TERT-independent telomere elongation and shelterin dysregulation after pulmonary exposure to stainless-steel welding fume in-vivo.

Telomeres are inert DNA sequences (TTAGGG) at the end of chromosomes that protect genetic information and maintain DNA integrity. Emerging evidence has demonstrated that telomere alteration can be closely related to occupational exposure and the development of various disease conditions, including cancer. However, the functions and underlying molecular mechanisms of telomere alteration and shelterin dysregulation after welding fume exposures have not been broadly defined. In this study, we analyzed telomere length and shelterin complex proteins in peripheral blood mononuclear cells (PBMCs) and in lung tissue recovered from male Sprague-Dawley rats following exposure by intratracheal instillation (ITI) to 2 mg/rat of manual metal arc-stainless steel (MMA-SS) welding fume particulate or saline (vehicle control). PBMCs and lung tissue were harvested at 30 d after instillation. Our study identified telomere elongation and shelterin dysregulation in PBMCs and lung tissue after welding fume exposure. Mechanistically, telomere elongation was independent of telomerase reverse transcriptase (TERT) activation. Collectively, our findings demonstrated that welding fume-induced telomere elongation was (a) TERT-independent and (b) associated with shelterin complex dysregulation. It is possible that an alteration of telomere length and its regulatory proteins may be utilized as predictive biomarkers for various disease conditions after welding fume exposure. This needs further investigation.

Urban and Rural Mpox Incidence Among Persons Aged 15-64 Years - United States, May 10-December 31, 2022.

During May 10-December 31, 2022, a total of 29,980 confirmed and probable† U.S. monkeypox (mpox) cases were reported to CDC, predominantly in cisgender adult men reporting recent same-gender sexual partners (1). Urban-rural differences in health (2) and diagnosis of HIV (3,4) and other sexually transmitted infections (5) are well documented nationally. This report describes urban-rural differences in mpox incidence (cases per 100,000 population) among persons aged 15-64 years, by gender and race and ethnicity. Urbanicity was assessed using the 2013 National Center for Health Statistics (NCHS) Urban-Rural Classification Scheme for Counties (2). Substantial differences in incidence by urbanicity, gender, and race and ethnicity were observed; most (71.0%) cases occurred in persons residing in large central urban areas. Among the cases in large central urban areas, most (95.7%) were in cisgender men. The overall incidence of mpox in the United States was 13.5 per 100,000 persons aged 15-64 years and peaked in August in both urban and rural areas. Among cisgender men, incidence in rural areas was approximately 4% that in large central urban areas (risk ratio [RR] = 0.04). Among cisgender women, incidence in rural areas was approximately 11% that in large central urban areas (RR = 0.11). In both urban and rural areas, incidence among non-Hispanic Black or African American (Black) and Hispanic or Latino (Hispanic) persons was consistently higher than that among non-Hispanic White (White) persons; RRs between Black and White persons were highest in rural areas. Support and maintenance of mpox surveillance and prevention efforts including vaccinations should focus on urban areas with the highest incidence of mpox during the 2022 outbreak; however, surveillance and prevention efforts should include all genders, persons of color, and persons residing in both urban and rural areas who are at increased risk for mpox.

Profiling Metal-Induced Genotoxic Endpoints.

Many toxic metals are involved in the initiation and progression of DNA damage that can result in the activation of DNA damage response machinery at double- and single-stranded DNA; this response can result in global and gene-specific DNA alteration. The toxicological profiles from the Agency for Toxic Substances and Disease Registry (ATSDR) and several other studies have demonstrated the influence of metal exposure-induced genotoxic endpoints and epigenetic modifications. Our review systematically summarizes accumulating evidence from ATSDR toxicological profiles and the available literature that demonstrate a possible induction of various genotoxic endpoints and metal exposures. We include in this article studies on chromium, arsenic, nickel, lead, mercury, and zinc.

A possible relationship between telomere length and markers of neurodegeneration in rat brain after welding fume inhalation exposure.

