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Long-term cell culture is an important biological approach but is also characterized by degeneration in cellular morphology, proliferation rate, and function. To explore this phenomenon in a systematic way, we conducted an integrative proteomics-metabolomics measurement of two cardiovascular cell lines of AC16 and HUVECs. The 18th culturing passages, i.e., G18, showed as the turning points by cell metabolism profiles, in which the metabolomic changes demonstrated the dysfunction of energy, amino acid, and ribonucleotide metabolism metabolic pathways. Although active protein networks showed mitochondria abundance AC16 and oxidative/nitrative sensitive HUVECs indicated the different degeneration patterns, the G18 and G30 proteomics evidenced the senescence by processes of signal transduction, signaling by interleukins, programmed cell death, cellular responses to stimuli, cell cycle, mRNA splicing, and translation. Some crucial proteins (RPS8, HNRNPR, SOD2, LMNB1, PSMA1, DECR1, GOT2, OGDH, PNP, CBS, ATIC, and IMPDH2) and metabolites (L-glutamic acid, guanine, citric acid, guanosine, guanosine diphosphate, glucose 6-phosphate, and adenosine) that contributed to the dysregulation of cellular homeostasis are identified by using the integrative proteomic-metabolomic analysis, which highlighted the increased cellular instability. These findings illuminate some vital molecular processes when culturing serial passages, which contribute holistic viewpoints of in vitro biology with emphasis on the replicative senescence of cardiovascular cells.
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Carbon black nanoparticles (CBNPs) are widely distributed in the environment and are increasingly recognized as a contributor in the development of cardiovascular disease. A variety of cardiac injuries and diseases result from structural and functional damage to cardiomyocytes. This study explored the mechanisms of CBNPs-mediated myocardial toxicity. CBNPs were given to mice through intra-tracheal instillation and it was demonstrated that the particles can be taken up into the cardiac tissue. Exposure to CBNPs induced cardiomyocyte inflammation and apoptosis. In combination with in vitro experiments, we showed that CBNPs increased the ROS and induced mitochondria fragmentation. Functionally, CBNPs-exposed cardiomyocyte exhibited depolarization of the mitochondrial membrane potential, release of cytochrome c, and activation of pro-apoptotic BAX, thereby initiating programmed cell death. On the other hand, CBNPs impaired autophagy, leading to the inadequate removal of dysfunctional mitochondria. The excess accumulation of damaged mitochondria further stimulated NF-κB activation and triggered the NLRP3 inflammasome pathway. Both the antioxidant N-acetylcysteine and the autophagy activator rapamycin were effective to attenuate the damage of CBNPs on cardiomyocytes. Taken together, this study elucidated the potential mechanism underlying CBNPs-induced myocardial injury and provided a scientific reference for the evaluation and prevention of the CBNPs-related heart risk.
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Apoptose , Autofagia , Potencial da Membrana Mitocondrial , Dinâmica Mitocondrial , Miócitos Cardíacos , Nanopartículas , Espécies Reativas de Oxigênio , Fuligem , Animais , Fuligem/toxicidade , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Espécies Reativas de Oxigênio/metabolismo , Autofagia/efeitos dos fármacos , Camundongos , Apoptose/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Inflamassomos/metabolismo , NF-kappa B/metabolismo , NF-kappa B/genética , Acetilcisteína/farmacologia , Masculino , Sirolimo/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Many environmental toxicants can cause systemic effects, such as fine particulate matter (PM2.5), which can penetrate the respiratory barrier and induce effects in multiple tissues. Although metabolomics has been used to identify biomarkers for PM2.5, its multi-tissue toxicology has not yet been explored holistically. Our objective is to explore PM2.5 induced metabolic alterations and unveil the intra-tissue responses along with inter-tissue communicational effects. In this study, following a single intratracheal instillation of multiple doses (0, 25, and 150 µg as the control, low, and high dose), non-targeted metabolomics was employed to evaluate the metabolic impact of PM2.5 across multiple tissues. PM2.5 induced tissue-specific and dose-dependent disturbances of metabolites and their pathways. The remarkable increase of both intra- and inter-tissue correlations was observed, with emphasis on the metabolism connectivity among lung, spleen, and heart; the tissues' functional specificity has marked their toxic modes. Beyond the inter-status comparison of the metabolite fold-changes, the current correlation network built on intra-status can offer additional insights into how the multiple tissues and their metabolites coordinately change in response to external stimuli such as PM2.5 exposure.
