FUNDACIÓN MAPFRESeguridad y Medio Ambiente

Year 31 Nº 123 2011

Weak magnetic fields and lipoatrophia semicircularisINDUSTRIAL HYGIENE

The occupational exhibition to magnetic fields issued by IT equipments as cofactor potential of this pathology

Lipoatrophia semicircularis (Ls) (also called semicircular lipoatrophy) is a medical condition that consists of semicircular ribs of atrophied subcutaneous adipose tissue, generally on the anterior face of one or both thighs. Recent years have seen an increase in the incidence of Ls in certain working environments. Although the specific causal factors of this condition have yet to be identified, exposure to the electromagnetic fields generated by computer equipment and other desktop electrical equipment has been put forward as a cofactor in the genesis of Ls. This study tests the hypothesis that in vitro exposure to weak 50 Hz magnetic fields, a level slipping under the radar of international protection thresholds in working environments (B = 500 microtesla), could affect the adipocyte differentiation of human cells. According to the study results, the exposed samples showed significant falls in the synthesis of fatty acids, as well as alterations in cell mechanisms involved in adipocyte differentiation. These findings support the hypothesis of the potential action of weak magnetic fields on adipocyte differentiation and represent the first experimental evidence that low-frequency magnetic fields could intervene as a cofactor in the genesis or development of occupationally caused Ls.

By ALEJANDRO ÚBEDA MAESO. Researcher, Section Head, Servicio BEM-Investigación, Hospital Ramón y Cajal, Madrid (axumaeso@gmail.com).

M.A. MARTÍNEZ PASCUAL. Doctor of Science, Servicio BEM-Investigación, Hospital Ramón y Cajal.

M.A. CID TORRES. Doctor of Science, Professor of the Biomedical Sciences, European University of Madrid.

M.A. TRILLO RUIZ. Researcher, Servicio BEM-Investigación, Hospital Ramón y Cajal

C.L. PAÍNO BELARRINAGA. Researcher, Servicio de Neurobiología-Investigación, Hospital Ramón y Cajal.

Lypodystrophy takes in a heterogeneous set of conditions affecting the adipose tissue; it is characterised by a loss of body fat, which might be general or partial. Lipoatrophia semicircularis (Ls) is a partial type lypodystrophy that is described as an idiopathic lesion characterised by a semicircular depression usually located on the anterior or anterolateral part of the thighs (figure 1), caused by an atrophy of the subcutaneous adipose tissue without affecting the skin or muscle tissue1. In most cases the depression is bilateral, symmetrical and without any associated symptoms. Nonetheless, cases have also been described of unilateral lesions2-4, multiple and/or in association with cramp, heat, pain and/or a sensation of heaviness5. (figure 1)

LIPOATROPHIA SEMICIRCULARIS (LS) SHOWS UP AS RIBS OF SUBCUTANEOUS ATROPHIED ADIPOSE TISSUE, GENERALLY ON THE ANTERIOR FACE OF ONE OR BOTH THIGHS

Although the first cases of lipoatrophia semicircularis were described by Gschwandtner and Münzberger back in 19746, its incidence has increased significantly in the last decade among the office staff of companies trading in various countries such as Japan, Belgium, Holland, France, the UK, Germany, Italy and Spain. The rate is particularly high among women working in recently constructed or renewed offices.

Although the causes of lipoatrophia semicircularis have yet to be fully determined, several candidate factors have been put forward. The microtraumas caused by constant friction against the edges of work tables5,7,8, the pressure exerted by the seat of the work chairs9 or wearing tight-fitting clothes10-12 are the culprits most often cited in the conclusions of these studies. Nonetheless, the same studies concur in considering friction as a necessary but not sufficient condition. A hypothesis frequently put forward is that exposure to low frequency magnetic fields (MF) generated by computer equipment or other desktop office equipment might act as a cofactor in the development of Ls13. The effect would arise from a perturbation by the magnetic fields of the normal cell differentiation processes in adipose tissue, which processes intervene in repair of the friction-caused microtraumas.