Inhalation of welding fume (WF) can result in the deposition of toxic metals, such as manganese (Mn), in the brain and may cause neurological changes in exposed workers. Alterations in telomere length are indicative of cellular aging and, possibly, neurodegeneration. Here, we investigated the effect of WF inhalation on telomere length and markers of neurodegeneration in whole brain tissue in rats. Male Fischer-344 (F-344) rats were exposed by inhalation to stainless steel WF (20 mg/m3 x 3 h/d x 4 d/wk x 5 wk) or filtered air (control). Telomere length, DNA-methylation, gene expression of Trf1, Trf2, ATM, and APP, protein expression of p-Tau, α-synuclein, and presenilin 1 and 2 were assessed in whole brain tissue at 12 wk after WF exposure ended. Results suggest that WF inhalation increased telomere length without affecting telomerase in whole brain. Moreover, we observed that components of the shelterin complex, Trf1 and Trf2, play an important role in telomere end protection, and their regulation may be responsible for the increase in telomere length. In addition, expression of different neurodegeneration markers, such as p-Tau, presenilin 1-2 and α-synuclein proteins, were increased in brain tissue from the WF-exposed rats as compared to control. These findings suggest a possible correlation between epigenetic modifications, telomere length alteration, and neurodegeneration because of the presence of factors in serum after WF exposure that may cause extra-pulmonary effects as well as the translocation of potentially neurotoxic metals associated with WF to the central nervous system (CNS). Further studies are needed to investigate the brain region specificity and temporal response of these effects.

Inhalation of welding fumes reduced sperm counts and high fat diet reduced testosterone levels; differential effects in Sprague Dawley and Brown Norway rats.

BACKGROUND: Previous studies have shown that inhalation of welding fumes may induce pulmonary and systemic inflammation and organ accumulation of metal, to which spermatogenesis and endocrine function may be sensitive. Also obesity may induce low-grade systemic inflammation. This study aimed to investigate the effects on sperm production of inhaled metal nanoparticles from stainless steel welding, and the potential exacerbation by intake of a high fat diet. Both the inbred Brown Norway and the outbred Sprague Dawley rat strains were included to study the influence of strain on the detection of toxicity. Rats were fed regular or high fat (HF) diet for 24 weeks and were exposed to 20 mg/m3 of gas metal arc-stainless steel (GMA-SS) welding fumes or filtered air for 3 h/day, 4 days/week for 5 weeks, during weeks 7-12. Outcomes were assessed upon termination of exposure (week 12) and after recovery (week 24). RESULTS: At week 12, the GMA-SS exposure induced pulmonary inflammation in both strains, without consistent changes in markers of systemic inflammation (CRP, MCP-1, IL-6 and TNFα). GMA-SS exposure lowered daily sperm production compared to air controls in Sprague Dawley rats, but only in GMA-SS Brown Norway rats also fed the HF diet. Overall, HF diet rats had lower serum testosterone levels compared to rats on regular diet. Metal content in the testes was assessed in a limited number of samples in Brown Norway rats, but no increase was obsedrved. At week 24, bronchoalveolar lavage cell counts had returned to background levels for GMA-SS exposed Sprague Dawley rats but remained elevated in Brown Norway rats. GMA-SS did not affect daily sperm production statistically significantly at this time point, but testicular weights were lowered in GMA-SS Sprague Dawley rats. Serum testosterone remained lowered in Sprague Dawley rats fed the HF diet. CONCLUSION: Exposure to GMA-SS welding fumes lowered sperm production in two strains of rats, whereas high fat diet lowered serum testosterone. The effect on sperm counts was likely not mediated by inflammation or lowered testosterone levels. The studied reproductive outcomes seemed more prone to disruption in the Sprague Dawley compared to the Brown Norway strain.

Analysis of DDT and its metabolites in soil and water samples obtained in the vicinity of a closed-down factory in Bangladesh using various extraction methods.

