Analysis of gene expression in EMF research

Several groups have described experiments in which nonthermal electric field pulses with durations of 10 to 300 ns and magnitudes of 1 to 150 kV/cm cause effects associated with subcellular structures.Field-induced apoptosis is the most striking effect.OBJECTIVES: We are creating progressively more realistic models of cells, such that models contain not only the outer plasma membrane (PM), but also models for subcellular structures such as the nucleus, endoplasmic reticulum and several mitochondria.This provides microdosimetry at the cellular and subcellular level.With suitable biophysical coupling models this also provides estimates of chemical change by predicting molecular and ionic transport within a cell model.METHODS: We use a transport lattice approach (Gowrishankar and Weaver, PNAS, 2003) to create two dimensional (2D) mammalian cell models that include subcellular structures.These models include local models for conductive and dielectric properties of membranes and of the extra-and intracellular electrolytes, with the dielectric properties of electrolytes important for short pulses with high frequency components.The membrane also contains local models for the resting potential and a local nonlinear, hysteretic model for lipid membrane electroporation, which involves solving an ordinary differential equation at ~600 local sites within the cell model (Stewart et al, submitted).We also use a 3 µm X 3 µm membrane planar patch model with a Smoluchowski equation-based model to investigate local electroporation behavior due to pulses of a wide range of durations and amplitudes. RESULTS:The planar patch model shows that supra-electroporation (two to three orders of magnitude more pores per area than conventional electroporation) is expected for the very large, submicrosecond pulses (Vailkoski et al., in preparation), and that only minimum size pores (r ~ 1 nm) are involved in preventing the transmembrane voltage from exceeding ~1.5 V.The 2D cell models show that the PM is supra-electroporated.Both displacement and conductive currents create sufficiently large intracellular fields that the mitochondrial inner membrane is electroporated, with the postpulse, slowly decaying pore population sufficient to create a quasi-voltage clamp of ~0 V (transmembrane voltage).This should open the mitochondrial permeability transition pore (MPTP), one proposed mechanism for initiating apoptosis by a permeability transition (Halestrap et al.Biochimie, 2002; Zamzami and Kroemer, Curr.Biol.2003).A general feature of our models is that supra-electroporation occurs extensively in the PM and less but significant electroporation occurs in membranes of the nucleus, endoplasmic reticulum and both the inner and outer mitochondrial membranes.The small, residual pores have lifetimes of order seconds, which is a mechanism for translating submicrosecond interactions to the physiological time scale of 0.1 ms to seconds.Translocation of membrane components is expected for both conventional (pulses with > 100 microsecond durations and ~ 1 kV/cm magnitudes) and supra-electroporation, and the persistence of translocated phospholipids or proteins generates signals that can last for even longer times.Both molecular and ionic transport of residual pores and signaling by translocated membrane molecules may contribute to diverse and potentially specific intracellular effects that are caused by the exposure of cells and tissues to extremely large, submicrosecond pulses.

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