Lead, Mercury, and Cadmium Concentrations in Blood Products Transfused to Neonates: Elimination Not Just Mitigation.

Lead (Pb), mercury (Hg), and cadmium (Cd) are identified as potent developmental neurotoxicants. Neonates are the main group receiving multiple blood transfusions. The exposure of neonates to these heavy metals (HMs) can occur through blood transfusions. This study aimed to determine the concentrations of lead (Pb), mercury (Hg), and cadmium (Cd) in various blood products (plasma, platelets, packed red blood cells (pRBCs), and whole blood (WB)) to explore the probability of concurrent exposure of these HMs and to identify the metal load per transfusion with risk assessment. Residual bloods from blood bank bags were collected after neonatal transfusion. Pb, Hg, and Cd concentrations were determined in 120 samples of blood products by inductively coupled plasma mass spectrometry (ICP-MS). Pb and Cd levels were over the normal levels in 19.2 and 5.9% of all blood units, respectively. In 35 and 0.8% of blood units, the Pb and Cd concentrations, respectively, were higher than that recommended for transfusions in premature neonates. The anticipated safe value was surpassed by 2.5% for Cd of all transfusions, primarily because of WB. However, Hg was detected only in 5.8% of all samples and their concentrations were within the normal range. The concurrent neonatal exposure to Pb, Hg, and Cd was statistically significant. Hazard quotients of Hg and Cr were >1 and Pb cancer risk was 2.41 × 10-4. To the best of our knowledge, this study is the first report examining Pb, Hg, and Cd in blood products other than WB and pRBCs using ICP-MS. This study demonstrated the exposure of neonates to Pb, Hg, and Cd during transfusion with a considerable amount of Pb. It confirms the significant concurrent exposure to the three HMs, which maximize their potential developmental neurotoxicity with a high probability of developing non-carcinogenic and carcinogenic health effects.

Insights into the regulation of cellular Mn2+ homeostasis via TMEM165.

Golgi cation homeostasis is known to be crucial for many cellular processes including vesicular fusion events, protein secretion, as well as for the activity of Golgi glycosyltransferases and glycosidases. TMEM165 was identified in 2012 as the first cation transporter related to human glycosylation diseases, namely the Congenital Disorders of Glycosylation (CDG). Interestingly, divalent manganese (Mn) supplementation has been shown to suppress the observed glycosylation defects in TMEM165-deficient cell lines, thus suggesting that TMEM165 is involved in cellular Mn homeostasis. This paper demonstrates that the origin of the Golgi glycosylation defects arises from impaired Golgi Mn homeostasis in TMEM165-depleted cells. We show that Mn supplementation fully rescues the Mn content in the secretory pathway/organelles of TMEM165-depleted cells and hence the glycosylation process. Strong cytosolic and organellar Mn accumulations can also be observed in TMEM165- and SPCA1-depleted cells upon incubation with increasing Mn concentrations, thus demonstrating the crucial involvement of these two proteins in cellular Mn homeostasis. Interestingly, our results show that the cellular Mn homeostasis maintenance in control cells is correlated with the presence of TMEM165 and that the Mn-detoxifying capacities of cells, through the activity of SPCA1, rely on the Mn-induced degradation mechanism of TMEM165. Finally, this paper highlights that TMEM165 is essential in secretory pathway/organelles Mn homeostasis maintenance to ensure both Golgi glycosylation enzyme activities and cytosolic Mn detoxification.

Four-year follow-up of surface contamination by antineoplastic drugs in a compounding unit.

