HAL du Programme national de recherche environnement-santé-travail (PNR EST)
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Impairment of Base Excision Repair in Dermal Fibroblasts Isolated From Nevoid Basal Cell Carcinoma Patients
No full textInternational audienceThe nevoid basal cell carcinoma syndrome (NBCCS), also called Gorlin syndrome is an autosomal dominant disorder whose incidence is estimated at about 1 per 55,600–256,000 individuals. It is characterized by several developmental abnormalities and an increased predisposition to the development of basal cell carcinomas (BCCs). Cutaneous fibroblasts from Gorlin patients have been shown to exhibit an increased sensitivity to ionizing radiations. Mutations in the tumor suppressor gene PTCH1, which is part of the Sonic Hedgehog (SHH) signaling pathway, are responsible for these clinical manifestations. As several genetic mutations in the DNA repair genes are responsible of photo or radiosensitivity and high predisposition to cancers, we hypothesized that these effects in Gorlin syndrome might be due to a defect in the DNA damage response (DDR) and/or the DNA repair capacities. Therefore, the objective of this work was to investigate the sensitivity of skin fibroblasts from NBCCS patients to different DNA damaging agents and to determine the ability of these agents to modulate the DNA repair capacities. Gorlin fibroblasts showed high radiosensitivity and also less resistance to oxidative stress-inducing agents when compared to control fibroblasts obtained from healthy individuals. Gorlin fibroblasts harboring PTCH1 mutations were more sensitive to the exposure to ionizing radiation and to UVA. However, no difference in cell viability was shown after exposure to UVB or bleomycin. As BER is responsible for the repair of oxidative DNA damage, we decided to assess the BER pathway efficacy in Gorlin fibroblasts. Interestingly, a concomitant decrease of both BER gene expression and BER protein activity was observed in Gorlin fibroblasts when compared to control. Our results suggest that low levels of DNA repair within Gorlin cells may lead to an accumulation of oxidative DNA damage that could participate and partly explain the radiosensitivity and the BCC-prone phenotype in Gorlin syndrome
MEHP/ethanol co-exposure favors the death of steatotic hepatocytes, possibly through CYP4A and ADH involvement
No full textInternational audienceLiver steatosis has been associated with various etiological factors (obesity, alcohol, environmental contaminants). How those factors work together to induce steatosis progression is still scarcely evaluated. Here, we tested whether phthalates could potentiate death of steatotic hepatocytes when combined with ethanol. Pre-steatotic WIF-B9 hepatocytes were co-exposed to mono(2-ethylhexyl) (MEHP, 500 nM; main metabolite of di(2-ethylhexyl) phthalate or DEHP) and ethanol (5 mM) for 5 days. An increased apoptotic death was detected, involving a DNA damage response. Using 4-Methypyrazole to inhibit ethanol metabolism, and CH-223191 to antagonize the AhR receptor, we found that an AhR-dependent increase in alcohol dehydrogenase (ADH) activity was essential for cell death upon MEHP/ethanol co-exposure. Toxicity was also prevented by HET0016 to inhibit the cytochrome P450 4A (CYP4A). Using the antioxidant thiourea, a role for oxidative stress was uncovered, notably triggering DNA damage. Finally, co-exposing the in vivo steatosis model of high fat-diet (HFD)-zebrafish larvae to DEHP (2.56 nM)/ethanol (43 mM), induced the pathological progression of liver steatosis alongside an increased Cyp4t8 (human CYP4A homolog) mRNA expression. Altogether, these results further emphasized the deleterious impact of co-exposures to ethanol/ environmental pollutant towards steatosis pathological progression, and unraveled a key role for ADH and CYP4A in such effects
Estimated whole-brain and lobe-specific radiofrequency electromagnetic fields doses and brain volumes in preadolescents
No full textInternational audienceObjective: To assess the association between estimated whole-brain and lobe-specific radiofrequency electromagnetic fields (RF-EMF) doses, using an improved integrated RF-EMF exposure model, and brain volumes in preadolescents at 9-12 years old. Methods: Cross-sectional analysis in preadolescents aged 9-12 years from the Generation R Study, a population-based birth cohort set up in Rotterdam, The Netherlands (n = 2592). An integrated exposure model was used to estimate whole-brain and lobe-specific RF-EMF doses (mJ/kg/day) from different RF-EMF sources including mobile and Digital Enhanced Cordless Telecommunications (DECT) phone calls, other mobile phone uses than calling, tablet use, laptop use, and far-field sources. Whole-brain and lobe-specific RF-EMF doses were estimated for all RF-EMF sources together (i.e. overall) and for three groups of RF-EMF sources that lead to a different pattern of RF-EMF exposure. Information on brain volumes was extracted from magnetic resonance imaging scans. Results: Estimated overall whole-brain RF-EMF dose was 84.3 mJ/kg/day. The highest overall lobe-specific dose was estimated in the temporal lobe (307.1 mJ/kg/day). Whole-brain and lobe-specific RF-EMF doses from