Catherine Le Quément

Millimeter-wave interactions with the human body: state of knowledge and recent advances

The biocompatibility of millimeter-wave devices and systems is an important issue due to the wide number of emerging body-centric wireless applications at millimeter waves. This review article provides the state of knowledge in this field and mainly focuses on recent results and advances related to the different aspects of millimeter-wave interactions with the human body. Electromagnetic, thermal, and biological aspects are considered and analyzed for exposures in the 30-100 GHz range with a particular emphasis on the 60-GHz band. Recently introduced dosimetric techniques and specific instrumentation for bioelectromagnetic laboratory studies are also presented. Finally, future trends are discussed.

Macrophage metalloelastase (MMP-12) as a target for inflammatory respiratory diseases

Background: MMPs are known to regulate the turnover of extracellular matrix and have been suggested to be important in lung disease associated with tissue remodeling. Macrophage elastase (MMP-12) is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling in inflammatory respiratory diseases such as chronic obstructive pulmonary diseases (COPD), including emphysema. Recent studies using MMP-12 inhibitors have demonstrated a reduction in both the inflammatory process and airspace enlargement in lung tissue. Objective/methods: This review discusses the potential involvement of MMP-12 in the pathophysiological process and proposes MMP-12 as a target for inflammatory disorders of the respiratory system. Results/conclusions: MMP-12 plays a predominant role in the inflammatory process induced by cigarette smoke, and therefore is potentially an important therapeutic target for the treatment of COPD.

MMP-12 induces IL-8/CXCL8 secretion through EGFR and ERK1/2 activation in epithelial cells

Macrophage metalloelastase (MMP-12) is described to be involved in pulmonary inflammatory response. To determine the mechanisms linking MMP-12 and inflammation, we examined the effect of recombinant human MMP-12 (rhMMP-12) catalytic domain on IL-8/CXCL8 production in cultured human airway epithelial (A549) cells. Stimulation with rhMMP-12 resulted in a concentration-dependent IL-8/CXCL8 synthesis 6 h later. Similar results were also observed in cultured BEAS-2B bronchial epithelial cells. In A549 cells, synthetic matrix metalloproteinase (MMP) inhibitors prevented rhMMP-12-induced IL-8/CXCL8 release. We further demonstrated that in A549 cells, rhMMP-12 induced transient, peaking at 5 min, activation of ERK1/2. Selective MEK inhibitors (U0126 and PD-98059) blocked both IL-8/CXCL8 release and ERK1/2 phosphorylation. IL-8/CXCL8 induction and ERK1/2 activation were preceded by EGF receptor (EGFR) tyrosine phosphorylation, within 2 min, and reduced by selective EGFR tyrosine kinase inhibitors (AG-1478 and PD168393) by a neutralizing EGFR antibody and by small interfering RNA oligonucleotides directed against EGFR, implicating EGFR activation. In addition, we observed an activation of c-Fos in A549 cells stimulated by rhMMP-12, dependent on ERK1/2. Using small interfering technique, we showed that c-Fos is involved in rhMMP-12-induced IL-8/CXCL8 production. From these results, we conclude that one mechanism, by which MMP-12 induces IL-8/CXCL8 release from the alveolar epithelium, is the EGFR/ERK1/2/activating protein-1 pathway.

Near-field dosimetry for in vitro exposure of human cells at 60 GHz

Due to the expected mass deployment of millimeter-wave wireless technologies, thresholds of potential millimeter-wave-induced biological and health effects should be carefully assessed. The main purpose of this study is to propose, optimize, and characterize a near-field exposure configuration allowing illumination of cells in vitro at 60 GHz with power densities up to several tens of mW/cm(2) . Positioning of a tissue culture plate containing cells has been optimized in the near-field of a standard horn antenna operating at 60 GHz. The optimal position corresponds to the maximal mean-to-peak specific absorption rate (SAR) ratio over the cell monolayer, allowing the achievement of power densities up to 50 mW/cm(2) at least. Three complementary parameters have been determined and analyzed for the exposed cells, namely the power density, SAR, and temperature dynamics. The incident power density and SAR have been computed using the finite-difference time-domain (FDTD) method. The temperature dynamics at different locations inside the culture medium are measured and analyzed for various power densities. Local SAR, determined based on the initial rate of temperature rise, is in a good agreement with the computed SAR (maximal difference of 5%). For the optimized exposure setup configuration, 73% of cells are located within the ±3 dB region with respect to the average SAR. It is shown that under the considered exposure conditions, the maximal power density, local SAR, and temperature increments equal 57 mW/cm(2) , 1.4 kW/kg, and 6 °C, respectively, for the radiated power of 425 mW.