OBJECTIVES: This study aimed to monitor the contamination by antineoplastic drugs on work surfaces in a compounding unit 4 years after its implementation. METHODS: This descriptive study was done in a unit performing on average 45 000 preparations per year. Surface sampling points (N=23) were monitored monthly in the frame of routine activity from the opening of an anticancer drug compounding unit. Contamination with nine antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-fluorouracil, methotrexate, gemcitabine, cytarabine, irinotecan and doxorubicin) was assessed on wipes with a local liquid chromatography coupled with a tandem mass spectrometer analysis. The contamination rate (CR, %) was prospectively monitored every month during the entire study period. The occurrence of critical incidents was also registered. The effect of each safety measure implemented during this period was also analysed. RESULTS: Based on the 1104 samples collected between March 2016 and March 2020, the CR was 18.5%. If three different critical incidents among a vial breakage that occurred were individually considered, this CR was slightly lower than that in the literature. Eight months after opening and taking different corrective actions, the overall CR dropped from 42.39% to 11.52% (p<0.001). Contamination was limited to the area that includes the compounding room and, more precisely, the welder and the QC-Prep+ sampling points. CONCLUSIONS: From the beginning of the study and from month to month, surface contamination was limited to the nearest sampling points to the compounding unit. This 4-year monitoring study allowed us to determine the intravenous conventional antineoplastic drugs and sampling points to be focused on.

Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects.

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment.

Stability of trace element concentrations in frozen urine - Effect on different elements of more than 10 years at - 80 °C.

BACKGROUND: Analysis of urinary trace elements is widely used in Human Biology, especially in occupational and environmental biomonitoring. Collections of urine samples are of great interest for those studying trace elements but many of them are actually unused, in part perhaps because of a lack of knowledge about the stability of trace element concentrations under such storage conditions. The aim of this study was to evaluate the impact of a long-term frozen storage on the measurement of the urinary concentration of 10 trace elements. METHOD: Forty-eight urinary samples were re-analysed by inductively coupled plasma mass spectrometry (ICP-MS) for the quantification of As, Cd, Co, Cr, Mn, Ni, Pb, Sb, Tl, and Zn, after 11-13 years of frozen storage at - 80 °C. RESULTS: A slight water loss likely occurred, even at - 80 °C, but seems to be compensated by using creatinine-adjusted concentrations. Concentrations of As, Cd, Pb, Tl, Zn, and possibly Mn, did not suffer from major modification during storage, while the plastic container likely contaminated samples with Sb. The technological evolution over 13 years may have affected some results, especially those with lower concentrations, and must be taken into account when comparing data over time. CONCLUSION: This study provides some promising preliminary data on the stability of trace element concentrations during long-term frozen storage, and some evidence that urine samples in existing biobanks remain a valuable resource, even if they were collected many years ago.

Assessment of Pb(II), Cd(II), and Al(III) Removal Capacity of Bacteria from Food and Gut Ecological Niches: Insights into Biodiversity to Limit Intestinal Biodisponibility of Toxic Metals.

Toxic metals (such as lead, cadmium, and, to a lesser extent, aluminum) are detrimental to health when ingested in food or water or when inhaled. By interacting with heavy metals, gut and food-derived microbes can actively and/or passively modulate (by adsorption and/or sequestration) the bioavailability of these toxins inside the gut. This "intestinal bioremediation" involves the selection of safe microbes specifically able to immobilize metals. We used inductively coupled plasma mass spectrometry to investigate the in vitro ability of 225 bacteria to remove the potentially harmful trace elements lead, cadmium, and aluminum. Interspecies and intraspecies comparisons were performed among the Firmicutes (mostly lactic acid bacteria, including Lactobacillus spp., with some Lactococcus, Pediococcus, and Carnobacterium representatives), Actinobacteria, and Proteobacteria. The removal of a mixture of lead and cadmium was also investigated. Although the objective of the study was not to elucidate the mechanisms of heavy metal removal for each strain and each metal, we nevertheless identified promising candidate bacteria as probiotics for the intestinal bioremediation of Pb(II) and Cd(II).

Comparison of the chemical composition of aerosols from heated tobacco products, electronic cigarettes and tobacco cigarettes and their toxic impacts on the human bronchial epithelial BEAS-2B cells.

The electronic cigarettes (e-cigs) and more recently the heated tobacco products (HTP) provide alternatives for smokers as they are generally perceived to be less harmful than conventional cigarettes. However, it is crucial to compare the health risks of these different emergent devices, in order to determine which product should be preferred to substitute cigarette. The present study aimed to compare the composition of emissions from HTP, e-cigs and conventional cigarettes, regarding selected harmful or potentially harmful compounds, and their toxic impacts on the human bronchial epithelial BEAS-2B cells. The HTP emitted less polycyclic aromatic hydrocarbons and carbonyls than the conventional cigarette. However, amounts of these compounds in HTP aerosols were still higher than in e-cig vapours. Concordantly, HTP aerosol showed reduced cytotoxicity compared to cigarette smoke but higher than e-cig vapours. HTP and e-cig had the potential to increase oxidative stress and inflammatory response, in a manner similar to that of cigarette smoke, but after more intensive exposures. In addition, increasing e-cig power impacted levels of certain toxic compounds and related oxidative stress. This study provides important data necessary for risk assessment by demonstrating that HTP might be less harmful than tobacco cigarette but considerably more harmful than e-cig.

