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 phones10 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

-230-230 -160-160 +1 (bp)+1 (bp)-320-320 -192-192 -107-107 -68-68-100-100-166-166

HSPHSPMYCMYC AA

HSP70HSP70

Sp1Sp1 AP-2AP-2 HSEHSE Sp1Sp1 AP-2AP-2 HSEHSE SRESRE

AATFTF

TTAATTAA

Sp1Sp1 AP-2AP-2

HSPHSPMYCMYC CC

HSPHSPMYCMYC BB

Temperature DomainTemperature Domain (thermal)(thermal)

EMF EMF DomainDomain(non-(non-thermal)thermal)

. .

EMF Specific Domain in HSP70

Lin et al (1999) J Cellular Biochem 75:170-176.

EMF-Specific DNA can be moved

countscounts

Chloramphenicol transferase Chloramphenicol transferase (CAT) Activity(CAT) Activity

00

1010

2020

3030

4040

5050

6060

BBaacckkggrroouunnddEEMM

NNeeggaattiivvee CCoonnttrrooll

Luciferase ActivityLuciferase Activitycountscounts

00

1010

2020

3030

4040

5050

6060

BBaacckkggrroouunnddEEMM

NNeeggaattiivvee CCoonnttrrooll

Experimental ConditionsExperimental Conditions Experimental ConditionsExperimental 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, 1996cytochrome oxidase 5-6mG Blank & Soo, 1998ornithine decarboxylase ~20mG Mullins et al, 1999Belousov-Zhabotinsky <5mG Blank & Soo, 2001

Biosynthesis of stress proteinsHL60, Sciara, yeast, <8mG Goodman et al,1994breast (HTB124, MCF7) <8mG Lin et al, 1998 chick embryo (anoxia) ~20mG DiCarlo et al, 2000

Disease relatedblock melatonin inhibition of breast carcinoma 2<12mG Liburdy et al, 1993leukemia 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