Figure 1. A) Patient diagnosed with lipoatrophia semicircularis. Note the rib in the anterior face of each thigh due to the localised loss of subcutaneous panniculus adiposus. B) Example of an electric/magnetic risk environment.

Adipogenesis is the process of differentiation whereby, through a precise genetic pattern following a specific chronological sequence [14], a precursor cell state (pre-adipocyte) is developed into a mature adipocyte in which most of the cell volume is taken up by a lipid droplet. It is therefore feasible that some lypodystrophic disorders might have been unleashed by alterations in the adipocyte differentiation process.

At molecular level one of the main regulators of adipocyte differentiation and of the storage of fatty acids is the peroxisome proliferator-activated receptor gamma (PPARγ), also known as the glitazone receptor, belonging to the nuclear receptor subfamily of hormones. In fact, several types of lypodystrophies have been brought into relation with a fall or deficiency in the activity of the PPARγ factor15,16. Working from this premise it could be argued that a perturbation in the regulation of the PPARγ expression, induced by MF exposure, might upset the adipocyte differentiation process. This hypothesis would be supported by recent data showing that sinusoidal MF of 15 Hz, applied at high intensities (1 militesla), might induce in mesenchymal cells of the bone marrow an adipogenesis inhibitory effect together with a reduction of the PPARγ expression17.

Another molecule involved in the regulation of adipogenesis is extracellular-signal-regulated kinase (ERK1/2). Its specific effect on differentiation would be dependent on timing factors. Under certain conditions, therefore, and in specific time intervals, activation of ERK tends to enhance adipocyte differentiation, while in other periods it might have an inhibitory effect. It has been argued that ERK1/2 regulates PPARγ, thus influencing adipocyte differentiation18. On the other hand, studies predating ours have shown that a magnetic field of 50 Hz and 100 μT significantly affects ERK1/2 in NB69 human neuroblastoma cells19, suggesting that weak MFs might act on the ERK1/2s of the pre-adipocytes, affecting the expression of PPARγ and ipso facto altering the adipogenesis process.

OCCUPATIONAL EXPOSURE TO MAGNETIC FIELDS GENERATED BY DESKTOP ELECTRICAL EQUIPMENT HAS BEEN PUT FORWARD AS A COFACTOR IN THE GENESIS OF LS

This study aims to ascertain, using an in vitro adipogenesis model, whether a weak MF of 100 microteslas (100 μT) and industrial frequency might cause partial inhibition of the adipocyte differentiation processes. To do so we have analysed the formation of fatty acids in adipocytes generated in culture from ADSC and also the expression of PPARγ and ERK1/2 under control conditions or under MF exposure. Proof that industrial-frequency magnetic fields might affect adipocyte differentiation would be the first experimental evidence that continued and focused exposure to weak MFs, present in certain working environments, could act as a cofactor in the genesis of lipoatrophia semicircularis.


Figure 2. Biological system. ADSCs were used for analysing potential alterations in the early adipocyte differentiation phases, in the absence or presence of an experimentally imposed MF.


Figure 3. ADSC culture protocol. Depending on the analytical procedure to be applied, cells were seeded in multiwell plates or Petri dishes.

METHODOLOGY

Biological model and culture protocol

The biological model chosen for studying the potential action of MF was mesenchymal stem cell cultures from the stromal vascular fraction of adipose tissue, ADSC (fig. 2), taken from the subcutaneous panniculus of healthy adult donators [20] by means of the procedure summed up in figure 3. After a first passage of culture growth the ADSCs were aliquoted and frozen until needed for the diverse experiment replicas. (fig. 2)

