DMF Exposure Research Articles

Robust carbon nitride nanosheet interlayered thin-film nanocomposite membrane for enhanced organic solvent nanofiltration

The integration of a nanomaterial interlayer within a thin-film composite membrane can markedly enhance its performance in organic solvent nanofiltration (OSN). However, this enhancement often comes at the expense of membrane integrity due to differential swelling behaviors in diverse solvents. In this study, we present an interlayered thin film nanocomposite (TFNi) membrane that demonstrates both high permeance and robust stability, utilizing green, porous, and reactive crystalline carbon nitride (CCN) nanosheets as the functional interlayer. The results revealed that ascribed to the presence of the CCN interlayer, the membranes retained their rejection towards organic dyes even after 10 h of DMF exposure, while the organic solvent permeance was significantly improved by the DMF treatment. The methanol permeance of the CCN-TFNi-DMF membrane reached an impressive 8.77 L m−2 h−1 bar−1, sustaining stable performance throughout a 72 h test period under a pressure of 10 bar. We attributed this performance enhancement to the extra nanochannels introduced by the CCN nanosheets that bolstered the permeance of the TFNi membrane, as well as the formation of a stable polyamide film resulting from the reaction between the amino groups on the CCN nanosheet surface and trimesoyl chloride during the interfacial polymerization process. This work provides valuable insights into the development of structurally reinforced TFNi membranes with exceptional performance for OSN separation applications.

NLRP3 inflammasome activation triggers severe inflammatory liver injury in N, N-dimethylformamide-exposed mice

N,N-dimethylformamide (DMF) is a widely utilized chemical solvent with various industrial applications. Previous studies have indicated that the liver is the most susceptible target to DMF exposure, whereas the underlying mechanisms remain to be elucidated. This study aimed to investigate the role of NLRP3 inflammasome in DMF-induced liver injury in mice by using two NLRP3 inflammasome inhibitors, Nlrp3−/− mice, Nfe2l2−/− mice, and a macrophage-depleting agent. RNA sequencing revealed that endoplasmic reticulum (ER) stress and NLRP3 inflammasome-associated pathways were activated in the mouse liver after acute DMF exposure, which was validated by Western blotting. Interestingly, DMF-induced liver injury was effectively suppressed by two inflammasome inhibitors, MCC950 and Dapansutrile. In addition, knockout of Nlrp3 markedly attenuated DMF-induced liver injury without affecting the metabolism of DMF. Furthermore, silencing Nfe2l2 aggravated the liver injury and the NLRP3 inflammasome activation in mouse liver. Finally, the depletion of hepatic macrophages by clodronate liposomes significantly reduced the liver damage caused by DMF. These results suggest that NLRP3 inflammasome activation is the upstream molecular event in the development of acute liver injury induced by DMF.

The potential health risks of N,N-dimethylformamide: An updated review.

N,N-dimethylformamide (DMF) is a universally used industrial material with exponential growth in production and consumption worldwide. The frequently reported occupational DMF poisoning cases in some countries and the gradually recognized unavoidable health risks to the general population highlight that DMF should still be a matter of concern. Previous studies have demonstrated that the liver is the primary target organ of DMF exposure and multiple mechanisms have been revealed. However, most of these studies investigate the detrimental effects of acute and subacute DMF exposure, while the effects of chronic DMF exposure are rarely studied. Furthermore, the key mechanism for the acute hepatotoxicity of DMF remains to be elucidated. Future research may focus on the identification of efficient preventive measures against the toxicity of DMF to occupational workers, the investigation of the detrimental effects of DMF at environmentally relevant doses, and the studies on the elimination and recycling of DMF in industrial wastes. Herein, we present an updated review of the metabolism of DMF, the biomarker of DMF exposure, underlying molecular mechanisms of DMF-induced hepatotoxicity, and the toxicity of DMF to both occupational workers and general populations and discuss the possible directions in future studies.