This study was conducted to monitor the spread of dichlorodiphenyltrichloroethane (DDT) and its metabolites (dichlorodiphenyldichloroethylene (DDE), dichlorodiphenyldichloroethane (DDD)) in soil and water to regions surrounding a closed DDT factory in Bangladesh. This fulfillment was accomplished using inter-method and inter-laboratory validation studies. DDTs (DDT and its metabolites) from soil samples were extracted using microwave-assisted extraction (MAE), supercritical fluid extraction (SFE), and solvent extraction (SE). Inter-laboratory calibration was assessed by SE, and all methods were validated by intra- and inter-day accuracy (expressed as recovery %) and precision (expressed as relative standard deviation (RSD)) in the same laboratory, at three fortified concentrations (n = 4). DDTs extracted from water samples by liquid-liquid partitioning and all samples were analyzed by gas chromatography (GC)-electron capture detector (ECD) and confirmed by GC/mass spectrometry (GC/MS). Linearities expressed as determination coefficients (R (2)) were ≥0.995 for matrix-matched calibrations. The recovery rate was in the range of 72-120 and 83-110%, with <15% RSD in soil and water, respectively. The limit of quantification (LOQ) was 0.0165 mg kg(-1) in soil and 0.132 µg L(-1) in water. Greater quantities of DDTs were extracted from soil using the MAE and SE techniques than with the SFE method. Higher amounts of DDTs were discovered in the southern (2.2-936 × 10(2) mg kg(-1)) or southwestern (86.3-2067 × 10(2) mg kg(-1)) direction from the factory than in the eastern direction (1.0-48.6 × 10(2) mg kg(-1)). An exception was the soil sample collected 50 ft (15.24 m) east (2904 × 10(2) mg kg(-1)) of the factory. The spread of DDTs in the water bodies (0.59-3.01 µg L(-1)) was approximately equal in all directions. We concluded that DDTs might have been dumped randomly around the warehouse after the closing of the factory.

An immunoinformatic investigation on Rift Valley fever virus protein reveals possible epitopes for vaccines.

INTRODUCTION: This immunoinformatic study identified potential epitopes from the envelopment polyprotein (Gn/Gc) of Rift Valley fever virus (RVFV), a pathogenic virus causing severe fever in humans and livestock. Effective vaccination is crucial for controlling RVFV outbreaks. The identification of suitable epitopes is crucial for the development of safe and effective vaccines. METHODOLOGY: Protein sequences were obtained from the UniProt database, and evaluated through VaxiJen v2.0 to predict the B and T-cell epitopes within the RVFV glycoprotein. Gn/Gc protein sequences were analyzed with bioinformatics tools and algorithms. The predicted T-cell and B-cell epitopes were evaluated for antigenicity, allergenicity, and toxicity by the VaxiJen v2.0 system, AllerTop v2.0, and ToxinPred server, respectively. RESULTS: We employed computational methods to screen the RVFV envelopment polyprotein encompassing N-terminal and C-terminal glycoprotein segments, to discover antigenic T- and B-cell epitopes. Our analysis unveiled multiple potential epitopes within the RVFV glycoprotein, specifically within the Gn/Gc protein sequences. Subsequently, we selected eleven cytotoxic T-lymphocytes (CTL) and four helper T-lymphocytes (HTL) for population coverage analysis, which collectively extended to cover 97.04% of the world's population, representing diverse ethnicities and regions. Notably, the CTL epitope VQADLTLMF exhibited binding affinity to numerous human leukocyte antigen (HLA) alleles. The identification of glycoprotein (Gn/Gc) epitopes through this immunoinformatic study bears significant implications for advancing the development of an effective RVFV vaccine. CONCLUSIONS: These findings provide valuable insights into the immunological aspects of the disease and may contribute towards the development of broad-spectrum antiviral therapies targeting other RNA viruses with similar polymerase enzymes.

Unveiling the molecular basis of paracetamol-induced hepatotoxicity: Interaction of N-acetyl-p-benzoquinone imine with mitochondrial succinate dehydrogenase.