all RF-EMF sources together, from mobile and DECT phone calls, and from far-field sources were not associated with global, cortical, or subcortical brain volumes. However, a higher whole-brain RF-EMF dose from mobile phone use for internet browsing, e-mailing, and text messaging, tablet use, and laptop use while wirelessly connected to the internet was associated with a smaller caudate volume. Conclusions: Our results suggest that estimated whole-brain and lobe-specific RF-EMF doses were not related to brain volumes in preadolescents at 9-12 years old. Screen activities with mobile communication devices while https://doi. T wirelessly connected to the internet lead to low RF-EMF dose to the brain and our observed association may thus rather reflect effects of social or individual factors related to these specific uses of mobile communication devices. However, we cannot discard residual confounding, chance finding, or reverse causality. Further studies on mobile communication devices and their potential negative associations with brain development are warranted, regardless whether associations are due to RF-EMF exposure or to other factors related to their use
Maternal and perinatal characteristics, congenital malformations and the risk of wilms tumor: the ESTELLE study
No full textInternational audiencePurpose: Wilms tumor (WT), or nephroblastoma, is an embryonic tumor that constitutes the most common renal tumor in children. Little is known about the etiology of WT. The aim of this study was to investigate whether maternal or perinatal characteristics were associated with the risk of WT.Methods: The ESTELLE study is a national-based case-control study that included 117 cases of WT and 1,100 controls younger than 11 years old. The cases were children diagnosed in France in 2010-2011 and the controls were frequency matched with cases by age and gender. The mothers of case and control children responded to a telephone questionnaire addressing sociodemographic and perinatal characteristics, childhood environment, and lifestyle. Unconditional logistic regression models adjusted on potential cofounders were used to estimate the odds ratios (OR) and their confidence intervals (95% CI).Results: High birth weight and the presence of congenital malformation were associated with WT (OR 1.9 [95% CI 1.0-3.7] and OR 2.5 [95% CI 1.1-5.8], respectively). No association with breastfeeding or folic acid supplementation was observed.Conclusions: Although potential recall bias cannot be excluded, our findings reinforce the hypothesis that high birth weight and the presence of congenital malformation may be associated with an increased risk of WT. Further investigations are needed to further elucidate the possible role of maternal characteristics in the etiology of W
Differential influences of the BPA, BPS and BPF on in vitro IL-17 secretion by mouse and human T cells
No full textInternational audienceThe endocrine disruptor and food contaminant bisphenol A (BPA) is frequently present in consumer plastics and can produce several adverse health effects participating in the development of inflammatory and autoimmune diseases. Regulatory restrictions have been established to prevent risks for human health, leading to the substitution of BPA by structural analogues, such as bisphenol S (BPS) and F (BPF). In this study, we aimed at comparing the in vitro impact of these bisphenols from 0.05 to 50,000 nM on Th17 differentiation, frequency and function in mouse systemic and intestinal immune T cells and in human blood T cells. This study reports the ability of these bisphenols, at low and environmentally relevant concentration, i.e, 0.05 nM, to increase significantly IL-17 production in mouse T cells but not in human T lymphocytes. The use of an aryl hydrocarbon receptor (AhR) specific inhibitor demonstrated its involvement in this bisphenol-induced IL-17 production. We also observed an increased IL-17 secretion by BPS and BPF, and not by BPA, in mouse naive T cells undergoing in vitro Th17 differentiation. In total, this study emphasizes the link between bisphenol exposures and the susceptibility to develop immune diseases, questioning thus the rational of their use to replace BPA
Toxicokinetics of bisphenol-S and its glucuronide in plasma and urine following oral and dermal exposure in volunteers for the interpretation of biomonitoring data
No full textInternational audienceThe measurement of bisphenol-S (BPS) and its glucurono-conjugate (BPSG) in urine may be used for the bio-monitoring of exposure in populations. However, this requires a thorough knowledge of their toxicokinetics. The time courses of BPS and BPSG were assessed in accessible biological matrices of orally and dermally exposed volunteers. Under the approval of the Research Ethics Committee of the University of Montreal, six volunteers were orally exposed to a BPS-d8 deuterated dose of 0.1 mg/kg body weight (bw). One month later, 1 mg/kg bw of BPS-d8 were applied on 40 cm 2 of the forearm and then washed 6 h after application. Blood samples were taken prior to dosing and at fixed time periods over 48 h after treatment; complete urine voids were collected pre-exposure and at pre-established intervals over 72 h postdosing. Following oral