Influence of polycyclic aromatic hydrocarbon exposure on IVF: now is the time to focus on women.

RESEARCH QUESTION: Is polycyclic aromatic hydrocarbon (PAH) exposure associated with the reproductive outcomes of IVF treatment? DESIGN: A prospective, small-scale monocentric cohort study of couples who underwent IVF treatment between January 2018 and June 2019. Both members of each couple answered a questionnaire on PAH exposure and provided urine samples to measure urinary 1-hydroxypyrene (1-OHP) the day before oocyte retrieval and semen collection for fertilization. To assess the specific PAH exposure of gamete cells, immunostaining was conducted on both spermatozoa and granulosa cells obtained during IVF with an anti-benzo(a)pyrene diol epoxide (BPDE) monoclonal antibody that recognizes BDPE-DNA adducts. To assess DNA damage, a comet assay on spermatozoa was conducted. The PAH exposure was compared between couples who had positive HCG and couples who had negative HCG on day 14 after embryo transfer. RESULTS: Eighteen couples were included. The mean 1-OHP level in women whose HCG tests were positive (n = 6) was significantly lower than that in women with negative HCG tests (0.098 [0.042-0.170] versus 0.177 [0.067-0.812] µg/g creatinine; P = 0.048). The presence of BPDE-DNA adducts in granulosa cells of women with a negative (29.7 [16.2-57.5] arbitrary units) or positive HCG test (20.3 [9.3-23.3] arbitrary units) were not significantly different (P = 0.092). The urinary 1-OHP levels of men and BPDE-DNA adducts in spermatozoa showed no differences between groups. CONCLUSIONS: This exploratory research should encourage further studies to determine the effect of women's exposure to PAHs on reproductive outcomes of IVF treatment.

Texture parameters of R2* maps are correlated with iron concentration and red blood cells count in clot analogs: A 7-T micro-MRI study.

BACKGROUND AND PURPOSE: Previous studies have suggested that mechanical revascularization in acute ischemic stroke (AIS) patients could be affected by clot histology. In this 7-T micro-MRI study, we used R2* relaxometry of clot analogs to evaluate the relationship between texture parameters of R2* maps and clot constituents. MATERIALS AND METHODS: Twelve AIS clot analogs were experimentally generated to obtain a wide range of red blood cell concentrations. All clots underwent a MR acquisition using a 7-T micro-MR system. A 3D multi-echo gradient-echo sequence was performed and R2* maps were generated. First order and second order statistics of R2* histograms within the clots were calculated. Iron concentration in clots was measured using absorption spectrometry and red blood cell count (RBC) was obtained by histopathological analysis. RESULTS: RBC count was strongly correlated with iron concentration within clots (r=0.87, P<.001). Higher RBC count and iron concentration were significantly correlated with first order parameters including: (a) global positive shift of the R2* histogram with higher '10th percentile', 'median', 'mean' and '90th percentile'; (b) increase of the global magnitude of voxel values with higher 'total energy' and 'root mean squared'; (c) greater uniformity of the voxel values with higher 'uniformity' and lower 'entropy'. Second order statistical parameters confirmed that higher RBC count and iron concentration correlated with (a) greater concentration of high gray-level values in the image; (b) more "coarse" texture of R2* maps. CONCLUSIONS: Texture analysis of MRI-R2* maps can accurately estimate the red blood cell count and iron content of AIS clot analogs.

Influence of puffing conditions on the carbonyl composition of e-cigarette aerosols.

