Zhengping Xu

Association between extremely low-frequency electromagnetic fields occupations and amyotrophic lateral sclerosis: a meta-analysis.

Objectives To estimate the relationship between exposure to extremely low-frequency electromagnetic fields (ELF-EMF) and the risk of amyotrophic lateral sclerosis (ALS) by a meta-analysis. Methods Through searching PubMed databases (or manual searching) up to April 2012 using the following keywords: “occupational exposure”, “electromagnetic fields” and “amyotrophic lateral sclerosis” or “motor neuron disease”, seventeen studies were identified as eligible for this meta-analysis. The associations between ELF-EMF exposure and the ALS risk were estimated based on study design (case-control or cohort study), and ELF-EMF exposure level assessment (job title or job-exposure matrix). The heterogeneity across the studies was tested, as was publication bias. Results Occupational exposure to ELF-EMF was significantly associated with increased risk of ALS in pooled studies (RR = 1.29, 95%CI = 1.02–1.62), and case-control studies (OR = 1.39, 95%CI = 1.05–1.84), but not cohort studies (RR = 1.16, 95% CI = 0.80–1.69). In sub-analyses, similar significant associations were found when the exposure level was defined by the job title, but not the job-exposure matrix. In addition, significant associations between occupational exposure to ELF-EMF and increased risk of ALS were found in studies of subjects who were clinically diagnosed but not those based on the death certificate. Moderate heterogeneity was observed in all analyses. Conclusions Our data suggest a slight but significant ALS risk increase among those with job titles related to relatively high levels of ELF-EMF exposure. Since the magnitude of estimated RR was relatively small, we cannot deny the possibility of potential biases at work. Electrical shocks or other unidentified variables associated with electrical occupations, rather than magnetic-field exposure, may be responsible for the observed associations with ALS.

Cell Type-Dependent Induction of DNA Damage by 1800 MHz Radiofrequency Electromagnetic Fields Does Not Result in Significant Cellular Dysfunctions

Background Although IARC clarifies radiofrequency electromagnetic fields (RF-EMF) as possible human carcinogen, the debate on its health impact continues due to the inconsistent results. Genotoxic effect has been considered as a golden standard to determine if an environmental factor is a carcinogen, but the currently available data for RF-EMF remain controversial. As an environmental stimulus, the effect of RF-EMF on cellular DNA may be subtle. Therefore, more sensitive method and systematic research strategy are warranted to evaluate its genotoxicity. Objectives To determine whether RF-EMF does induce DNA damage and if the effect is cell-type dependent by adopting a more sensitive method γH2AX foci formation; and to investigate the biological consequences if RF-EMF does increase γH2AX foci formation. Methods Six different types of cells were intermittently exposed to GSM 1800 MHz RF-EMF at a specific absorption rate of 3.0 W/kg for 1 h or 24 h, then subjected to immunostaining with anti-γH2AX antibody. The biological consequences in γH2AX-elevated cell type were further explored with comet and TUNEL assays, flow cytometry, and cell growth assay. Results Exposure to RF-EMF for 24 h significantly induced γH2AX foci formation in Chinese hamster lung cells and Human skin fibroblasts (HSFs), but not the other cells. However, RF-EMF-elevated γH2AX foci formation in HSF cells did not result in detectable DNA fragmentation, sustainable cell cycle arrest, cell proliferation or viability change. RF-EMF exposure slightly but not significantly increased the cellular ROS level. Conclusions RF-EMF induces DNA damage in a cell type-dependent manner, but the elevated γH2AX foci formation in HSF cells does not result in significant cellular dysfunctions.

Angiogenin Enhances Cell Migration by Regulating Stress Fiber Assembly and Focal Adhesion Dynamics

Angiogenin (ANG) acts on both vascular endothelial cells and cancer cells, but the underlying mechanism remains elusive. In this study, we carried out a co-immunoprecipitation assay in HeLa cells and identified 14 potential ANG-interacting proteins. Among these proteins, β-actin, α-actinin 4, and non-muscle myosin heavy chain 9 are stress fiber components and involved in cytoskeleton organization and movement, which prompted us to investigate the mechanism of action of ANG in cell migration. Upon confirmation of the interactions between ANG and the three proteins, further studies revealed that ANG co-localized with β-actin and α-actinin 4 at the leading edge of migrating cells. Down-regulation of ANG resulted in fewer but thicker stress fibers with less dynamics, which was associated with the enlargements of focal adhesions. The focal adhesion kinase activity and cell migration capacity were significantly decreased in ANG-deficient cells. Taken together, our data demonstrated that the existence of ANG in the cytoplasm optimizes stress fiber assembly and focal adhesion formation to accommodate cell migration. The finding that ANG promoted cancer cell migration might provide new clues for tumor metastasis research.