Allyl methyl disulfide (AMDS) prevents N,N-dimethyl formamide-induced liver damage by suppressing oxidative stress and NLRP3 inflammasome activation

N,N-dimethylformamide (DMF), a widely consumed industrial solvent with persistent characteristics, can induce occupational liver damage and pose threats to the general population due to the enormous DMF-containing industrial efflux and emission from indoor facilities. This study was performed to explore the roles of allyl methyl disulfide (AMDS) in liver damage induced by DMF and the underlying mechanisms. AMDS was found to effectively suppress the elevation in the liver weight/body weight ratio and serum aminotransferase activities, and reduce the mortality of mice induced by DMF. In addition, AMDS abrogated DMF-elicited increases in malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels and decreases in glutathione (GSH) levels in mouse livers. The increase in macrophage number, mRNA expression of M1 macrophage biomarkers, and protein expression of key components in the NF-κB pathway and NLRP3 inflammasome induced by DMF exposure were all suppressed by AMDS in mouse livers. Furthermore, AMDS inhibited DMF-induced cell damage and NF-κB activation in cocultured AML12 hepatocytes and J774A.1 macrophages. However, AMDS per se did not significantly affect the protein level and activity of CYP2E1. Collectively, these results demonstrate that AMDS effectively ameliorates DMF-induced acute liver damage possibly by suppressing oxidative stress and inactivating the NF-κB pathway and NLRP3 inflammasome.

Vulnerable Factors Affecting Urinary N-Methylformamide Concentration among Migrant Workers in Manufacturing Industries in Comparison with Native Workers in the Republic of Korea (2012-2019).

Background: Occupational studies on N-N-dimethylformamide (DMF) exposure among migrant workers in Korea are scarce. We determined the urine concentration of N-methylformamide (NMF) among migrant workers with DMF exposure and compared the data with those of native workers. Methods: Data were collected from Workers’ Special Health Examination and Work Environment Monitoring databases during 2014–2019. Workers aged ≥20 years were eligible to participate in the special health examination for DMF exposure. Urine concentrations of NMF were determined and compared between migrant and native workers. We also evaluated the factors affecting the difference in the urine concentration of NMF between the migrant and native workers. Multiple logistic regression was performed by adding confounders step by step. Results: Among 9259 subjects, 504 (5.2%) were migrant workers. The mean urinary concentration of NMF was 6.73 mg/L in migrant workers, which was significantly higher than that in native workers (2.06 mg/L, p < 0.001). The odds of a urine concentration of NMF > 30 mg/L were significantly higher in migrant workers than in native workers after adjusting for sex and age (odds ratio [OR] = 7.31, 95% confidence interval [CI] = 4.66–11.45). However, the odds between the native and migrant workers were not significantly different when fully adjusted for confounders (OR = 1.12, 95% CI = 0.65–1.94). Conclusions: The excessive exposure to DMF among migrant workers was attributed not to differences in biological characteristics but to their work environment. Workers must have awareness of the use of protective equipment and knowledge of hazardous chemicals that they may be exposed to, especially at the workplace.

N, N-dimethylformamide exposure induced liver abnormal mitophagy by targeting miR-92a-1-5p-BNIP3L pathway in vivo and vitro

N, N-dimethylformamide (DMF) is a widely existing harmful environmental pollutant from industrial emission which can threat human health for both occupational and general populations. Epidemiological and experimental studies have indicated liver as the primary target organ of DMF. However, the molecular mechanism under DMF-induced hepatoxicity remains unclear. In the present study, we identified that DMF could induce abnormal autophagy flux in cells. We also showed that DMF-induced mitochondrial dysfunction and lethal mitophagy which further leads to autophagic cell death. Next, miRNA microarray analysis identified miR-92a-1-5p as the most down-regulated miRNA upon DMF exposure. Mechanistically, miR-92a-1-5p regulated mitochondrial function and mitophagy by targeting mitochondrial protein BNIP3L. Exogenous miR-92a-1-5p significantly attenuated DMF-induced mitochondrial dysfunction and mitophagy in vitro and in vivo. Our study highlights the mechanistic link between miRNAs and mitophagy under environmental stress, which provided a new clue for the mitochondrial epigenetics mechanism on environmental toxicant-induced hepatoxicity.