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Poluentes Atmosféricos , Metabolômica , Material Particulado , Material Particulado/toxicidade , Animais , Camundongos , Poluentes Atmosféricos/toxicidade , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Biomarcadores/metabolismo , MasculinoRESUMO
Microplastics (MPs) and nanoplastics (NPs) have been suspected as contaminants in various foodstuffs, including salts, all over the world. Regarding the different sizes and polymer types, the mass concentrations of actual plastic particles in salt are not very clear. The purpose of this study is to develop a scalable method for qualitative and quantitative analysis of MPs and NPs by using Pyrolysis Gas Chromatography Quadrupole-Time of Flight mass spectrometry (Py-GC/QTOFMS) to detect their mass concentrations in salt samples. The targeted and suspected lists of polymers in salts were compiled based on the combined results of the high-resolution mass spectrometry (HRMS) full scanning with auxiliary MS dataset and the laser direct infrared (LDIR) chemical imaging analysis. The seven targeted MPs with polymer standards, i.e., polyvinyl chloride (PVC), polymethyl methacrylate (PMMA), polypropylene (PP), polystyrene (PS), polyethylene (PE), polyethylene terephthalate (PET), and polycarbonate (PC), were first subjected to a full MS scanning mode of the Py-GC/QTOFMS analysis. Subsequently, the parental masses of their pyrolysis compounds were used as the seeds to generate the related daughter masses. This process established both retention time and mass-pairs matching for the target MS/MS mode for enabling the identification and quantification of the particles. The suspected MPs with a matching degree >0.65 in the LDIR list were explored either by the full scan MS. Only PVC was identified, and PET was suspected. The Py-GC/QTOFMS result is complementary and comparable to the LDIR detection with the matching degree >0.85. We identified that PVC and PET (suspected) can be measured in both commercial and bulk sea salts, and their concentrations in sea salts are much higher than in rock salts, implying heavy contamination of the seawater.
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Plásticos , Poluentes Químicos da Água , Plásticos/análise , Microplásticos , Sais , Pirólise , Espectrometria de Massas em Tandem , Cromatografia Gasosa-Espectrometria de Massas/métodos , Polímeros/química , Poluentes Químicos da Água/análiseRESUMO
Human biomonitoring of toxic trace elements is of critical importance for public health protection. The current study aims to assess the levels of selected trace metals (Cd, Co, Cr, Cu, Mn, Ni, Pb, and Zn) into paired human nail and hair samples (n = 180 each) from different altitudinal setting along the Indus River, and which were measured by using inductively coupled plasma mass spectrometry (ICP-MS). The human samples (hair and nail) were collected from four different ecological zones of Pakistan which include frozen mountain zone (FMZ), wet mountain zone (WMZ), riverine delta zone (RDZ), and low-lying southern areas (LLZ). Our results showed the following occurrence trends into studied hair samples: higher values (ppm) of Zn (281), Co (0.136), and Mn (5.65) at FMZ; Cr (1.37), Mn (7.83), and Ni (1.22) at WMZ; Co (0.15), Mn (11.89), and Ni (0.99) at RDZ; and Mn (8.99) and Ni (0.90) at LLZ. While in the case of nails, the levels (ppm) of Mn (9.91) at FMZ and Mn (9.38, 24.1, and 12.5), Cr (1.84, 3.87, and 2.33), and Ni (10.69, 8.89, and 12.6) at WMZ, RDZ and LLZ, respectively, showed higher concentration. In general, among the studied trace elements, Mn and Ni in hair/nail samples were consistently higher and exceeded the WHO threshold/published reference values in most of the studied samples (> 50-60%) throughout the Indus basin. Similarly, hair/nail Pb values were also higher in few cases (2-10%) at all studied zones and exceeded the WHO threshold/published reference values. Our area-wise comparisons of studied metals exhibited altitudinal trends for Cd, Cr, Zn, and Mn (p < 0.05), and surprisingly, the values were increasing from south to north (at higher altitudes) and indicative of geogenic sources of the studied toxic elements, except Mn, which was higher at lower floodplain areas. Estimated daily intake (EDI) values showed that food and drinking water had the highest contribution towards Zn, Cu, Mn, and Ni and accumulation at all studied zones. Whereas, dust also acts as the main exposure route for Mn, Co, Cr, and Cd followed by the food, and water.