For the experiments the ADSCs, which were kept in proliferation in culture flasks until the fourth passage (1 passage a week), were seeded in culture plates; when the cells were confluent (after 5 days of culture) they were subjected to standard adipocyte differentiation treatment. At this point the cultures were stimulated with MF (exposed samples) or kept in sham exposure conditions (control samples, see below). After periods of 18 or 42 hours in exposure or control conditions, the cells were processed for quantification of the intracellular fatty acid content and also for study of the expression of PPARγ and ERK1/2 by immunofluorescence image analysis and by western blot. (fig. 3)

Magnetic field exposure protocol

The exposed cells were subjected to a 50 Hz sinusoidal magnetic field, applied in cycles of 3 hours on - 3 hours off for periods of 18 or 42 hours. The chosen magnetic flux, B = 100 μT, is equivalent to 20% of the benchmark level B = 500 μT established by international regulations as harmless in the case of occupational exposure21,22.

Magnetic fields and lipoatrophia semicircularis

The exposure system employed a pair of identical incubators (Forma Scientific). A pair of Helmholtz coils was then placed in each incubator, inside a shielding box (co-netic metal; Amuneal Corp., Philadelphia, PA) against spurious low-frequency environmental fields, such as those generated by heating systems and incubator ventilation. In consecutive experiment replicas each pair of coils was used alternatively for the magnetic exposure or the sham exposure. Each pair comprised two parallel solenoids, positioned to produce an even magnetic field, of vertical polarisation. The two sets of Helmholtz coils were alternatively fed by a single low frequency generator (Newtronic Mod. 200MSTPC, Madrid). The generator signal was permanently monitored by a multimeter (Hewlett Packard, 974A, Loveland, CO) connected up in series to the coils. Both the 24-cell culture plates and Petri dishes were stacked up inside the coils (fig. 4). The magnetic flux B in the exposure area was monitored with a magnetometer (EFA-3, Wandel & Golterman GMW & Co.). (fig. 4)


Figure 4. System for exposing ADSC cultures to MF. The exposure coil is kept in a shielding box within a CO2 incubator. To the right of the generator is another incubator, containing a shielding box and coil, identical to the former, for simultaneous maintenance of control samples.


Figure 5. Effect of the MF on the fatty acid content. Amount of Oil Red O incorporated by the ADSCs by means of spectrophotometric analysis (left) or immunocytochemical /image analysis (right). Means ± SEM of 10 experiment replicas. Values normalised vs. the respective controls, (*: 0.01<0.05; **: p<0.01; Student t).

THE AIM OF THIS STUDY IS TO CHECK EXPERIMENTALLY WHETHER IN VITRO EXPOSURE TO WEAK 50 HZ FIELDS MIGHT AFFECT THE ADIPOCYTE DIFFERENTIATION OF HUMAN CELLS

Analytical procedures

The amount of fatty acids stained with Oil Red O was calculated by image analysis and spectrophotometric techniques. The expression of PPARγ and of the phosphorylated (activated) form of ERK1/2 was assessed by immunofluorescence-image analysis techniques (software Image Analy-SIS, Soft Imaging System, GMBH, Münster, Germany) and transference and immunodetection (western blot), using standard techniques that employ specific antibodies against said molecules.

Results and discussion

Influence of the magnetic field on lipogenesis. Analysis of the fatty acid content

Figure 5 shows a comparison between the fatty acid (FA) content of the samples exposed to the MF for 42 hours and the corresponding controls. Depending on the technique applied, the amount of Oil Red O incorporated by the cells exposed to the MF fell significantly, by 24% (spectrophotometry) or by 29% (microscopy and image analysis). Both techniques therefore show mutually coherent results, confirming that exposure to MF of 50 Hz and 100 μT induces in the ADSCs a statistically significant reduction of the amount of fatty acids built up in the form of vesicles in the cytoplasm.


Figure 6. Photomicrographs showing ADSC cultures in early lipogenesis phases. The fatty acids build up in the cytoplasm in the form of red-stained vesicles. In the MF-exposed culture both the percentage of cells incorporating Oil Red O and the amount and size of the colorant-stained vesicles were much lower.

