⁺ oscillations in myometrial cells

Benzo-a-pyrene (BaP) is a polycyclic aromatic hydrocarbon that exists as a major environmental pollutant. The effect of this carcinogen/mutagen upon myometrial Ca²⁺ signaling in a human myometrial cell line (PHM1) was examined. Exposure of cells to BaP did not alter basal Ca²⁺ levels or the inositol(1,4,5) trisphosphate-releasable Ca²⁺ pool. However, BaP significantly decreased the initial oxytocin-induced Ca²⁺ transient and the frequency of oxytocin-induced Ca²⁺oscillations as well as delayed their onset. To determine the specific effects of BaP, pharmacologic agents that target intracellular Ca²⁺ homeostasis mechanisms were used. Genistein (a non-specific tyrosine kinase inhibitor) and AG1478 (an epidermal growth factor receptor blocker) markedly reduced the oxytocin-induced Ca²⁺ oscillations in control, but had no effect in BaP treated cells. Addition of epidermal growth factor or serum before or after oxytocin restored the Ca²⁺ oscillations in BaP treated cells to a level similar to control cells, while the K⁺ channel blocker tetraethylammonium chloride, partially restored the Ca²⁺ response. These data suggest that the tyrosine kinase pathway, which is part of the G-protein coupled receptor pathway response to oxytocin in PHM1 cells, is a target of BaP action and that EGF or serum can restore the oxytocin-induced Ca²⁺ oscillations.