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Água Potável , Metais Pesados , Oligoelementos , Humanos , Monitoramento Ambiental/métodos , Monitoramento Biológico , Cádmio/análise , Paquistão , Chumbo/análise , Oligoelementos/análise , Água Potável/análise , Metais Pesados/análiseRESUMO
Environmental arsenic exposure is one of the major global public health problems. Studies have shown that arsenic exposure can cause renal fibrosis, but the underlying mechanism is still unclear. Integrating the in vivo and in vitro models, this study investigated the potential molecular pathways for arsenic-induced renal fibrosis. In this study, SD rats were treated with 0, 5, 25, 50, and 100 mg/L NaAsO2 for 8 weeks via drinking water, and HK2 cells were treated with different doses of NaAsO2 for 48 h. The in vivo results showed that arsenic content in the rats' kidneys increased as the dose increased. Body weight decreased and kidney coefficient increased at 100 mg/L. As a response to the elevated NaAsO2 dose, inflammatory cell infiltration, renal tubular injury, glomerular atrophy, tubulointerstitial hemorrhage, and fibrosis became more obvious indicated by HE and Masson staining. The kidney transcriptome profiles further supported the protein-protein interactions involved in NaAsO2-induced renal fibrosis. The in vivo results, in together with the in vitro experiments, have revealed that exposure to NaAsO2 disturbed mitochondrial dynamics, promoted mitophagy, activated inflammation and the TGF-ß1/SMAD signaling pathway, and finally resulted in fibrosis. In summary, arsenic exposure contributed to renal fibrosis via regulating the mitochondrial dynamics and the NLRP3-TGF-ß1/SMAD signaling axis. This study presented an adverse outcome pathway for the development of renal fibrosis due to arsenic exposure through drinking water.
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Arsênio , Rim , Dinâmica Mitocondrial , Transdução de Sinais , Animais , Humanos , Masculino , Ratos , Arsênio/toxicidade , Linhagem Celular , Fibrose/induzido quimicamente , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Gestational diabetes mellitus (GDM) is a complex metabolic condition during pregnancy with an intricate link to gut microbiota alterations. Throughout gestation, notable shifts in the gut microbial component occur. GDM is marked by significant dysbiosis, with a decline in beneficial taxa like Bifidobacterium and Lactobacillus and a surge in opportunistic taxa such as Enterococcus. These changes, detectable in the first trimester, hint as the potential early markers for GDM risk. Alongside these taxa shifts, microbial metabolic outputs, especially short-chain fatty acids and bile acids, are perturbed in GDM. These metabolites play pivotal roles in host glucose regulation, insulin responsiveness, and inflammation modulation, which are the key pathways disrupted in GDM. Moreover, maternal GDM status influences neonatal gut microbiota, indicating potential intergenerational health implications. With the advance of multi-omics approaches, a deeper understanding of the nuanced microbiota-host interactions via metabolites in GDM is emerging. The reviewed knowledge offers avenues for targeted microbiota-based interventions, holding promise for innovative strategies in GDM diagnosis, management, and prevention.
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Per- and polyfluoroalkyl substances (PFAS) can pass through the placental barrier and pose health risks to fetuses. However, exposure and transplacental transfer patterns of emerging PFAS remain unclear. Here, 24 PFAS were measured in paired maternal whole blood (n = 228), umbilical cord whole blood (n = 119) and serum (n = 120). Orthogonal partial least-squares discriminant analysis (OPLS-DA) was used to differentiate PFAS between different matrices. The transplacental transfer (TPT) of PFAS was calculated using cord to maternal whole blood concentration ratios. PFOS and PFOA were still the dominant PFAS in maternal samples. The emerging PFAS had higher TPT than PFOS and PFOA. Moreover, PFAS with the same chain length but different functional groups and C-F bonds showed different TPT, such as PFOS and PFOSA (C8, median: 0.090 vs. 0.305, p < 0.05) and PFHxS and 4:2 FTS (C6, median: 0.220 vs. 1.190, p < 0.05). A significant sex difference in 4:2 FTS (median: boys 1.250, girls 1.010, p < 0.05) were found. Furthermore, we observed a significant U-shaped trend for the TPT of carboxylates with increasing carbon chain length. PFAS showed a compound-specific transfer through placental barrier and a compound-specific distribution between different matrices in this study.