Angiogenin stimulates ribosomal RNA transcription by epigenetic activation of the ribosomal DNA promoter

Angiogenin (ANG) undergoes nuclear translocation and promotes ribosomal RNA (rRNA) transcription thereby enhancing cell growth and proliferation. However, the mode of action of ANG in stimulating rRNA transcription is unclear. Here, we show that ANG enhances the formation of RNA polymerase I (Pol I) pre‐initiation complex at the ribosomal DNA (rDNA) promoter. ANG binds at the upstream control element (UCE) of the promoter and enhances promoter occupancy of RNA Pol I as well as the selectivity factor SL1 components TAFI48 and TAFI110. We also show that ANG increases the number of actively transcribing rDNA by epigenetic activation through promoter methylation and histone modification. ANG binds to histone H3, inhibits H3K9 methylation, and activates H3K4 methylation as well as H4 acetylation at the rDNA promoter. These data suggest that one of the mechanisms by which ANG stimulates rRNA transcription is through an epigenetic activation of rDNA promoter. J. Cell. Physiol. 229: 521–529, 2014.

Transcriptional activation of follistatin by Nrf2 protects pulmonary epithelial cells against silica nanoparticle-induced oxidative stress

Silica nanoparticles (SiO2 NPs) cause oxidative stress in respiratory system. Meanwhile, human cells launch adaptive responses to overcome SiO2 NP toxicity. However, besides a few examples, the regulation of SiO2 NP-responsive proteins and their functions in SiO2 NP response remain largely unknown. In this study, we demonstrated that SiO2 NP induced the expression of follistatin (FST), a stress responsive gene, in mouse lung tissue as well as in human lung epithelial cells (A549). The levels of Ac-H3(K9/18) and H3K4me2, two active gene markers, at FST promoter region were significantly increased during SiO2 NP treatment. The induction of FST transcription was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2), as evidenced by the decreased FST expression in Nrf2-deficient cells and the direct binding of Nrf2 to FST promoter region. Down-regulation of FST promoted SiO2 NP-induced apoptosis both in cultured cells and in mouse lung tissue. Furthermore, knockdown of FST increased while overexpression of FST decreased the expression level of NADPH oxidase 1 (NOX1) and NOX5 as well as the production of cellular reactive oxygen species (ROS). Taken together, these findings demonstrated a protective role of FST in SiO2 NP-induced oxidative stress and shed light on the interaction between SiO2 NPs and biological systems.

Using model organism Saccharomyces cerevisiae to evaluate the effects of ELF-MF and RF-EMF exposure on global gene expression.

The potential health hazard of exposure to electromagnetic fields (EMF) continues to cause public concern. However, the possibility of biological and health effects of exposure to EMF remains controversial and their biophysical mechanisms are unknown. In the present study, we used Saccharomyces cerevisiae to identify genes responding to extremely low frequency magnetic fields (ELF-MF) and to radiofrequency EMF (RF-EMF) exposures. The yeast cells were exposed for 6 h to either 0.4 mT 50 Hz ELF-MF or 1800 MHz RF-EMF at a specific absorption rate of 4.7 W/kg. Gene expression was analyzed by microarray screening and confirmed using real-time reverse transcription-polymerase chain reaction (RT-PCR). We were unable to confirm microarray-detected changes in three of the ELF-MF responsive candidate genes using RT-PCR (P > 0.05). On the other hand, out of the 40 potential RF-EMF responsive genes, only the expressions of structural maintenance of chromosomes 3 (SMC3) and aquaporin 2 (AQY2 (m)) were confirmed, while three other genes, that is, halotolerance protein 9 (HAL9), yet another kinase 1 (YAK1) and one function-unknown gene (open reading frame: YJL171C), showed opposite changes in expression compared to the microarray data (P < 0.05). In conclusion, the results of this study suggest that the yeast cells did not alter gene expression in response to 50 Hz ELF-MF and that the response to RF-EMF is limited to only a very small number of genes. The possible biological consequences of the gene expression changes induced by RF-EMF await further investigation.