N,N-dimethylformamide-induced acute liver damage is driven by the activation of NLRP3 inflammasome in liver macrophages of mice

N,N-dimethylformamide (DMF) is a non-negligible volatile hazardous material in indoor and outdoor environments. Although the hepatotoxicity of DMF has been well recognized, the underlying mechanisms remain unclear and prophylactic medicine is still lacking. Herein, we established a DMF-induced acute liver injury mouse model and investigated the underlying mechanisms focusing on oxidative stress and the nucleotide-binding domain and leucine-rich repeat receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome. DMF was found to induce oxidative stress, evidenced by the elevation of hepatic malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) adducts levels, and the decline of reduced glutathione (GSH) levels. However, neither N-acetyl cysteine (NAC) nor sulforaphane (SF) ameliorated the hepatoxicity induced by DMF in mice. Interestingly, DMF exposure led to focal necrosis of hepatocytes and NLRP3 inflammasome activation before the onset of obvious liver damage. In addition, DMF exposure induced infiltration and proinflammatory/M1 polarization of macrophages in mice livers. Furthermore, the inactivation of hepatic macrophages by GdCl3 significantly suppressed DMF-induced elevation of serum aminotransferase activities, neutrophile infiltration, and activation of NLRP3 inflammasome in mice liver. Collectively, these results suggest that DMF-induced acute hepatotoxicity may be attributed to the activation of NLRP3 inflammasome in liver macrophages, but not oxidative stress.

Exposure of mouse oocytes to N,N-dimethylformamide impairs mitochondrial functions and reduces oocyte quality.

N,N-dimethylformamide (DMF) is a widely-used solvent for the synthesis of synthetic fibers such as polyacrylonitrile fiber, and can also be used to make medicine. Although this organic solvent has multipurpose applications, its biological toxicity cannot be ignored and its impact on mammalian reproduction remains largely unexplored. Our study found that DMF exposure inhibited oocyte maturation and fertilization ability. Transcriptomic analysis indicated that DMF exposure changed the expression of genes and transposable elements in oocytes. Subcellular structure examination found that DMF exposure caused mitochondrial dysfunction, abnormal aggregation of mitochondria and decreased mitochondrial membrane potential in mouse oocytes. Its exposure also caused abnormal distribution of Golgi apparatus and endoplasmic reticulum which formed large number of clusters. In addition, oxidative stress occurs in oocytes exposed to DMF, which was manifested by an increase in the level of reactive oxygen species. We found that DMF exposure induced disordered spindle and chromosomes abnormality. Meanwhile, we examined various histone modification levels in oocytes exposed to DMF and found that DMF exposure reduced H3K9me3, H3K9ac, H3K27ac, and H4K16ac levels in mouse oocytes. Moreover, DMF-treated oocytes failed to form pronuclei after fusion with normal sperm. Collectively, DMF exposure caused mitochondrial damage, oxidative stress, spindle assembly and chromosome arrangement disorder, leading to oocyte maturation arrest and fertilization failure.

Aberrant expression of SNHG12 contributes to N, N-dimethylformamide-induced hepatic apoptosis both in short-term and long-term DMF exposure.