Background and aim: N-acetyl-p-benzoquinoneimine (NAPQI), a toxic byproduct of paracetamol (Acetaminophen, APAP), can accumulate and cause liver damage by depleting glutathione and forming protein adducts in the mitochondria. These adducts disrupt the respiratory chain, increasing superoxide production and reducing ATP. The goal of this study was to provide computational proof that succinate dehydrogenase (SDH), a subunit of complex II in the mitochondrial respiratory chain, is a favorable binding partner for NAPQI in this regard. Method: Molecular docking, molecular dynamics simulation, protein-protein interaction networks (PPI), and KEGG metabolic pathway analysis were employed to identify binding characteristics, interaction partners, and their associations with metabolic pathways. A lipid membrane was added to the experimental apparatus to mimic the natural cellular environment of SDH. This modification made it possible to develop a context for investigating the role and interactions of SDH within a cellular ecosystem that was more realistic and biologically relevant. Result: The molecular binding affinity score for APAP and NAPQI with SDH was predicted -6.5 and -6.7 kcal/mol, respectively. Furthermore, RMSD, RMSF, and Rog from the molecular dynamics simulations study revealed that NAPQI has slightly higher stability and compactness compared to APAP at 100 ns timeframe with mitochondrial SDH. Conclusion: This study serves to predict the mechanistic process of paracetamol toxicity by using different computational approaches. In addition, this study will provide information about the drug target against APAP hepatotoxicity.

Elucidation of anti-hyperglycemic activity of Psidium guajava L. leaves extract on streptozotocin induced neonatal diabetic Long-Evans rats.

BACKGROUND: Psidium guajava L (Guava) belongs to the Myrtaceae family and has been claimed to possess several pharmacological properties including antidiabetic. OBJECTIVE: This study was designed to evaluate the anti-hyperglycemic activity of P guajava L leaves aqueous extract on neonatal streptozotocin-induced type 2 diabetic model rats. METHODS: Streptozotocin was induced (90 mg/kg) intraperitoneally to 48 h old Long Evans rat pups. After three months, 18 male type-2 diabetic model rats were confirmed by OGTT (FG > 7 mmol/L). Therefore, experimental rats were divided into three groups 2) Diabetic water control (10 ml/kg), 3) Gliclazide treated (20 mg/kg), and 4) Extract treated group (1.25g/kg)] Six normal female rats comprised group 1 [Non-diabetic water control (10 ml/kg)]. All rats were treated orally with their respective treatment for 28 consecutive days. Blood samples were collected on 0 days (by tail cut method) and the end day (by cardiac puncture) of the experiment. The anti-hyperglycemic activity was evaluated by measuring fasting glucose, serum insulin, lipid profile, hepatic glycogen content, and intestinal glucose absorption by standard methods. RESULTS: The serum glucose level of extract treated group was decreased by 16% as well as significantly (p<0.05) increased the serum insulin level (M±SD, 0 day vs 28thday; 0.319 ± 0.110 vs 0.600 ± 0.348, µg/L). Moreover, the extract-treated group also significantly (p<0.05) enhanced liver glycogen content and inhibited glucose absorption from the upper intestine. Besides, a significant (p < 0.05) reduction of LDL-cholesterol level was found in the extract-treated group (M±SD, 55 ± 33 vs 14 ± 9, mg/dl) compared with baseline values where other groups did not show any statistically remarkable changes. CONCLUSION: Current study concludes that P guajava leaves aqueous extract enhances insulin secretion from pancreatic beta-cells and promotes glycogen synthesis in the liver. The extract also inhibits glucose absorption from the upper intestine and improves dyslipidemia to some extent. Therefore, possesses the potential for drug development against T2DM.

Topical metal chelation therapy ameliorates oxidation-induced toxicity in diabetic cataract.

Oxidative stress plays a critical role in cataractogenesis, the leading cause of blindness worldwide. Since transition metals generate reactive oxygen species (ROS) formation, metal chelation therapy has been proposed for treatment of cataracts. However, the effectiveness of most chelators is limited by low tissue penetrability. This study is the first to demonstrate that the topically applied divalent metal chelator ethylenediamine tetraacetic acid (EDTA) combined with the carrier and permeability enhancer methyl sulfonyl methane (MSM) ameliorates both oxidation-induced lens opacification and the associated toxic accumulation of protein-4-hydroxynonenal (HNE) adducts. Both in vitro (rat lens culture) and in vivo (diabetic rats), EDTA-MSM (1) significantly reduced lens opacification by about 40-50%, (2) significantly diminished lens epithelial cell proliferation and fiber cell swelling in early stages of cataract formation in vivo, and (3) notably decreased the levels of protein-HNE adducts. These findings have important implications specifically for the treatment of cataract and generally for other diseases in which oxidative stress plays a key pathogenic role.