Complex permittivity of representative biological solutions in the 2–67 GHz range

The main purpose of this study is to provide experimental data on the complex permittivity of some biological solutions in the 2-67 GHz range at room and human body temperatures. The permittivity measurements are performed using an open-ended coaxial probe. Permittivity spectra of several representative monomolecular solutions of proteins, amino acids, nucleic acids, and carbohydrates are analyzed and compared. Furthermore, measurements have also been performed for complex biomolecular solutions, including bovine serum albumin (BSA)-DNA-glucose mixture, culture medium, and yeast extract solution. The results demonstrate that for concentrations below 1%, the permittivity spectra of the solutions do not substantially differ from that of distilled water. Measurements carried out for 4% and 20% BSA solutions show that the presence of proteins results in a decrease in permittivity. For highly concentrated RNA solutions (3%), a slight increase in the imaginary part of the permittivity is observed below 10 GHz. Experimental data show that free water permittivity can be used for modeling of the culture medium above 10 GHz. However, at lower frequencies a substantial increase in the imaginary part of the permittivity due to ionic conductivity should be carefully taken into account. A similar increase has also been observed for the yeast extract solution in the lower frequency region of the considered spectrum. Above 10 GHz, the high concentration of proteins and other low-permittivity components of the yeast extract solution results in a decrease in the complex permittivity compared to that of water. Obtained data are of utmost importance for millimeter-wave dosimetry studies.

Whole-genome expression analysis in primary human keratinocyte cell cultures exposed to 60 GHz radiation.

The main purpose of this study is to investigate potential responses of skin cells to millimeter wave (MMW) radiation increasingly used in the wireless technologies. Primary human skin cells were exposed for 1, 6, or 24 h to 60.4 GHz with an average incident power density of 1.8 mW/cm(2) and an average specific absorption rate of 42.4 W/kg. A large-scale analysis was performed to determine whether these exposures could affect the gene expression. Gene expression microarrays containing over 41,000 unique human transcript probe sets were used, and data obtained for sham and exposed cells were compared. No significant difference in gene expression was observed when gene expression values were subjected to a stringent statistical analysis such as the Benjamini-Hochberg procedure. However, when a t-test was employed to analyze microarray data, 130 transcripts were found to be potentially modulated after exposure. To further quantitatively analyze these preselected transcripts, real-time PCR was performed on 24 genes with the best combination of high fold change and low P-value. Five of them, namely CRIP2, PLXND1, PTX3, SERPINF1, and TRPV2, were confirmed as differentially expressed after 6 h of exposure. To the best of our knowledge, this is the first large-scale study reporting on potential gene expression modification associated with MMW radiation used in wireless communication applications.

Transcriptome Analysis Reveals the Contribution of Thermal and the Specific Effects in Cellular Response to Millimeter Wave Exposure

Radiofrequency radiations constitute a new form of environmental pollution. Among them, millimeter waves (MMW) will be widely used in the near future for high speed communication systems. This study aimed therefore to evaluate the biocompatibility of MMW at 60 GHz. For this purpose, we used a whole gene expression approach to assess the effect of acute 60 GHz exposure on primary cultures of human keratinocytes. Controls were performed to dissociate the electromagnetic from the thermal effect of MMW. Microarray data were validated by RT-PCR, in order to ensure the reproducibility of the results. MMW exposure at 20 mW/cm2, corresponding to the maximum incident power density authorized for public use (local exposure averaged over 1 cm2), led to an increase of temperature and to a strong modification of keratinocyte gene expression (665 genes differentially expressed). Nevertheless, when temperature is artificially maintained constant, no modification in gene expression was observed after MMW exposure. However, a heat shock control did not mimic exactly the MMW effect, suggesting a slight but specific electromagnetic effect under hyperthermia conditions (34 genes differentially expressed). By RT-PCR, we analyzed the time course of the transcriptomic response and 7 genes have been validated as differentially expressed: ADAMTS6, NOG, IL7R, FADD, JUNB, SNAI2 and HIST1H1A. Our data evidenced a specific electromagnetic effect of MMW, which is associated to the cellular response to hyperthermia. This study raises the question of co-exposures associating radiofrequencies and other environmental sources of cellular stress.