Additionally, analysis of the photomicrographic image (fig. 6) showed that the MF-stimulated samples presented a lower number of lipid vesicles per cell and also a lower proportion of cells with vesicles. This would indicate that the magnetic stimulus could affect cell differentiation itself, either since the start of lipogenesis or in very early stages thereof. The figures obtained chime in with our preliminary results, indicating that the MF effect is strongest in the early fatty tissue formation phases, whereas latter processes of adipocyte differentiation, such as lipolysis, would not be significantly affected by MF exposure. (fig. 5) (fig. 6)

Influence of MF on the expression of the adipocyte differentiation factor PPARγ. Western blot study

Application of the western blot technique showed that incubation in an adipogenic-differentiation stimulating medium induces a significant increase in the expression of PPARγ by the ADSCs (fig. 7). This response confirmed that the expression of PPARγ is an appropriate parameter for studying the response to a potential anti-adipogenic agent. The PPARγ expression in cells in process of adipogenic differentiation was not significantly altered by MF exposure of 18 hours. Exposure of 42 hours, however, significantly reduced the PPARγ expression as compared to unexposed cells. (fig. 7)


Figure 7. A) Expression of PPARγ in MF-stimulated ADSCs in a medium for adipogenic differentiation. Optical density after 18 or 42 hours MF exposure in comparison to unexposed cells. B) Blots representing the expression of PPARγ in undifferentiated ADSC (control, C) and in ADSCs subjected to adipogenic differentiation, which were exposed to a magnetic field (MF) or not exposed (Cd). Actin was used as control of protein quantity. n = 6 replicas; ***: p<0.001 (Student t).

Taken as a whole these results show that 42-hour MF exposure blocks or inhibits the increment response in the expression of PPAR, necessary for progression of adipocyte differentiation of ADSCs.


Figure 8. Expression of p-ERK1/2. A) Optical density of the blots: The chemical treatment inhibits the expression of p-ERK1/2, and the MF (42 h) blocks said subexpression response. B) Blots representing the expression of p-ERK1/2 in undifferentiated ADSC (control, C) and in chemically differentiated ADSC and simultaneously stimulated with magnetic field (MF) or not stimulated (Cd). Actin: control of protein quantity. n = 6 experiment replicas; **: p<0.01 Cd vs C; MF vs Cd: p<0.05 (Student t).

Influence of the differentiation medium and MF effect on activation of ERK1/2 (p-ERK1/2)

Activation of MAP-kinase ERK1/2 was assessed by western blot quantification of the expression levels of the active phosphorylated form of ERK1/2 (p-ERK1/2). To do so, as in the previous experiment, the samples were subjected to an adipocyte-differentiation inducing chemical treatment for 42 hours in presence and absence of MF. As shown in figure 8A, the differentiating treatment (Cd) significantly reduced (57.22%; p<0.01) the p-ERK1/2 expression as compared with the spontaneous expression recorded in the control condition ADSCs (C). Conversely, the exposure to MF significantly inhibited (p<0.05) this chemically induced fall in the expression levels of p-ERK1/2. (fig. 8)

Our results therefore suggest that MF exposure might produce inhibition or delay of adipocyte differentiation due to a blocking of the subexpression of p-ERK1/2. This type of effect chimes in with the observations made in the above sections, showing that MF exposure inhibits two phenomena that are inherent to the adipose differentiation process: increase in the content of fatty acids and expression of the differentiation factor PPARγ.

Immunocytochemical Study

To crosscheck the results obtained by western blot, an additional analysis was made of the expression of PPARγ and p-ERK1/2 by means of immunocytochemical techniques. The results are summed up in figure 9, showing that after 42-hour MF exposure there was a significant fall in the percentage of cells expressing PPAR(27.9% less than the control samples, in differentiated media not exposed to MF, p<0.01) accompanied with a significant increase in the rate of cells expressing the active form p-ERK1/2 (37.3 % on unexposed controls p<0.001). The immunocytochemical data and those obtained by western blot are hence consistent as a whole and show that exposure to MF of 50 Hz and 100 μT induces alterations in the intracellular signalling paths in which the factors PPARγ and p-ERK1/2 intervene, these alterations then causing a delay or inhibition in the adipocyte differentiation process. (fig. 9)