N, N-Dimethylformamide (DMF) can cause liver damage in occupationally exposed workers, but the molecular mechanism of DMF-induced liver damage has not been fully elucidated. Researches have proved that lncRNA plays a major function in chemical-induced liver toxicity and can be used as a biomarker and therapeutic target for liver injury. In order to verify that lncRNA also participates in DMF-induced liver damage, we treated HL-7702 cells with 75 or 150 mM DMF, and obtained lncRNA expression profiles through high-throughput sequencing. Among the differentially expressed lncRNAs, lncRNA SNHG12 was proved to be significantly downregulated in DMF-treated HL-7702 cells and participate in DMF-mediated apoptosis, even under long-term low-dose DMF exposure (5-10 mM, 8 weeks). In addition, according to bioinformatics analysis, miR-218-5p is expected to be a potential target of SNHG12, which was verified by the dual luciferase reporter assay in HEK293FT cells. MiR-218-5p mimic can induce apoptosis in HL-7702 cells. Among the predicted targets of miR-218-5p, protein kinase C epsilon (PRKCE) was reported to be involved in apoptosis, and was indeed downregulated by miR-218-5p mimic in our study. Further experiments showed that changes of the expression of SNHG12 can affect the expression of PRKCE. In the epidemiological study of occupational population, we also found that SNHG12 was downregulated in the serum exosomes of workers exposed to DMF. These results indicated that SNHG12 can mediate DMF-induced apoptosis of HL-7702 cells through miR-218-5p/PRKCE pathway.

Hsa_circ_0005915 promotes N,N-dimethylformamide-induced oxidative stress in HL-7702 cells through NRF2/ARE axis

N,N-dimethylformamide (DMF) is an organic compound widely used in industrial production processes as a solvent with a low evaporation rate. Excessive exposure to DMF may lead to liver damage. Oxidative stress has been reported as one of the main causes of DMF-induced hepatotoxicity. Several doses of DMF (0, 1, 5, and 10 mM) were used to treat HL-7702 cells for a relatively long period to simulate the actual exposure pattern in occupational settings, and oxidative stress was induced. Previous studies illustrated that circular RNA (circRNA) plays a vital role in sustaining hepatocyte physiological function. To explore whether aberrant circRNA expression is involved in DMF-induced excessive ROS generation and hepatotoxicity, high-throughput transcriptional sequencing was performed to identify the altered circRNA expression profiles in HL-7702 liver cells after treatment with 0, 75, or 150 mM DMF for 48 h. We found that levels of induced oxidative stress were similar to those in the long-term exposure model. Among the altered circRNAs, one circRNA (hsa_circ_0005915) was significantly upregulated after DMF exposure, and it affected DMF-mediated oxidative stress in HL-7702 cells. Further experiments revealed that hsa_circ_0005915 downregulated the expression of nuclear factor erythoid-2-related factor 2 (NRF2) at the post-transcriptional level via promoting the ubiquitination and degradation of NRF2, which led to the increase of ROS accumulation. Further investigation demonstrated that the expression levels of NRF2-regulated antioxidative genes—heme oxygenase 1 (HO1) and NAD(P)H quinone dehydrogenase 1 (NQO1)—indeed declined after the overexpression of hsa_circ_0005915. In vivo study also indicated that DMF exposure can upregulate the expression of mmu_circ_0007941 (homologous circRNA of hsa_circ_0005915) and downregulated Nrf2 and Ho1 proteins. In summary, our results revealed that hsa_circ_0005915 plays an important role in promoting DMF-induced oxidative stress by inhibiting the transcriptional activity of the NRF2/ARE axis, which provides a potential molecular mechanism of DMF-mediated hepatotoxicity.