Reduction of AUF1-mediated follistatin mRNA decay during glucose starvation protects cells from apoptosis

Follistatin (FST) performs several vital functions in the cells, including protection from apoptosis during stress. The expression of FST is up-regulated in response to glucose deprivation by an unknown mechanism. We herein showed that the induction of FST by glucose deprivation was due to an increase in the half-life of its mRNA. We further identified an AU-rich element (ARE) in the 3′UTR of FST mRNA that mediated its decay. The expression of FST was elevated after knocking down AUF1 and reduced when AUF1 was further expressed. In vitro binding assays and RNA pull-down assays revealed that AUF1 interacted with FST mRNA directly via its ARE. During glucose deprivation, a majority of AUF1 shuttled from cytoplasm to nucleus, resulting in dissociation of AUF1 from FST mRNA and thus stabilization of FST mRNA. Finally, knockdown of AUF1 decreased whereas overexpression of AUF1 increased glucose deprivation-induced apoptosis. The apoptosis promoting effect of AUF1 was eliminated in FST expressing cells. Collectively, this study provided evidence that AUF1 is a negative regulator of FST expression and participates in the regulation of cell survival under glucose deprivation.

Mobile phone signal exposure triggers a hormesis-like effect in Atm+/+ and Atm-/- mouse embryonic fibroblasts.

Radiofrequency electromagnetic fields (RF-EMFs) have been classified by the International Agency for Research on Cancer as possible carcinogens to humans; however, this conclusion is based on limited epidemiological findings and lacks solid support from experimental studies. In particular, there are no consistent data regarding the genotoxicity of RF-EMFs. Ataxia telangiectasia mutated (ATM) is recognised as a chief guardian of genomic stability. To address the debate on whether RF-EMFs are genotoxic, we compared the effects of 1,800 MHz RF-EMF exposure on genomic DNA in mouse embryonic fibroblasts (MEFs) with proficient (Atm+/+) or deficient (Atm−/−) ATM. In Atm+/+ MEFs, RF-EMF exposure for 1 h at an average special absorption rate of 4.0 W/kg induced significant DNA single-strand breaks (SSBs) and activated the SSB repair mechanism. This effect reduced the DNA damage to less than that of the background level after 36 hours of exposure. In the Atm−/− MEFs, the same RF-EMF exposure for 12 h induced both SSBs and double-strand breaks and activated the two repair processes, which also reduced the DNA damage to less than the control level after prolonged exposure. The observed phenomenon is similar to the hormesis of a toxic substance at a low dose. To the best of our knowledge, this study is the first to report a hormesis-like effect of an RF-EMF.

Relationships between urinary antimony levels and both mortalities and prevalence of cancers and heart diseases in general US population, NHANES 1999–2010

The effects of antimony (Sb) exposure on mortalities, cancers and cardiovascular diseases were controversial in occupational workers, and the evidence from the general population is limited. The objective of this study is to investigate the relationships between Sb exposure and specific health events in the general population. Totally, 7781 participants aged ≥20years were selected from the National Health and Nutrition Examination Survey (NHANES) 1999-2010 and were followed for an average of 6.04years. The Cox and logistic regression models were applied to evaluate the effects of urinary Sb (U-Sb) levels on the risks of all-cause and cause-specific mortalities, and the likelihoods of self-reported cancers and heart diseases, respectively. When setting quartile 1 of U-Sb levels as reference, the hazard ratios (HRs) [95% confidence intervals (CIs)] of the quartile 2 through 4 for all-cause mortality were 1.21 (0.84, 1.74), 1.49 (1.08, 2.04) and 1.66 (1.20, 2.28). The HR of quartile 3 of U-Sb levels for heart disease mortality was 2.18 (1.24, 3.86). Furthermore, increased odds ratios (ORs) from quartile 2 to 4 were 1.69 (1.05, 2.74), 1.42 (0.79, 2.55) and 2.11 (1.26, 3.55) for self-reported congestive heart failure, and 1.37 (0.95, 1.99), 1.96 (1.37, 2.82) and 1.81 (1.16, 2.83) for heart attack. Elevated U-Sb levels were not significantly related to mortality of malignant neoplasms, and self-reported cancers. The data demonstrated associations of increased U-Sb levels with all-cause and heart diseases mortalities, and prevalent congestive heart failure and heart attack, suggesting public concerns on the health hazards of Sb exposure in the general population.

Ribonuclease like 5 regulates zebrafish yolk extension by suppressing a p53-dependent DNA damage response pathway.

Ribonuclease like 5 (Rnasel5) is a novel member of the zebrafish ribonuclease A family and its expression is increased during early embryogenesis. However, the in vivo biological function of Rnasel5 remains to be elucidated. Here, we report that knockdown of Rnasel5 by morhpolinos caused shrunken yolk extension as well as increased DNA damage at yolk syncytial layer and external tissue layers via the activation of p53 pathway. In addition, the morphological defects caused by Rnasel5 knockdown can be partially rescued by mRNA injection. Our findings provide the first functional characterization of Rnasel5 in zebrafish development and reveal its critical role in yolk extension by modulation of the p53 pathway.