Figure 9. Influence of MF on the expression of PPARγ and p-ERK1/2. Immunomarked cell count at 42 hours of MF exposure. Normalised data with respect to the differentiated cells not exposed to MF. The MF significantly altered the number of positive cells, both for PPARγ and for p-ERK1/2, in keeping with the western blot studies. **: p<0.01; ***: p<0.001 with respect to the unexposed samples (Student t).

Conclusions

This study is an experimental trial of the hypothesis put forward by some authors to the effect that occupational exposure to weak MF might be a cofactor in the genesis of lipoatrophia semicircularis. In our study we used adipose derived stem cells (ADSCs) from an adult donor, subjected to an in vitro adipose-differentiation treatment in the absence or presence of stimulation by an intermittent, uniform magnetic field of 50 Hz y B=100 μT.

Our experiments show, firstly, that MF can produce a significant fall in the amount of fatty acids synthesised by cells exposed in early differentiation stages. This result is the first experimental evidence showing that, in initial stages, adipocyte differentiation may be slowed down or partially blocked by exposure to weak 50 Hz magnetic fields. The next step in the study focused on identification of the cell mechanisms involved in the identified cell response.

Different chemical agents, mostly growth factors, have been described as inhibitors of adipogenesis. In general this inhibiting effect has been associated with modulations or changes in the expression of PPARγ. Other studies have shown that adipogenesis inhibition is also mediated by changes in the expression/activation of the protein MAPK-ERK1/223-25. On the basis of this evidence we opted to study the potential involvement of the expression of the factor PPARγ and of the activation of ERK1/2 in the action of MF in adipocyte differentiation of the ADSCs. Effectively, the cultures exposed to MF showed a significant fall in comparison to the samples not stimulated with MF, both in the amount of the protein PPARγ and in the number of cells expressing same. We have also shown that 42-hour exposure to the magnetic field induces significant inhibition of the reduction, inherent to the adipocyte differentiation process, both in the rate of cells expressing the phosphorylated or active form ERK1/2 (p-ERK1/2) and in the amount of the protein p-ERK1/2 in the cells. These responses at molecular level represent an endorsement and possible explanation of the inhibiting effect exerted by MF in the early adipogenesis phases, as identified in the first part of the study.

EXPOSURE BROUGHT ABOUT ALTERATIONS IN THE FACTORS REGULATING ADIPOCYTE DIFFERENTIATION, ACCOMPANIED BY A FALL IN THE SYNTHESIS OF FATTY ACIDS

Mechanical stimulation has also been put forward as a factor capable of inhibiting adipocyte differentiation through modulation of the factor PPARγ26. It has also been proposed that activation of ERK1/2 would be involved in inhibition of the factor PPARγ caused by mechanical stimuli that inhibit adipocyte differentiation18. There is now a general consensus about the influence of mechanical type stimuli as a necessary but not sufficient condition in the development of lipoatrophia semicircularis. Although this aspect of the medical condition has not been addressed herein, therefore, many study results, interpreted within the evidence as a whole, suggest the existence of a possible synergy of factors, mechanical and electromagnetic, in the development of Ls in working environments.

Our results therefore show that intermittent low-dosage (20% of the occupational benchmark level) exposure to industrial frequency MF exerts a retard or inhibiting effect on early adipocyte differentiation in human ADSCs. The effect would be exercised, at least in part, through maintenance of high p-ERK1/2 levels, thereby balking the obtention of necessary PPARγ levels for progression of adipocyte differentiation. These findings represent an experimental endorsement of the hypothesis that occupational exposure to weak MF is a cofactor in the development of lipoatrophia semicircularis.