Integration of proteomics, lipidomics, and metabolomics reveals novel metabolic mechanisms underlying N, N-dimethylformamide induced hepatotoxicity

N, N-Dimethylformamide (DMF) is a universal organic solvent which widely used in various industries, and a considerable amount of DMF is detected in industrial effluents. Accumulating animal and epidemiological studies have identified liver injury as an early toxic effect of DMF exposure; however, the detailed mechanisms remain poorly understood. In this study, we systematically integrated the quantitative proteomics, lipidomics, and metabolomics data obtained from the primary human hepatocytes exposed to DMF, to depict the complicated biochemical reactions correlated to liver damage. Eventually, we identified 284 deregulated proteins (221 downregulated and 63 upregulated) and 149 deregulated lipids or metabolites (99 downregulated and 50 upregulated) induced by DMF exposure. Further, the integration of the protein-metabolite (lipid) interactions revealed that N-glycan biosynthesis (involved in the endoplasmic reticulum stress and the unfolded protein response), bile acid metabolism (involved in the lipid metabolism and the inflammatory process), and mitochondrial dysfunction and glutathione depletion (both contributed to reactive oxygen species) were the typical biochemical reactions disturbed by DMF exposure. In summary, our study identified the versatile protein, lipid, and metabolite molecules in multiple signaling and metabolic pathways involved in DMF induced liver injury, and provided new insights to elucidate the toxic mechanisms of DMF.

Aberrant expression of miRNA-192-5p contributes to N,N-dimethylformamide-induced hepatic apoptosis.

Excessive exposure to N,N-dimethylformamide (DMF) can lead to occupational liver poisoning in workers; however, the underlying mechanism is not fully clarified. The importance of microRNAs (miRNAs) in chemical-induced hepatotoxicity has been demonstrated. To determine whether miRNAs are also involved in DMF-induced hepatotoxicity, we systematically analyzed the miRNA expression profiles in DMF-treated (75 and 150 mm) HL-7702 liver cells and controls by high-throughput sequencing. Among the altered miRNAs, miR-192-5p was the most significantly upregulated in HL-7702 cells after DMF exposure and was involved in DMF-mediated cell apoptosis. By contrast, suppression of miR-192-5p in HL-7702 cells attenuated the apoptosis induced by DMF. Furthermore, the anti-apoptotic gene (NIN1/RPN12 binding protein 1 homolog [NOB1]) was predicted to be a potential miR-192-5p target according to bioinformatics analysis. The direct interaction between miR-192-5p and NOB1 was confirmed by the dual-luciferase activity assay in HEK293FT cells. Overexpression of miR-192-5p efficiently reduced NOB1 mRNA and protein expression in HL-7702 cells. Alteration in NOB1 expression influenced DMF-induced hepatotoxicity by affecting hepatic apoptosis. In addition, the inverse correlation between miR-192-5p expression levels and NOB1 expression was further confirmed in DMF-exposed mouse liver tissue samples. These observations demonstrated that promotion of apoptosis from the suppression of NOB1 by miR-192-5p overexpression was responsible for the DMF-induced hepatotoxicity. This work provides the molecular mechanism at the miRNA level for hepatic apoptosis induced by DMF.

The influence of airborne N,N-dimethylformamide on liver toxicity measured in industry workers: A systematic review and meta-analysis

Background: Modern industry is developing and so is the consumption of N, N-dimethylformamide (DMF) and the occupational population exposed to DMF. However, chronic occupational and experimental exposure to DMF has been especially linked to liver and gastrointestinal disturbances. Aims: This study aims to systematically review and evaluate with a meta-analysis the influence of DMF exposure on human liver toxicity. Methods: The PubMed/Medline, the ECHA restriction dossier and the Web of Science were searched. Midpoint DMF exposure levels were calculated, and the association between DMF exposure and liver toxicity was investigated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results: Of 92 screened articles, 19 articles were included in the review and of them, 10 articles were included in the meta-analysis. No association was observed when the midpoint DMF exposure was less than 20 mg/m3 (OR: 1.58, 95% CIs: 0.68–3.65). A positive association between DMF exposure and liver toxicity was observed when the midpoint DMF exposure was between 21 mg/m3 and 25 mg/m3 (OR: 3.26, 95% CIs: 1.38–7.73). Conclusions: Higher exposure DMF levels are associated with liver toxicity. However, these results tend to overestimate potential risks because the use of midpoint exposures includes and gives weight to populations at the upper end of the exposure distributions and because liver toxicity was defined as a statistical significant difference in liver enzyme levels compared to control groups, which is not identical to biologically relevant effects and adverse health effects.