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Ácidos Alcanossulfônicos , Poluentes Ambientais , Fluorocarbonos , Humanos , Masculino , Gravidez , Feminino , Estudos de Coortes , Placenta , Sangue Fetal/química , Fluorocarbonos/análise , China , Ácidos Alcanossulfônicos/análise , Poluentes Ambientais/análiseRESUMO
Nonalcoholic steatohepatitis (NASH) is multifactorial that lifestyle, genetic, and environmental factors contribute to its onset and progression, thereby posing a challenge for therapeutic intervention. Nanoplastic (NP) is emerged as a novel environmental metabolism disruptor but the etiopathogenesis remains largely unknown. In this study, C57BL/6 J mice were fed with normal chow diet (NCD) and high-fat diet (HFD) containing 70 nm polystyrene microspheres (NP). We found that dietary-derived NP adsorbed proteins and agglomerated during the in vivo transportation, enabling diet-induced hepatic steatosis to NASH. Mechanistically, NP promoted liver steatosis by upregulating Fatp2. Furthermore, NP stabilized the Ip3r1, and facilitated ER-mitochondria contacts (MAMs) assembly in the hepatocytes, resulting in mitochondrial Ca2+ overload and redox imbalance. The redox-sensitive Nrf2 was decreased in the liver of NP-exposed mice, which positively regulated miR26a via direct binding to its promoter region [-970 bp to -847 bp and -318 bp to -176 bp]. NP decreased miR26a simultaneously upregulated 10 genes involved in MAMs formation, lipid uptake, inflammation, and fibrosis. Moreover, miR26a inhibition elevated MAMs-tether Vdac1, which promoted the nucleus translocation of NF-κB P65 and Keap1 and functionally inactivated Nrf2, leading to a vicious cycle. Hepatocyte-specific overexpressing miR26a effectively restored ER-mitochondria miscommunication and ameliorated NASH phenotype in NP-exposed and Keap1-overexpressed mice on HFD. The hepatic MAM-tethers/Nrf2/miR26a feedback loop is an essential metabolic switch from simple steatosis to NASH and a promising therapeutic target for oxidative stress-associated liver damage and NASH.
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Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Microplásticos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Dieta Hiperlipídica , Oxirredução , Mitocôndrias/metabolismoRESUMO
Air pollution, particularly fine particulate matter (PM2.5), poses a major threat to human health. Exercise has long been recognized as a beneficial way to maintain physical health. However, there is limited research on whether exercise can mitigate the damage caused by PM2.5 exposure. In this study, the mice were exercised on the IITC treadmill for 1 h per day, then exposed to concentrated PM2.5 for 8 h. After 2, 4 and 6-month exercise and PM2.5 exposure, the glucose tolerance and insulin tolerance were determined. Meanwhile, the corresponding indicators in epididymal white adipose tissue (eWAT), brown adipose tissue (BAT) and skeletal muscle were detected. The results indicated that PM2.5 exposure significantly increased insulin resistance (IR), while exercise effectively attenuated this response. The observations of muscle, BAT and eWAT by transmission electron microscopy (TEM) showed that PM2.5 significantly reduced the number of mitochondria in all of the three tissues mentioned above, and decreased the mitochondrial area in skeletal muscle and BAT. Exercise reversed the changes in mitochondrial area in all of the three tissues, but had no effect on the reduction of mitochondrial number in skeletal muscle. At 2 months, the expressions of Mfn2, Mfn1, OPA1, Drp1 and Fis1 in eWAT of the PM mice showed no significant changes when compared with the corresponding FA mice. However, at 4 months and 6 months, the expression levels of these genes in PM mice were higher than those in the FA mice in skeletal muscle. Exercise intervention significantly reduced the upregulation of these genes induced by PM exposure. The study indicated that PM2.5 may impact mitochondrial biogenesis and dynamics by inhibiting the SIRT1/AMPKα/PGC1-α/NRF1 pathway, which further lead to IR, glucose and lipid disorders. However, exercise might alleviate the damages caused by PM2.5 exposure.