THESE FINDINGS ENDORSE THE HYPOTHESIS THAT OCCUPATIONAL EXPOSURE TO WEAK FIELDS IS A COFACTOR IN THE DEVELOPMENT OF LIPOATROPHIA SEMICIRCULARIS

This study also shows that human ADSCs are a useful in vitro model for studying the bioeffects of magnetic fields. Here we present experimental evidence that weak magnetic fields are capable of affecting the cellular physiology to the extent of producing metabolic changes within short time intervals. This type of response is not brought out by the classic epidemiological approach, whose methodology is inevitably hampered by the host of variables affecting human biology. An experimental approach similar to the one adopted herein could be used for defining minimum values of magnetic exposure capable of causing a given bioeffect or for studying the effects of exposure to electromagnetic emissions in different frequency ranges of medical or occupational interest. It should be borne in mind here that identification of a «biological effect» induced by a given environmental agent is not necessarily in itself an indication of «harmfulness». It is obvious, however, that it behoves us to find out the effect exerted by said agent on the cellular physiology, to weigh up its possible participation in pathological phenomena produced by the synergy of several elements with a subclinical effect. Lipoatrophia semicircularis, therefore, might be caused by a conjunction of inoffensive mechanical stress and exposure to low-intensity magnetic fields and both components might be necessary for the medical condition to occur. The elimination of only one of the factors, therefore, would be sufficient to solve the problem.

As for the results of this study, it should be stressed that, although MF exposure levels of the type used in our experiments (100 μT) might sometimes occur in working environments, the peak MF values in the offices where most Ls cases have cropped up are, in general, lower than said level by one or two orders of magnitude. Given its potential importance for occupational health purposes, therefore, this study should now be extended and enlarged by in vitro investigation of the minimum magnetic field levels capable of producing effects on adipogenesis. It would also be useful and enlightening to enlarge the study by using cells obtained from the adipose tissue of young women, more prone to develop Ls, and/or patients diagnosed with the condition.

In any case our results serve as reasonable grounds to back up proposals to establish strategies for controlling and reducing low frequency MF exposure in working environments of risk27,28. These strategies, including the earthing and/or screening of the wiring of desktop electrical equipment, have proven to be effective in preventing new cases of Ls and accelerating the recovery of sufferers1,29,30.

THE FINDINGS BACK UP PROPOSALS TO ADOPT STRATEGIES FOR CONTROLLING OR REDUCING EXPOSURE TO LOW FREQUENCY MAGNETIC FIELDS IN WORKING ENVIRONMENTS OF RISK


ACKNOWLEDGEMENTS

Study financed by a research grant awarded by FUNDACIÓN MAPFRE. The preliminary research serving as basis for the study was carried out within the Lipo-Search project (Cod. 810201-904070003)


A MODO DE GLOSARIO

Adipocytes. Spherical or polygonal cells making up adipose tissue. They specialise in the synthesis and storage of lipid substances in a large vacuole in the cytoplasm.

Adipogenesis. The adipocyte differentiation process regulated by growth factors, hormones and cytokines. The adipogenesis process implies activation of a highly coordinated and regulated cascade of transcription factors that lead between them to the establishment of the differentiated state.

ADSC (Adipose-Derived Stem Cells). Multipotent stem cells deriving from the stromal fraction of the adipose tissue. They can be broken down into specific lineages, such as adipogenic, chondrogenic, osteogenic, myogenic and neurogenic.

ERK1/2 (Extracellular signal-regulated kinase 1 & 2). These are kinases belonging to the MAPK group. By phosphorylation of the various proteins they can activate other signalling paths or diverse transcription factors; this leads to the transcriptional activation or repression of given genes involved in different cellular processes, including proliferation, migration, differentiation and apoptosis.

ICNIRP (International Commission on Non-Ionizing Radiation Protection). Commission set up by the International Radiation Protection Association (IRPA) to promote non-ionizing radiation (NIR) protection. It lays down guidelines and recommendations on protection against the immediate effects of intense NIR exposure.