Risk factors for lymphopenia in patients with relapsing-remitting multiple sclerosis treated with dimethyl fumarate.

To identify risk factors for DMF-induced lymphopenia and characterize its impact on T lymphocyte subsets in MS patients. We performed a retrospective analysis of 194 RRMS patients treated with DMF at the Beth Israel Deaconess Medical Center (BIDMC) over a median of 17months. We reviewed demographics, ethnic background, prior medication history, complete blood counts and T lymphocyte subsets. Possible lymphopenia risk factors examined included age, prior natalizumab exposure, vitamin D levels, and concomitant exposure to carbamazepine, opiates, tobacco, or steroids. Lymphopenia was defined as grade 1: absolute lymphocytes count (ALC) 800-999/μl; grade 2: ALC 500-799/μl; grade 3: ALC 200-499/μl; and grade 4: ALC < 200/μl. Of 194 DMF-treated patients, 73 (38%) developed lymphopenia and reached an ALC nadir after a median of 504days (range 82-932). Risk of developing DMF-induced lymphopenia increased with BMI 25-30, older age, white ethnicity, non-smoking status, and lowest quartile baseline ALC. Prior exposure to natalizumab or concomitant steroid, opiates or carbamazepine/oxcarbamazepine use was not associated with lymphopenia. Compared to baseline levels, CD8 T cells were significantly more reduced than CD4 cells. CD8 counts were more commonly reduced with age or white ethnicity. Subjects with BMI 25-30 was associated with a higher risk of abnormal CD4 cell count reductions. In contrast, non-smokers were more likely to experience reductions in both CD4 and CD8 counts while on DMF. Patients with low baseline lymphocyte counts, with intermediate BMI, with white ethnicity, with advanced age, or with no tobacco use, had a significantly higher incidence of lymphopenia on DMF. Intermediate BMI or lowest quartile baseline ALC predicted low CD4 levels, while advanced age or white ethnicity predicted low CD8 levels from DMF exposure.

The Cell Death Phenotype of MGC-803 Cells Inducing with "Dextran-Magnetic Layered Double Hydroxide-Fluorouracil" Drug Delivery System and Fluorouracil.

The purpose of the paper is to study the differences in cell death mechanism of MGC-803 induced by "dextran-magnetic layered double hydroxide-fluorouracil" (DMF) drug delivery system and 5-Fluorouracil (5-Fu), respectively. The inhibitory effect on the proliferation was detected via CCK-8. The morphology of cell death was detected by transmission electron microscopy (TEM). Intracellular ATP, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) and Cytosolic Free Ca (Ca2+) level were detected via some methods. The result showed that DMF had more obvious effect in suppressing proliferation compared with 5-Fu, and changed cell death pattern of 5-Fu from apoptosis to oncosis. The ATP decrease, MMP loss, Ca2+ increase, the activation of uncoupling protein-2 (UCP-2) and calpain-1 were significant after DMF exposure. However, DMF did not result in ROS accumulation. DMF could involve in activation of porimin, and the cascade reaction of caspases-3, -7, -9, and -12 and poly ADP-ribose polymerase (PARP) through Western blot. DMF showed a stronger injury on nuclear membrane in the cascade reaction of caspases-6, -8 and lamin-A. DMF triggered rapid depletion of ATP, which was consistent with the phenotype of oncosis. Endogenous mitochondrial apoptosis might not be the main cause of cell swelling. DMF could induce strong endoplasmic reticulum stress (ERS) effect, there might be some signaling pathways related with ERS during the process of oncosis. The calpain system might not be a key factor for structural damage in oncosis induced by DMF. DMF could induce the caspases cascade reactions similar to apoptosis, but inflicted a more strong damage on nuclear membrane and PARP.

