Stress protein synthesis: EMF interaction with DNA Prof. Martin Blank Columbia University New York, NY, USA

Cancer: DNA, EMF DNA damage believed to initiate cancer Exposure to EMF increases risk of cancer EMF interacts with DNA (protein synthesis, strand breaks) to cause changes, damage Specific DNA sequences interact with EMF mutations in DNA repair genes increase risk of leukemia OR= 4.39 Yang et al, Leukemia & Lymphoma, 2008)

EMF-DNA Interaction Very weak EMF causes DNA to initiate protein synthesis in the stress response Very weak EMF accelerates electron transfer suggests EMF-DNA interaction mechanism EMF interacts with electrons in DNA Conclusion: EMF safety standards need to be revised down by several orders of magnitude

ELF: Epidemiology of leukemia Wertheimer & Leeper, 1979 EMF- RAPID Report to US Congress (1999) ‘EMF…not entirely safe…minimize exposure’ Threshold for leukemia 3-4mG Greenland et al, 2000; Ahlbom et al, 2000 IARC - International Agency for Research on Cancer (2002) EMF ‘possible cause of cancer’

RF: Cell Phones and Brain Tumors Hardell et al, 2008 study of wireless phones 10 years latency period, use on same side Malignant brain tumors (e.g., glioma) OR = 2.7, 95% CI=1.3-6.0 (mobile) OR = 2.1, 95% CI=0.97-4.6 (cordless) Highest risk: age<20 years for first use OR = 5.2

Sutro Tower RF Study (Cherry, 2002) Tower: 577m Antennas: 400-570m FM: 54.7kW TV: 616kW UHF: 18.3MW Risk Ratio for all childhood cancers (1937-1988) is elevated, falls off with distance from antenna RR>5 at 3km, 1µW/cm2, (power density ~1000 times lower than safety standard)

Evidence of DNA Damage Repair DNA damage in normal biosynthesis Damage remains: DNA deletions, repeats - in older identical twins - in autism parents vs children EMF adds to DNA damage - stimulate biosynthesis, strand breaks - mutations in repair genes increase risk of leukemia OR= 4.39 (Yang et al, Leukemia & Lymphoma, 2008)

Stress Response: Molecular Damage Stress proteins are synthesized in reaction to potentially harmful environmental stimuli stress response: ‘... defense reaction of cells to damage that environmental forces inflict on macromolecules.’ (Kültz, Ann Rev Physiol, 2005) along with stress genes there are genes that sense and repair damage to DNA, proteins

Stress Response: EMF Safety stimulated by both ELF (Goodman, Blank, 1998) and RF (dePomerai et al, 2002) independent of SAR - in ELF, SAR ~10-12 W/kg (non-thermal) - in RF, SAR ~10-1 W/kg (thermal) (Blank, Goodman. BEMS 25:642-646, 2004) Conclude: EMF safety standards - based on biological responses, not SAR - include combined effects of frequencies

Human DNA is ~2 meters long and has ~3 billion base pairs

Stress Response: DNA protein synthesis starts with DNA reaction different DNA segments for thermal, EM ELF, RF use same non-thermal pathway nCTCTn sequences in promoter act as EM response elements (EMRE) introduce EMRE to get EM response

EMF Specific Domain in HSP70 MYC A MYC C MYC B -320 -230 -192 -166 -160 -107 -100 -68 +1 (bp) A TF T A T A HSP70 Sp1 AP-2 HSE Sp1 AP-2 HSE SRE Sp1 AP-2 EMF Domain (non-thermal) Temperature Domain (thermal) . Lin et al (1999) J Cellular Biochem 75:170-176.

EMF-Specific DNA can be moved Chloramphenicol transferase (CAT) Activity Luciferase Activity counts counts 10 20 30 40 50 60 B a c k g r o u n d E M N e t i v C l 60 B a c k g r o u n d E M N e t i v C l 50 40 30 20 10 Experimental Conditions Experimental Conditions Lin et al (2001) J Cellular Biochem 81:143-148.

CTCT in stress protein DNA low electron affinities; electrons move easily fluorescence decay rate shows more rapid energy loss than complementary GAGA (Schwalb and Temps, Science 322:243, 2008) pyrimidines (CT) H-bond with purines (GA) - smaller, smoother surface on splitting - greater repulsion - fewer multiple H-bonds

Biological Thresholds in the ELF Range Biological System Threshold Reference Biochemical reaction rates Na,K-ATPase 2-3mG Blank & Soo, 1996 cytochrome oxidase 5-6mG Blank & Soo, 1998 ornithine decarboxylase ~20mG Mullins et al, 1999 Belousov-Zhabotinsky <5mG Blank & Soo, 2001 Biosynthesis of stress proteins HL60, Sciara, yeast, <8mG Goodman et al,1994 breast (HTB124, MCF7) <8mG Lin et al, 1998 chick embryo (anoxia) ~20mG DiCarlo et al, 2000 Disease related block melatonin inhibition of breast carcinoma 2<12mG Liburdy et al, 1993 leukemia epidemiology 3-4mG Ahlbom et al, 2000 Greenland et al,2000

Plausible Mechanism Weak electric and magnetic fields affect electron transfer (DNA, enzymes) Displacement of electrons in DNA causes local charging Charging of molecular assemblies causes disaggregation (e.g., hemoglobin) EMF stimulated electron transfer in DNA leads to disaggregation of DNA strands and initiation of protein synthesis (Blank, EMBM 27: 3-23, 2008)

DNA Stimulation in Muscle

Electric Field Stimulates DNA in Muscle Nuclei Muscle action potential resting level to peak ~100mV rise time ~1ms propagates at ~10m/s (10mm/ms) in 1ms: 100mV over 10mm electric gradient: 10V/m>>3mV/m (HL60) 10V/m>>0.5mV/m (Na,K-ATPase)

Hartner et al (1989) Eur J Biochem

Scientific Basis for Precaution Bioinitiative report, 2007 An international group of scientists (including 3 presidents of the Bioelectromagnetics Society) and public health policy professionals provided a rationale for biologically-based precautionary exposure standards Pathophysiology, EMF issue, 2009 Scientists update report with additional scientific evidence and reemphasize the need for precautionary exposure standards

BioInitiative Recommendation Biologically-based precautionary standards ELF 1-2mG (vs. ~1G) RF 0.1µW/cm2 (vs. ~1mW/cm2) micro vs. milli