Lipolysis. This is the metabolic process whereby lipids are broken down into fatty acids and glycerol, necessary for meeting an organism’s energy needs.

MAPK (Mitogen-activated protein kinases). These are ubiquitously expressed cytosolic serine-threonine kinases whose characteristic function is to transform signals generated in the cell membrane into specific responses through a linear phosphorylation cascade. Six MAP kinase signalling pathways have been identified in mammals (ERK1/2, c-Jun N-terminal (JNK1/2/3) and p38 (p38•/‚/‰/Á), ERK7/8, ERK3/4 and ERK5). Microtesla (μT). The magnetic flux density measuring unit in the International System of Units.

PPARγ. Peroxisome Proliferator Activated Receptor (subtype Á). The nuclear receptors of this type act as transcription factors on numerous genes. There are 3 isoforms: PPAR•, PPAR ‚/‰ and PPAR. PPARforms part of the differentiation programme responsible for inducing maturation of the pre-adipocytes into adipocytes.

Immunocytochemical technique. The immunocytochemical procedure using antibodies to locate molecules in tissues.

Western blot or immunoblot. An analytical technique for detecting specific proteins in a given sample.


TO FIND OUT MORE

  1. Maes A., Curvers B., Verschaeve L. Lipoatrophia semicircularis: the electromagnetic hypothesis. Electromagnet Biol Med, 2003, (22) 183–193.
  2. Mallet R.B., Champion R.H. Lipoatrophia semicircularis. Br J Dermatol, 1981, (105) 591-593.
  3. Betti R., Urbani C.E., Inselvini E., Crosti C. Semicircular lipoatrophy. Clin Exp Dermatol, 1992, (17) 382-383.
  4. Bordel Gómez M.T. Lipoatrophia semicircularis unilateral. Piel, 2006, (21) 414-415.
  5. De Groot A.C. Is lipoatrophia semicircularis induced by pressure? Br J Dermatol, 1994, (131) 887–890.
  6. Gschwandtner W.R., Münzberger H. Lipoatrophia semicircularis. Linear and circular atrophy of the subcutaneous fat in the extremities. Hautarzt ,1974, (25) 222-227.
  7. Gruber P.C., Fuller L.C. Lipoatrophy semicircularis induced by trauma. Clin Exp Dermatol, 2001, (26) 269-271.
  8. Gómez-Espejo C., Bernal-Pérez A., Camacho- Martínez F. A new case of semicircular lipoatrophy associated with repeated external microtraumas and review of the literature. J Eur Acad Dermatol Venereol, 2005, (19) 459-461.
  9. Hermans V., Hautekiet M., Haex B., Spaepen A.J., Van der Perre G. Lipoatrophia semicircularis and the relation with office work. Appl Ergon, 1999, (30) 319–324.
  10. Mascaro J.M., Ferrando J. The perils of wearing jeans: lipoatrophia semicircularis. Int. J Dermatol, 1983, (22) 333.
  11. Herane M.I., Urbina F., Sudy E. Lipoatrophia semicircularis: a compressive lipoatrophy consecutive to persistent mechanical pressure. J Dermatol, 2007, (34) 390–393.
  12. Zafra-Cobo M.I., Yuste-Chaves M., Garabito- Solovera E., Santos-Briz Á., Morán-Estefanía M., de Unamuno-Pérez P. Lipoatrofía semicircular inducida por presión. Actas Dermosifiliogr, 2008, (99) 396-398.
  13. Sanz P., Nogue S., Farrús X., Molina J.M. Lipoatrofia semicircular en oficinistas. Med Clin (Barc), 2010, (134)135-136.
  14. Rosen E.D., Spiegelman B.M. Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol , 2000, (16)145-171.