N,N-dimethylformamide: evidence of carcinogenicity from national representative cohort study in South Korea.

Objective There is limited epidemiological evidence of carcinogenicity on exposure of N,N-dimethylformamide (DMF). This study aimed to identify the possible association between cancer mortality and DMF exposure. Methods A cohort of 11 953 workers exposed to DMF between 1 January 2000 and 31 December 2004 was studied. A urinary metabolite of DMF, N-methylformamide level (UNMFL), was used for exposure assessment. This cohort was matched with the mortality data of the Korean National Statistical Office and followed up for cancer mortality between 2000 and 2011. Standardized mortality ratios (SMR) of the DMF-exposed workers with reference to Korean men were calculated. Adjusted hazard ratios (HRadj; also controlling for age, other carcinogen exposure including hepatitis B and C) were calculated for the workers categorized in three exposure groups with reference to workers with no exposure. Results The HRadj of overall cancer mortality were significantly increased in workers with 7.5-<15 mg/L [HRadj 2.72, 95% confidence interval (CI) 1.09-6.81] and ≥15 mg/L (HRadj 2.41, 95% CI 1.03-5.66) compared with non-exposed workers. Hepatocellular carcinoma mortality (HRadj 3.73, 95% CI 1.05-13.24) of workers with ≥15 mg/L and lung cancer mortality (HRadj 14.36, 95% CI 1.41-146.86) in workers with 7.5-<15 mg/L were significantly increased. Conclusions Workers with high DMF exposure showed increased mortalities for overall, liver, and lung cancer. Our results suggest that DMF causes cancer, especially hepatocellular carcinoma, which is in agreement with earlier studies on liver cancer in animal experiments.

Delayed-release Dimethyl Fumarate-associated Lymphopenia: On-treatment and Post-treatment Implications

Introduction Following the occurrence of 1 case of progressive multifocal leukoencephalopathy (PML) the DMF label was amended in 2015 to recommend treatment interruption for patients with severe, prolonged lymphopenia. Objectives Examine the clinical implications of DMF-associated lymphopenia and post-treatment ALC dynamics in pts with RRMS. Patients and methods An integrated analysis of the DMF Phase 2b, Phase 3 (DEFINE/CONFIRM) and extension (ENDORSE) studies was conducted. Data from 1st DMF exposure were analysed. ALCs were assessed at weeks (weeks) 4, 8, 12, and every 12 weeks thereafter. Results As of 01 Sept 2017, the analysis population comprised 2513 pts (10454 patient-years). In pts followed for up to 11 yrs, severe, prolonged lymphopenia was not associated with increased incidence of serious infection (0.016 vs. 0.010 for patients with ALC always above normal) or serious herpes zoster (0 vs. 0.006 for patients with ALC always above normal). One fatal case of PML previously occurred in the setting of severe lymphopenia of ∼3.5 years duration. Discussion Following the implementation of a stopping rule requiring patients with an ALC Conclusion These data support that DMF-associated lymphopenia is not associated with increased incidence of serious/opportunistic infection aside from very rare PML. For the majority of pts, ALCs increased following DMF discontinuation within 2 months.

Relationship between N,N-dimethylformamide exposure, PNPLA3, GCKR, COL13A1 and TM6SF2 genes, and liver injury