Environmental exposure to POPs and heavy metals in urban children from Dhaka, Bangladesh.

Persistent organic pollutants (POPs) and heavy metals are well known environmental pollutants. Even though numerous studies have been carried out to assess human exposures to these compounds, there is still a lack of data on humans from developing countries, especially in underprivileged children. The objective of this study was to assess the exposure to POPs and heavy metals in children from Dhaka, Bangladesh. One specific aim was to investigate whether children working at, or living close to, open waste disposal sites (WDSs) were more heavily exposed than other urban children. In 2008, blood and serum were collected from 73 children aged 7-16 from five neighbourhoods. Some of the children lived and worked at WDSs (N = 31), others lived next to a WDS (N = 17), whereas some children lived far from such sites (N = 25). Blood levels of lead (B-Pb), cadmium (B-Cd), and selenium (B-Se) were determined by ICP-MS for all subjects. The metal levels were high, with B-Pb overall mean 120 µg L(-1) (range 40-220), B-Cd 0.74 µg L(-1) (0.22-4.1), and B-Se 120 µg L(-1) (81-170). There were no marked differences between children from the different neighbourhoods, or between WDS workers and other children. PCB levels were low and with no contrast between neighbourhoods, for CB-153 the overall mean was 7.0 ng g(-1) fat (2.8-51). In contrast, high levels of DDTs were observed in all children, for 4,4'-DDE 1300 ng g(-1) fat (420-4600), and for 4,4'-DDT 326 ng g(-1) fat (44-1400), indicating ongoing exposure. PBDE levels were low, and BDE-209 was quantitated mainly in children working at or living close to WDSs. In conclusion, the high levels of DDTs, lead and cadmium observed in children from Dhaka are of concern. Many children were exposed at levels where health effects have been observed, or at levels without safety margins.

Determination of chloramphenicol in meat samples using liquid chromatography-tandem mass spectrometry.

Chloramphenicol (CAP), a bacteriostatic antibiotic, is used for the treatment of bacterial infections in human and animals. Continual exposure of CAP residues into animal tissues may lead to antibiotic resistance. For the protection of humans and animals from this problem, a fast and highly sensitive analytical method based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was developed and validated in this study for the quantitative determination of CAP in poultry meat and beef samples. Quick, easy, cheap, effective, rugged, and safe (QuEChERS) method was used for the extraction of CAP residues. The developed method was validated in terms of linearity, accuracy, precision, and specificity. Poultry meat and beef samples were extracted with 20 ml water-acetonitrile (1:1, v/v) and cleaned up by MgSO4, primary secondary amine, and C18 powder. The method was found to be linear in a wide concentration range, with correlation coefficient of higher than 0.999. The repeatability and reproducibility of this method were satisfactory. The achieved limit of detection and limit of quantification were 0.16 and 0.50 ng/g, respectively. Recoveries were estimated at 5 and 10 ng/g spiking levels in the range of 99%-111% with the coefficient of variation 0.48%-12.48% for spiked samples, and the matrix enhancement effects were mild in the range of 80%-85%. In this study, the levels of CAP residue in tested real samples were found below the detection limit. The method proved to be suitable for CAP determination in all kinds of samples tested and also efficient for the application of routine analysis.

Telomeres in toxicology: Occupational health.