Owing to their harmful effects on human health, the presence of carbonyl compounds in e-cigarette aerosols raises concerns. To date, the reported concentration levels in e-vapors vary greatly between studies and several factors that markedly influence carbonyl emission during vaping have been highlighted including the heating temperature, the power supply, the device architecture, the filling level of the tank and the main e-liquid constituents. This study investigated the impact of puffing regimen parameters on the carbonyl composition of e-cigarette aerosols with the aim of: (1) better estimating the variability of carbonyl emissions depending on puffing conditions; (2) highlighting puffing profiles that increase the exposure to carbonyls; and (3) estimating to what extent puffing topography could be implied in the variability of carbonyl concentrations reported in the current literature. E-vapors from a single e-liquid were generated from two e-cigarette models with a smoking machine. A total of 7 different puffing regimens were used to individually study the influence of the puff volume, duration and frequency. Carbonyls were collected by DNPH cartridges and analysed by HPLC-UV. E-liquid consumption and e-vapor temperature were also monitored. E-vapor concentrations of formaldehyde, acetaldehyde, acetone, acrolein, propionaldehyde and methylglyoxal were affected, sometimes differently, by the modification of the puffing regimen, as well as by the e-cigarette model. For example, formaldehyde concentration ranged from 20 to 255 ng/puff depending on the puffing conditions. The results of principal component analyses, applied to the concentration data sets for the 6 carbonyls, suggest that the studied parameters interact and highlight some "carbonyl-emitting" combinations of concern (e-cigarette model/puffing regimen). However, the highest concentrations measured in the present study remain far lower than those observed in conventional cigarette mainstream smoke. This study confirms that the chosen puffing regimen contributes a part of the observed variability in the carbonyl levels reported in the scientific literature, hampering comparisons between studies and making interpretation difficult. Thus, harmonized and realistic protocols for the assessment of e-cigarette toxicity by physicochemical or experimental approaches are clearly needed.

Chemical Evaluation of Electronic Cigarettes: Multicomponent Analysis of Liquid Refills and their Corresponding Aerosols.

Electronic cigarette use has raised concern worldwide regarding potential health risks and its position in tobacco cessation strategies. As part of any toxicity assessment, the chemical characterization of e-liquids and their related vapors are among fundamental data to be determined. Considering the lack of available reference methods, we developed and validated several analytical procedures in order to conduct a multicomponent analysis of six e-liquid refills and their resultant vapor emissions (generated by a smoking machine), and compared them with tobacco smoke. We combined several techniques including gas-chromatography, high and ultra-performance liquid chromatography and inductively coupled plasma with mass spectrometry or ultraviolet and flame ionization detection in order to identify the main e-liquid constituents (propylene glycol, glycerol and nicotine), as well as multiple potentially harmful components (trace elements, polycyclic aromatic hydrocarbons (PAHs), pesticides and carbonyl compounds). Regarding propylene glycol, glycerol and nicotine concentrations, the six tested e-liquids comply with the advertised composition and contain only traces of pollutants. Noticeable lower concentrations of trace elements (≤3.4 pg/mL puff), pesticides (

Comparison of cellular and transcriptomic effects between electronic cigarette vapor and cigarette smoke in human bronchial epithelial cells.

The use of electronic cigarette (e-cig) can be considered as an alternative to smoking. However, due to a lack of thorough toxicological studies, absolute safety of these products cannot be guaranteed. The aim of this in vitro work was to investigate the potential toxicity of e-vapors generated by a smoking machine in human bronchial epithelial BEAS-2B cells cultured at air-liquid interface, in comparison to cigarette smoke (CS). Although CS decreased strongly cell viability from 48min exposure, e-vapors induced no cytotoxicity up to 288min exposure. Moreover, oxidative stress was evidenced only after exposure to CS, with a decrease secretion of GRO-ɑ from 8min and of IL-8 and MCP-1 after 48min exposure. Only a low increase of IL-6 secretion was measured in cells exposed to e-vapors. Finally, transcriptomic data of exposed cells indicated that a large number of genes were deregulated in response to CS, especially genes involved in important biological functions as oxidative stress and cell death, while e-vapors elicited very discrete modulation. These results strongly suggest a lower toxicity of e-vapors compared to CS in the BEAS-2B cell line and constitute a baseline for further experimental studies with a larger spectrum of e-liquids and e-cig models.