BackgroundCurrent researches show that N,N-dimethylformamide (DMF) exposure is associated with liver injury, but it is debatable whether PNPLA3, GCKR, COL13A1 and TM6SF2 gene polymorphisms are associated with liver injury. Our objective was to examine the relationship among DMF exposure, PNPLA3 rs738409, GCKR rs780094, COL13A1 rs1227756, TM6SF2 rs58542926 and liver injury. MethodsThe cohort consisted of 461 workers exposed above the DMF threshold limit value (TLV) and 211 exposed below the DMF TLV in China, who were followed for 5 years. The relationship between the measured dose of DMF and the relative risk (RR) of liver injury was also investigated by Poisson analysis. Logistic regression models were used to examine the association between measured dose of DMF, gene locus, and RR for liver injury. All workers had a annual physical examinations were conducted at certified physical examination centers in Taicang CDC, including liver serum transaminase assessment and abdominal ultrasound. Genomic DNA was extracted from peripheral blood leukocytes using a genomic DNA extraction kit. ResultsThe incidence of liver injury in the above DMF TLV group was significantly higher than in the below DMF TLV group. GCKR rs780094 was associated with liver injury. The interaction among the GCKR rs780094, DMF exposure and liver injury showed no significant association. ConclusionsOur data indicated that in DMF exposure, GCKR rs780094 may contribute to the risk of liver injury. Our results suggest that GCKR rs780094 is a useful genetic marker to help identify liver injury.

Validity of different biomonitoring parameters for the assessment of occupational exposure to N,N-dimethylformamide (DMF).

This study was performed to assess the relation between occupational exposure to N,N-dimethylformamide after an 8h work shift in the acrylic fibre industry and its three biological markers N-methylformamide (NMFtotal), N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC), and N-methylcarbamoyl adduct at haemoglobin (MCVal). External DMF exposure of 220 workers was determined during the whole shift. A standardised questionnaire was used to obtain information about the worker's general health status, medical treatment, smoking habits, protective measures, and possible symptoms caused by DMF exposure. NMF and AMCC were analysed in post-shift urine samples and MCVal in blood. For longitudinal assessment the average AMCC concentration was determined over a period of 4weeks (weekly sampling) in a sub-collective of 89 workers. The median of DMF concentration in air was 3.19mg/m3 (range < 0.15-46.9mg/m3). The biological markers showed a median of 4.80mg/L (range 0.20-50.6mg/L) for NMFtotal, 4.75mg/g creatinine (range 0.06-49.6mg/g creatinine) for AMCC, and 57.5nmol/g globin (range 0.5-414nmol/g) for MCVal. A significant linear relationship was observed between DMF in air and NMF as well as between DMF in air and AMCC in post-shift urine samples. The mean AMCC values measured weekly over a period of 4weeks correlated significantly with MCVal adducts too. Excluding workers who had been using breathing masks on the day of the study led to even tighter correlations. The results of the present study demonstrate the applicability of the DMF biomonitoring parameters NMFtotal in post-shift urine for the present-day exposure assessment, AMCC in the post-shift urine after several shifts for assessment of the cumulative exposure of the previous working days, and MCVal for assessment of long-term exposure during previous weeks and months. The data of the present study enable now the estimation of valid equivalents of these biomonitoring parameters to the external DMF exposure. From the risk assessment point of view, the exposure limit values for AMCC and MCVal, which are directly linked to the presumed toxic intermediate MIC, exhibit a significant advance.

Fluorescence detection of urinary N-methylformamide for biomonitoring of human occupational exposure to N,N-dimethylformamide by Eu(III) functionalized MOFs

N-methylformamide (NMF), the major metabolite of the N,N-dimethylformamide (DMF) in human body, is regarded as biomarker of DMF intoxication and represents the internal dose of DMF exposure in human body. Now we developed a novel and feasible method for NMF detection with luminescent Eu3+ functionalized metal organic frameworks (Eu(III)@MOF-1). The luminescence of Eu(III)@MOF-1 can be realized significant increase only by NMF even though in the presence of other chemical components of urine. This method is the first case to determine urinary NMF using the luminescent metal organic frameworks (Ln-MOFs). The optical sensor presents highlighted advantages for NMF detection, such as remarkable sensitivity, fast response, high selectivity, good reusability. Moreover, a portable test card is also made for immediate detection. Therefore, the discussed NMF sensing method can act as a promising application potential to monitor the intoxication of DMF contact.