  15. Guallar J.P., Rojas-Garcia R., García-Arumi E., Domingo J.C., Gallardo E., Andreu A.L., Domingo P., Illa I., Giralt M., Villarroya F. Impaired expression of mitochondrial and adipogenic genes in adipose tissue from a patient with acquired partial lipodystrophy (Barraquer- Simons syndrome): a case report. J Med Case Reports, 2008, (2) 284-289.
  16. Chehab F.F. Obesity and lipodystrophy-- where do the circles intersect? Endocrinology, 2008,(149) 925-934.
  17. Yang Y., Tao C., Zhao D., Li F., Zhao W., Wu H. EMF acts on rat bone marrow mesenchymal stem cells to promote differentiation to osteoblasts and to inhibit differentiation to adipocytes. Bioelectromagnetics, 2010, (31) 277-285.
  18. Tanabe Y., Koga M., Saito M., Matsunaga Y., Nakayama K. Inhibition of adipocyte differentiation by mechanical stretching through ERK-mediated downregulation of PPARgamma2. J Cell Sci, 2004, (117) 3605-3614.
  19. Martínez M.A., Cid M.A., Úbeda A., García V.J., Leal J., Trillo M.A. A role of ERK signaling in the proliferative effects of 50 Hz MF on human neuroblastoma cells. In Kostarakis P., editor. Biological Effects of Electromagnetic Fields. Proceedings from the 4th International Workshop on Biological Effects of Electromagnetic Fields. 2006, October 16-20. Crete, Greece (Vol II) 1051-1055.
  20. Zuk, P.A., Zhu M., Ashjian P., De Ugarte D.A., Huang J.I., Mizuno H., Alfonso Z.C., Fraser J.K., Benhaim P., Hedrick M.H. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell, 2002, (13) 4279–4295.
  21. CNIRP. Guidelines for limiting exposure to time- varying electric, magnetic & electromagnetic fields. Health Phys, 1998, (74) 494-522.
  22. Directive 2004/40/EC of the European Parliament and of the Council of 29 April 2004. http://eurlex. europa.eu/LexUriServ/LexUriServ.do?uri=C ONSLEG:2004L0040:20081211:ES:PDF
  23. Hu, E., Kim J.B., Sarraf P. and Spiegelman B.M. Inhibition of adipogenesis through MAP kinase- mediated phosphorylation of PPARgamma. Science,1996, (274) 2100-2103.
  24. Bost F., Aouadi M., Caron L., Binétruy B. The role of MAPKs in adipocyte differentiation and obesity. Biochimie, 2005, (87) 51-56.
  25. Kim K.A., Kim J.H., Wang Y., Sul H.S. Pref-1 (preadipocyte factor 1) activates the MEK/extracellular signal-regulated kinase pathway to inhibit adipocyte differentiation. Mol Cell Biol, 2007, (27) 2294-2308.
  26. David V., Martin A., Lafage-Proust M.H., Malaval L., Peyroche S., Jones D.B., Vico L., Guignandon A. Mechanical loading down-regulates peroxisome proliferator-activated receptor gamma in bone marrow stromal cells and favors osteoblastogenesis at the expense of adipogenesis. Endocrinology, 2007, (148) 2553-2562.
  27. Generalitat de Catalunya (2007). Lipoatrofia semicircular: protocolo de actuación. http://www.gencat.cat/treball/doc/doc_344 29608_2.pdf
  28. Comunidad de Madrid http://www.madrid.org/cs/Satellite?c=CM_P ublicaciones_FA&cid=1142453619567&idTema= 1109266533527&language=es&pagename= ComunidadMadrid/Estructura&pid=110 9265444831&segmento=1&sm=1
  29. Curvers, B., Maes, A. (2003). Lipoatrophia Semicircularis: a new office disease? 900 cases reported in Belgium. http://www.websindical. com/lipoatrofia/kbcbank.pdf.pdf
  30. Pérez A., Nebot M., Maciá M., Panadés R., on behalf of the Collaborative Group for the Evaluation of Ls Outbreak Control Measures. An Outbreak of 400 Cases of Lipoatrophia Semicircularis in Barcelona: Effectiveness of Control Measures. J Occup Environ Med, 2010, (52) 751-757.

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