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.

Absence of direct effect of low-power millimeter-wave radiation at 60.4 GHz on endoplasmic reticulum stress.

Millimeter waves (MMW) at frequencies around 60 GHz will be used in the very near future in the emerging local wireless communication systems and the potential health hazards of artificially induced environmental exposures represent a major public concern. The main aim of this study was to investigate the potential effects of low-power MMW radiations on cellular physiology. To this end, the human glial cell line, U-251 MG, was exposed to 60.4 GHz radiation at a power density of 0.14 mW/cm(2) and potential effect of MMW radiations on endoplasmic reticulum (ER) stress was investigated. ER is very sensitive to environmental insults and its homeostasis is altered in various pathologies. Through several assay systems, we found that exposure to 60.4 GHz does not modify ER protein folding and secretion, nor induces XBP1 or ATF6 transcription factors maturation. Moreover, expression of ER-stress sensor, BiP/GRP78 was examined by real-time PCR, in exposed or non-exposed cells to MMW radiations. Our data demonstrated the absence of significant changes in mRNA levels for BiP/GRP78. Our results showed that ER homeostasis does not undergo any modification at molecular level after exposure to low-power MMW radiation at 60.4 GHz. This report is the first study of ER-stress induction by MMW radiations.

Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes.

Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are therapeutic compounds widely administered in the clinic for their multiple uses (autoimmune diseases, post-transplant immunosuppression and cancer). Despite these advantages, their therapeutic potential is limited by occasional adverse effects (myelotoxicity and hepatotoxicity) and by a relatively frequent lack of efficacy. Previous studies have demonstrated that azathioprine decreased the viability of rat hepatocytes. In order to investigate cytotoxic effects of thiopurines in human liver, we used primary human hepatocytes and a highly differentiated human hepatoma cell line, HepaRG, treated or not with azathioprine, 6-mercaptopurine and 6-thioguanine. In parallel, expression of the genes involved in the metabolism of thiopurines, glutathione synthesis and antioxidant defences was measured by quantitative PCR. We clearly demonstrate that human liver parenchymal cells were much less sensitive than rat hepatocytes to thiopurine treatments. The toxic effects appeared after 96 h of treatment while ATP depletion was observed after a 24 h incubation with azathioprine and 6-mercaptopurine. Toxic effects were more pronounced for azathioprine and 6-mercaptopurine, when compared to 6-thioguanine, and might explain glutathione synthesis and antioxidant enzyme induction only by these two drugs. Finally, we also demonstrate for the first time an up-regulation by azathioprine and 6-mercaptopurine of inosine monophosphate dehydrogenase which might have consequences on the de novo biosynthesis of guanine nucleotides and thiopurines metabolism.

Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.

CONTEXT: Masculinization depends on the fetal testis. Exposure of the human fetus during pregnancy to paracetamol and/or to other mild analgesics is associated with an increased risk of cryptorchidism. OBJECTIVE: We aimed to determine whether mild analgesics disrupted the morphology and endocrine function of the human testis. DESIGN: We used an in vitro system based on the culture of human fetal testes exposed or not to paracetamol, its metabolite N-(4-hydroxyphenyl)-arachidonoylethanolamide (AM404), aspirin, indomethacin, and ketoconazole at 10(-4) to 10(-7) M. SETTING: The study was conducted at the University of Rennes I. PATIENTS/PARTICIPANTS: Human fetal testes were from pregnant women after induced abortion, between 7 and 12 weeks of gestation (GW). MAIN OUTCOME MEASURES: Testosterone (RIA), anti-Müllerian hormone (ELISA), insulin-like factor 3 (RIA), and prostaglandin (PG) D2 and PGE2 (ELISA) were assayed in the medium. Testicular cells were counted using histology and image analysis. The possible nuclear receptor-mediated activities of the analgesics were investigated using reporter cell lines expressing estrogen, androgen, and peroxisome proliferator-activated γ receptors. RESULTS: Indomethacin and aspirin stimulated testosterone production, particularly by the younger testes (8-9 GW vs 10-12 GW). Paracetamol, AM404, and ketoconazole decreased insulin-like factor 3 levels. Aspirin stimulated whereas ketoconazole inhibited AMH production. PGE2 levels were inhibited by paracetamol and aspirin in the 7 to 12 GW testes and by indomethacin but only in 7 to 9.86 GW testes. The inhibitory trends seen for PGD2 were not statistically significant. CONCLUSIONS: Analgesics at concentrations relevant to human exposure cause endocrine disturbances in the fetal testis. We suggest that the fetal human testis displays slight critical age windows for sensitivity to direct exposure to aspirin, indomethacin, and paracetamol. The analgesic-induced inhibition of INSL3 may be the mechanism by which analgesics increase the risk of cryptorchidism. Greater caution is required concerning consumption of analgesics during pregnancy.