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Resistência à Insulina , Material Particulado , Humanos , Animais , Camundongos , Material Particulado/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuína 1/farmacologia , Transdução de Sinais , Tecido Adiposo Branco/metabolismo , Glucose/metabolismoRESUMO
Arsenic containment is one of the most severe environmental problems. It has been reported that arsenic exposure could cause male reproductive damage. However, the evidence chain from sodium arsenite (NaAsO2) exposure to adverse male fertility outcomes has not been completed by molecular events. In this study, adult male rats were exposed to NaAsO2 for eight weeks via drinking water for verifying their reproductive capacity by checking the phenotypes of testis damage, sperm quality, and female pregnancy rate. H&E staining indicated testicular cells had atrophied, and necrosis was observed under transmission electron microscopy. Sperm viability tended to decrease, and sperm malformation increased. Notably, metabolites in the testes and sperm showed substantial disruption, especially sperm metabolites. The pregnancy rate tests showed that arsenic decreased male rats' reproduction, with some adverse outcomes of the increased numbers of unpregnant females. However, the fetal crown-rump length remained unaltered, indicating that the pregnancy rate was impacted by arsenic exposure but not fetal growth. On arsenic toxicometabolomics analysis, docosahexaenoic acid (DHA) in sperm was the clearest metabolic sign to correlate with the unpregnant rate. In summary, arsenic exposure can cause male infertility via the injured sperm, which results in decreased female pregnancy. The DHA information may imply the dietary intervention for improving sperm quality. Although the fetal growth of the successful pregnancy has not been affected, the changes in epigenetic phenotypes carried by sperms still need to be verified.
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Arsênio , Infertilidade Masculina , Gravidez , Humanos , Ratos , Masculino , Feminino , Animais , Testículo/metabolismo , Arsênio/toxicidade , Arsênio/metabolismo , Contagem de Espermatozoides , Sêmen , Ratos Sprague-Dawley , Espermatozoides , Infertilidade Masculina/induzido quimicamenteRESUMO
Chronic exposure to very low ambient PM2.5 has been linked to cardiovascular risks in epidemiological observation, which also brought doubts on its safety threshold. In this study, we approached this question by chronic exposure of AC16 to the non-observable acute effect level (NOAEL) PM2.5 5 µg/mL and its positive reference 50 µg/mL, respectively. The doses were respectively defined on the cell viabilities >95% (p = 0.354) and >90% (p = 0.004) when treated acutely (24 h). To mimic the long-term exposure, AC16 was cultured from the 1st to 30th generations and treated with PM2.5 24 h in every three generations. The integration of proteomic and metabolomic analysis was applied, and 212 proteins and 172 metabolites were significantly altered during the experiments. The NOAEL PM2.5 induced both dose- and time-dependent disruption, which showed the dynamic cellular proteomic response and oxidation accumulation, the main metabolomics changes were ribonucleotide, amino acid, and lipid metabolism that have involved in stressed gene expression, and starving for energy metabolism and lipid oxidation. In summary, these pathways interacted with the monotonically increasing oxidative stress and led to the accumulated damage in AC16 and implied that the safe threshold of PM2.5 may be non-existent when a long-term exposure occurred.
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Aqueous environments are generally thought to be a source of pooling and re-distribution for both micro-plastics (MPs) and nano-plastics (NPs); however, significantly less data on NPs than MPs have been reported. The occurrence of salts, proteins, and other organic matter may promote or inhibit the aggregation of NPs to form agglomeration particles, making their detection more difficult. In this study, 80 and 500 nm polystyrene nano-plastics (PS-NPs) modified by four different functional groups (PS-Bare, PS-COOH, PS-NH2, and PS-CHO-500 nm) were selected to mimic the flocculation and/or sedimentation of NPs in salts (NaCl, CaCl2, and Na2SO4) and protein solutions. The results showed that the 80 nm PS-NPs are only colloidal in pure water. All four strong electrolyte solutions that were tested significantly promoted the aggregation of PS-NPs, including those that were protein-coated. In addition, 500 nm PS-CHO did not flocculate but gradually settled into sedimentation. Therefore, Raman spectrometry can be used to analyze assembled PS-NPs, but is not suitable for analyzing normal PS-NPs. By combining fractal morphology, this study provides insight into the comprehensive analysis of PS-NPs in water solutions, including the digestion of biological samples.