Unraveling Complex Interplay between Heat Shock Factor 1 and 2 Splicing Isoforms

Chaperone synthesis in response to proteotoxic stress is dependent on a family of transcription factors named heat shock factors (HSFs). The two main factors in this family, HSF1 and HSF2, are co-expressed in numerous tissues where they can interact and form heterotrimers in response to proteasome inhibition. HSF1 and HSF2 exhibit two alternative splicing isoforms, called α and β, which contribute to additional complexity in HSF transcriptional regulation, but remain poorly examined in the literature. In this work, we studied the transcriptional activity of HSF1 and HSF2 splicing isoforms transfected into immortalized Mouse Embryonic Fibroblasts (iMEFs) deleted for both Hsf1 and Hsf2, under normal conditions and after proteasome inhibition. We found that HSF1α is significantly more active than the β isoform after exposure to the proteasome inhibitor MG132. Furthermore, we clearly established that, while HSF2 had no transcriptional activity by itself, short β isoform of HSF2 exerts a negative role on HSF1β-dependent transactivation. To further assess the impact of HSF2β inhibition on HSF1 activity, we developed a mathematical modelling approach which revealed that the balance between each HSF isoform in the cell regulated the strength of the transcriptional response. Moreover, we found that cellular stress such as proteasome inhibition could regulate the splicing of Hsf2 mRNA. All together, our results suggest that relative amounts of each HSF1 and HSF2 isoforms quantitatively determine the cellular level of the proteotoxic stress response.

Impact of 60-GHz millimeter waves and corresponding heat effect on endoplasmic reticulum stress sensor gene expression

Emerging high data rate wireless communication systems, currently under development, will operate at millimeter waves (MMW) and specifically in the 60 GHz band for broadband short-range communications. The aim of this study was to investigate potential effects of MMW radiation on the cellular endoplasmic reticulum (ER) stress. Human skin cell lines were exposed at 60.4 GHz, with incident power densities (IPD) ranging between 1 and 20 mW/cm(2) . The upper IPD limits correspond to the ICNIRP local exposure limit for the general public. The expression of ER-stress sensors, namely BIP and ORP150, was then examined by real-time RT-PCR. Our experimental data demonstrated that MMW radiations do not change BIP or ORP150 mRNA basal levels, whatever the cell line, the exposure duration or the IPD level. Co-exposure to the well-known ER-stress inducer thapsigargin (TG) and MMW were then assessed. Our results show that MMW exposure at 20 mW/cm(2) inhibits TG-induced BIP and ORP150 over expression. Experimental controls showed that this inhibition is linked to the thermal effect resulting from the MMW exposure.

Anti-inflammatory properties of MMP inhibitors in experimental models of chronic obstructive pulmonary disease and lung inflammation

Matrix metalloproteinases (MMPs) are a group of proteases known to regulate the turnover of extracellular matrix and thus are suggested to be important in the process of lung disease associated with tissue remodelling. Furthermore, the concept that modulation of airway remodelling including excessive proteolysis damage of the tissue, may be of interest as a basis for future treatment. Among the metalloproteinases (MMPs) family, macrophage elastase (MMP-12) is able to degrade extracellular matrix components such as elastin and is involved in tissue remodelling processes in chronic obstructive pulmonary disease including emphysema. Recent studies using broad spectrum MMP or dual MMP-9/MMP-12 inhibitors have demonstrated a reduction in both inflammatory process and airspace enlargement in lung tissue. In the present chapter, we also report the inhibitory activity of a new MMP-9/MMP-12 inhibitor, AS112108, on acute lung inflammatory processes induced by cigarette smoke.