exposure, the plasma concentration time courses of BPS-d8 and BPSG-d8 over 48 h evolved in parallel, and showed a rapid appearance and elimination. Average peak values (± SD) were reached at 0.7 ± 0.1 and 1.1 ± 0.4 h postdosing and mean (± SD) apparent elimination half-lives (t ½) of 7.9 ± 1.1 and 9.3 ± 7.0 h were calculated from the terminal phase of BPS-d8 and BPSG-d8 in plasma, respectively. The fraction of BPS-d8 reaching the systemic circulation unchanged (i.e. bioavailability) was further estimated at 62 ± 5% on average (± SD) and the systemic plasma clearance at 0.57 ± 0.07 L/kg bw/h. Plasma concentration-time courses and urinary excretion rate profiles roughly evolved in parallel for both substances, as expected. The average percent (± SD) of the administered dose recovered in urine as BPS-d8 and BPSG-d8 over the 0-72 h period postdosing was 1.72 ± 1.3 and 54 ± 10%. Following dermal application, plasma levels were under the lower limit of quantification (LLOQ) at most time points. However, peak values were reached between 5 and 8 h depending on individuals, suggesting a slower absorption rate compared to oral exposure. Similarly, limited amounts of BPS-d8 and its conjugate were recovered in urine and peak excretion rates were reached between 5 and 11 h postdosing. The average percent (± SD) of the administered dose recovered in urine as BPS-d8 and BPSG-d8 was about 0.004 ± 0.003 and 0.09 ± 0.07%, respectively. This study provided greater precision on the kinetics of this contaminant in humans and, in particular, evidenced major differences between BPA and BPS kinetics with much higher systemic levels of active BPS than BPA, an observation explained by a higher oral bioavailability of BPS than BPA. These data should also be useful in developing a toxicokinetic model for a better interpretation of biomonitoring data
Environmental DNA for detecting Bulinus truncatus: a new environmental surveillance tool for schistosomiasis emergence risk assessment
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The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor
No full textInternational audienceThe human pregnane X receptor (hPXR) is activated by a large set of endogenous and exogenous compounds and plays a critical role in the control of detoxifying enzymes and transporters regulating liver and gastrointestinal drug metabolism and clearance. hPXR is also involved in both the development of multidrug resistance and enhanced cancer cells aggressiveness. Moreover, its unintentional activation by pharmaceutical drugs can mediate drug-drug interactions and cause severe adverse events. In that context, the potential of the anticancer BRAF inhibitor dabrafenib suspected to activate hPXR and the human constitutive androstane receptor (hCAR) has not been thoroughly investigated yet. Using different reporter cellular assays, we demonstrate that dabrafenib can activate hPXR as efficiently as its reference agonist SR12813, whereas it does not activate mouse or zebrafish PXR nor hCAR. We also showed that dabrafenib binds to recombinant hPXR, induces the expression of hPXR responsive genes in colon LS174T-hPXR cancer cells and human hepatocytes and finally increases the proliferation in LS174T-hPXR cells. Our study reveals that by using a panel of different cellular techniques it is possible to improve the assessment of hPXR agonist activity for new developed drugs
Upper-extremity musculoskeletal disorders: how many cases can be prevented? Estimates from the COSALI cohort
No full textInternational audienceObjective This study aimed to estimate the proportion and number of incident upper-extremity musculoskeletal disorders (UEMSD) cases attributable to occupational risk factors in a working population.Methods Between 2002−2005, occupational physicians randomly selected 3710 workers, aged 20–59, from the Pays de la Loire (PdL) region. All participants underwent a standardized clinical examination. Between 2007−2010, 1611 workers were re-examined. This study included 1246 workers who were free of six main clinically diagnosed UEMSD at baseline but were diagnosed with at least one of these UEMSD at follow-up [59% of men, mean age: 38 (standard deviation 8.6) years]. Relative risks and population-attributable fractions (PAF) were calculated using Cox multivariable models with equal follow-up time and robust variance. The total number of incident UEMSD in the PdL region was estimated after adjustment of the sample weights using 2007 census data. The estimated number of potentially avoidable UEMSD was calculated by multiplying PAF by the total number of incident UEMSD in PdL.Results At follow-up, 139 new cases of UEMSD (11% of the study sample) were diagnosed. This represented an estimated 129 320 incident cases in the PdL in 2007. Following adjustment for personal factors, 26 381 (20.4% of all incident UEMSD) were attributable to high physical exertion, 16 682 (12.9%) to low social support, and 8535 (6.6%) to working with arms above shoulder level.Conclusions A large number and important proportion of incident UEMSD may be preventable by reducing work exposures to physical exertion and working with arms above shoulder level as well as improving social support from co-workers/supervisors