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Microplásticos , Poluentes Químicos da Água , Poliestirenos/química , Sais , Íons , Cloreto de Sódio , Poluentes Químicos da Água/análiseRESUMO
Background: Caesarean section (CS) is associated with newborns' health risks due to the blocking of microbiome transfer. The gut microbiota of CS-born babies was different from those born vaginally, which may be attributed to reduced exposure to maternal vaginal microbes during labour. To understand the microbial transfer and reduce CS disadvantages, the effect of vaginal microbiota exposure on infant gut microbiota composition was evaluated using 16s rDNA sequencing-based techniques. Results: Pregnant women were recruited in the Women and Children's Hospital, School of Medicine, Xiamen University from June 1st to August 15th, 2017. Maternal faeces (n = 26), maternal vaginal fluids (n = 26), and neonatal transitional stools (n = 26) were collected, while the participants underwent natural delivery (ND) (n = 6), CS (n = 4) and CS with the intervention of vaginal seedings (I) (n = 16). 26 mothers with the median age 26.50 (25.00-27.25) years showed no substantial clinical differences. The newborns' gut microbiota altered among ND, CS and I, and clustered into two groups (PERMANOVA P = 0.001). Microbial composition of ND babies shared more features with maternal vaginal samples (PERMANOVA P = 0.065), while the microbiota structure of ND babies was obviously different from that of sample of maternal faeces. The genus Bacteroides in CS-born babies with intervention approached to vaginal-born neonates, compared with CS-born neonates without intervention. Conclusions: Neonatal gut microbiota was dependent on the delivery mode. And the gut microbiota CS newborns with vaginal seeding shared more features with those of ND babies, which hinted the aberrant gut microbiota composition initiated by CS might be partly mitigated by maternal vaginal microbiota exposure.
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Microbioma Gastrointestinal , Microbiota , Lactente , Criança , Recém-Nascido , Humanos , Feminino , Gravidez , Adulto , Cesárea , FezesRESUMO
Bisphenol F (BPF), BPS and BPAF are gaining popularity as main substitutes to BPA, but there is no clear evidence that these compounds disrupt glycemic homeostasis in the same way. In this study, four bisphenols were administered to C57BL/6 J mice, and showed that the serum insulin was elevated in the BPA and BPS exposed mice, whereas BPF exposed mice exhibited lower serum insulin and higher blood glucose. BPF decreased oxidized glutathione/reduced glutathione ratio (GSSG/GSH) and N6-methyladenosine (m6A) levels, which was responsible for pancreatic apoptosis in mice. Additionally, the downregulation of Nrf2 and the aberrant regulation of the p53-lncRNA H19 signaling pathway further increased miR-200 family in the BPF-exposed pancreas. The miR-200 family directly suppressed Mettl14 and Xiap by targeting their 3' UTR, leading to islet apoptosis. Antioxidant treatment not only elevated m6A levels and insulin contents but also suppressed the miR-200 family in the pancreas, ultimately improving BPF-induced hyperglycemia. Taken together, miR-200 family could serve as a potential oxidative stress-responsive regulator in the pancreas. And moreover, we demonstrated a novel toxicological mechanism in that BPF disrupted the Keap1-Nrf2 redox system to upregulate miR-141/200b/c which controlled pancreatic insulin production and apoptosis via Mettl14 and Xiap, respectively. As the major surrogates of BPA in various applications, BPF was also diabetogenic, which warrants attention in future research.
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Hiperglicemia , MicroRNAs , Animais , Camundongos , Camundongos Endogâmicos C57BL , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2/genética , Sulfonas , Compostos Benzidrílicos/toxicidade , Estresse Oxidativo , Insulina , Oxirredução , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Pâncreas , MicroRNAs/genéticaRESUMO
Millions of people are at risk of consuming arsenic (As) contaminated drinking water in Pakistan. The current study aimed to investigate urinary arsenic species [iAsIII, iAsV, dimethylarsinic acid (DMA), methylarsonic acid (MMA)] and their potential toxicity biomarkers (based on urinary metabolome) in order to characterize the health effects in general adult male participants (n = 588) exposed to various levels of arsenic in different floodplain areas of Pakistan. The total urinary arsenic concentration (mean; 161 µg/L) of studied participants was lower and/or comparable than those values reported from other highly contaminated regions, but exceeded the Agency for Toxic Substances and Disease Registry (ATSDR) limits. For all the participants, the most excreted species was DMA accounting for 65% of the total arsenic, followed by MMA (20%) and iAs (16%). The percentage of MMA detected in this study was higher than those of previously reported data from other countries. These results suggested that studied population might have high risk of developing arsenic exposure related adverse health outcomes. Furthermore, random forest machine learning algorithm, partial correlation and binary logistic regression analysis were performed to screen the arsenic species-related urinary metabolites. A total of thirty-eight metabolites were extracted from 2776 metabolic features and identified as the potential arsenic toxicity biomarkers. The metabolites were mainly classified into xanthines, purines, and amino acids, which provided the clues linking the arsenic exposure with oxidative stress, one-carbon metabolism, purine metabolism, caffeine metabolism and hormone metabolism. These results would be helpful to develop early health warning system in context of arsenic exposure among the general populations of Pakistan.
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Arsênio , Arsenicais , Adulto , Masculino , Humanos , Arsênio/análise , Paquistão , Arsenicais/análise , Ácido Cacodílico , Biomarcadores/metabolismo , Metaboloma , Exposição Ambiental/análiseRESUMO
Organic pollutants (OPs) including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and polycyclic aromatic hydrocarbons (PAHs) have showed neuro-damaging effects, but studies concerning the autism spectrum disorder (ASD) risk are limited. A case-control study with ASD (n = 125) and healthy control (n = 125) children was conducted on the different land use settings across Punjab, Pakistan. Serum concentrations of 26 OCPs, 29 PCB congeners, 11 PBDEs and 32 PAHs were measured. Serum PCB77 (AOR = 2.00; 95% CI: 1.43, 2.18), PCB118 (AOR = 1.49; 95% CI: 1.00, 2.00), PCB128 (AOR = 1.65; 95% CI: 1.01, 1.91), PCB153 (AOR = 1.80; 95% CI: 1.55, 1.93) were significantly higher, but PCB187 (AOR = 0.37; 95% CI: 0.24, 0.49) was significantly lower in the ASD cases when compared to the controls. Serum BDE99 (AOR = 0.48; 95% CI: 0.26, 0.89) was significantly higher in the healthy controls than in the ASD cases. Among the analyzed OCPs, p,p'-DDE (AOR = 1.50; 95% CI: 1.00, 1.85) was significantly elevated in the ASD cases with comparison in the controls. For PAHs, serum dibenzothiophene (AOR = 7.30; 95% CI: 1.49, 35.85) was significantly higher in the ASD, while perylene (AOR = 0.25; 95% CI: 0.06, 1.10) and fluorene (AOR = 0.21; 95% CI: 0.06, 0.72) were significantly higher in the controls. In addition, many of the serum pollutants were significantly associated with GSTT1, GSTM1 (null/present polymorphism) and presented the genotypic variation to respond xenobiotics in children. The children living in proximity to urban and industrial areas had a greater exposure to most of the studied pollutants when compared to the rural children, however children residing in rural areas showed higher exposure to OCPs. This comprehensive study documents an association between environmental exposure risk of several organic pollutants (OPs) from some contaminated environmental settings with ASD risk in children from Pakistan.
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Transtorno do Espectro Autista , Poluentes Ambientais , Hidrocarbonetos Clorados , Praguicidas , Bifenilos Policlorados , Hidrocarbonetos Policíclicos Aromáticos , Criança , Humanos , Éteres Difenil Halogenados/análise , Transtorno do Espectro Autista/epidemiologia , Estudos de Casos e Controles , Hidrocarbonetos Clorados/análise , Bifenilos Policlorados/análise , Praguicidas/análise , Monitoramento AmbientalRESUMO
Humans are simultaneously and constantly exposed to various lipophilic chain phthalate acid esters. The association of urinary phthalate metabolites with altered male steroid hormone synthesis and metabolism was examined using epidemiology and toxicology studies. We measured 8 phthalate metabolites [monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), mono-n-octylphthalate (MOP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono (2-ethyl-5-oxohexyl) phthalate (MEOHP)] and two sex hormones [testosterone (T) and estradiol (E2)] in single serum and repeated spot urine samples among 451 reproductive-age males. Moreover, in vitro experiments with Leydig cell MLTC-1 steroidogenesis and liver cell HepG2 efflux in response to mixed and individual phthalates were designed to simulate real-world scenarios of human exposure. As a joint mixture, the phthalate metabolite was inversely associated with serum T and E2 concentrations but positively associated with urinary T and E2 concentrations. Combined with in vitro experiments, DEHP metabolites were identified as the predominant contributor to the decline in hormone synthesis, and ATP-binding cassette (ABC) gene activation might be involved in hormone excretion. Exposure to environmentally relevant phthalates was associated with both altered steroid synthesis and excretion, which provides additional insights into the endocrine-disrupting potential of phthalates.
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Poluentes Ambientais , Ácidos Ftálicos , Exposição Ambiental , Poluentes Ambientais/metabolismo , Hormônios , Humanos , Masculino , Ácidos Ftálicos/metabolismo , Reprodução , EsteroidesRESUMO
Few studies have reported the accumulation of non-observable acute effect (NOAE) of PM2.5, especially exposure to the NOAE doses (NOAEDs) of PM2.5 in chronic way. To address this issue, HUVECs were cultured from the 1st to 30th generations (G1 to G30) and treated by the NOAED PM2.5 once every three passages. The generational changes of oxidative damage markers, inflammatory factors, and cell adhesion molecules (CAMs) were monitored in HUVECs at G6, G12, G18, G24, and G30, and proteomes at G18 and G30, respectively. The oxidative damages monotonically accumulated with exposure time elongation and PM2.5 dose increases. Similar to the oxidative trends, VCAM1 and ICAM1 significantly and dose-dependently increased at G30. However, many inflammatory factors altered with complex patterns to respond the NOAEDs' PM2.5. Proteomic results demonstrated most proteins expressed stably, and the generational proteome alterations were more apparent than the NOAEDs' PM2.5 induced ones. The PM2.5-related proteins varied much, but only few can cross the doses and generations. These observations suggested that the proteins changed holistically rather than individually. In summary, SOD1, SUMO2, and H3F3A may initiate HUVECs responses to PM2.5, and then broadcast and accumulate the NOAE via DNA repair, immune response, and glycolysis.
Assuntos
Poluentes Atmosféricos , Material Particulado , Poluentes Atmosféricos/toxicidade , Oxirredução , Estresse Oxidativo , Material Particulado/toxicidade , ProteômicaRESUMO
Indoor particulate matter (PM) and black carbon (BC) are associated with adverse cardiopulmonary effect. However, the cumulative and interactive effects of the mixture of size-fractioned PMs and BC on cardiopulmonary function are not well understood, and the underlying biological mechanisms remain unclear. This repeated-measure study was conducted to assess the joint cardiopulmonary effect and metabolic mechanisms of multiple-size particles and BC among 46 children. PM0.5, PM1, PM2.5, PM5, PM10 and BC were monitored for 5 weekdays. Cardiorespiratory function measurements and urine samples collection were conducted three times. Untargeted-metabolomics and meet-in-metabolite approach were applied to mechanism investigation. Bayesian machine kernel regression was adopted to analyze associations among PMs, cardiopulmonary function and metabolites. Lung function and heart rate variability significantly decreased with the increased PMs and BC co-exposure (p < 0.05). The effective particles were BC, PM1-2.5 and PM0.5 in turn. No interaction effects of different particles on cardiopulmonary function were observed at different lag days. BC-related glucose and fatty acid increase, and PM1-2.5-related branched-chain amino acid degradation were primarily observed. Other metabolisms were successively disturbed. The greatest joint effects of PMs and BC on metabolism were mainly at lag0 and lag01 day. They occurred earlier than the strongest effects on cardiopulmonary function, which were at lag01 and lag02 day. BC, PM1-2.5 and PM0.5 were mainly associated with cardiorespiratory indices by disturbing amino acids, glucose, lipid, isoflavone and purine metabolism. Mitochondrial productivity and antioxidation reduction are pivotal to the relevant metabolic alterations. More attention should be paid to BC and smaller-size PMs to control indoor PM pollution and its adverse effect on children.