The ends of chromosomes shorten at each round of cell division, and this process is thought to be affected by occupational exposures. Occupational hazards may alter telomere length homeostasis resulting in DNA damage, chromosome aberration, mutations, epigenetic alterations and inflammation. Therefore, for the protection of genetic material, nature has provided a unique nucleoprotein structure known as a telomere. Telomeres provide protection by averting an inappropriate activation of the DNA damage response (DDR) at chromosomal ends and preventing recognition of single and double strand DNA (ssDNA and dsDNA) breaks or chromosomal end-to-end fusion. Telomeres and their interacting six shelterin complex proteins in coordination act as inhibitors of DNA damage machinery by blocking DDR activation at chromosomes, thereby preventing the occurrence of genome instability, perturbed cell cycle, cellular senescence and apoptosis. However, inappropriate DNA repair may result in the inadequate distribution of genetic material during cell division, resulting in the eventual development of tumorigenesis and other pathologies. This article reviews the current literature on the association of changes in telomere length and its interacting proteins with different occupational exposures and the potential application of telomere length or changes in the regulatory proteins as potential biomarkers for exposure and health response, including recent findings and future perspectives.

Using liquid chromatography mass spectrometry (LC-MS) to assess the effect of age, high-fat diet, and rat strain on the liver metabolome.

The goal of this study was to use liquid chromatography mass spectrometry to assess metabolic changes of two different diets in three distinct rat strains. Sprague-Dawley, Fischer 344, and Brown-Norway male rats were maintained on a high-fat, or regular diet for 24 weeks. Liver tissue was collected at 4, 12, and 24 weeks to assess global small molecule metabolite changes using high resolution accurate mass spectrometry coupled to ultra-high-performance liquid chromatography. The results of the global metabolomics analysis revealed significant changes based on both age and diet within all three strains. Principal component analysis revealed that the influence of diet caused a greater variation in significantly changing metabolites than that of age for the Brown Norway and Fisher 344 strains, whereas diet had the greatest influence in the Sprague Dawley strain only at the 4-week time point. As expected, metabolites involved in lipid metabolism were changed in the animals maintained on a high fat diet compared to the regular diet. There were also significant changes observed in the concentration of Tri carboxylic acid cycle intermediates that were extracted from the liver of all three strains based on diet. The results of this study showed that a high fat diet caused significant liver and metabolic changes compared to a regular diet in multiple rat strains. The inbred Fisher 344 and Brown Norway rats were more metabolically sensitive to the diet changes than outbred Sprague Dawley strain. The study also showed that age, as was the case for Sprague Dawley, is an important variable to consider when assessing metabolic changes.

Welding fume inhalation exposure and high-fat diet change lipid homeostasis in rat liver.

It is estimated that greater than 1 million workers are exposed to welding fume (WF) by inhalation daily. The potentially toxic metals found in WF are known to cause multiple adverse pulmonary and systemic effects, including cardiovascular disease, and these metals have also been shown to translocate to the liver. This occupational exposure combined with a high fat (HF) Western diet, which has been shown to cause hyperlipidemia and non-alcoholic fatty liver disease (NAFLD), has the potential to cause significant mixed exposure metabolic changes in the liver. The goal of this study was to use matrix assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) to analyze the spatial distribution and abundance changes of lipid species in Sprague Dawley rat liver maintained on a HF diet combined with WF inhalation. The results of the MALDI-IMS analysis revealed unique hepatic lipid profiles for each treatment group. The HF diet group had significantly increased abundance of triglycerides and phosphatidylinositol lipids, as well as decreased lysophosphatidic lipids and cardiolipin. Ceramide-1-phosphate was found at higher abundance in the regular (REG) diet WF-exposed group which has been shown to regulate the eicosanoid pathway involved in pro-inflammatory response. The results of this study showed that the combined effects of WF inhalation and a HF diet significantly altered the hepatic lipidome. Additionally, pulmonary exposure to WF alone increased lipid markers of inflammation.

Bioactivity of Circulatory Factors After Pulmonary Exposure to Mild or Stainless Steel Welding Fumes.

Studies suggest that alterations in circulating factors are a driver of pulmonary-induced cardiovascular dysfunction. To evaluate, if circulating factors effect endothelial function after a pulmonary exposure to welding fumes, an exposure known to induce cardiovascular dysfunction, serum collected from Sprague Dawley rats 24 h after an intratracheal instillation exposure to 2 mg/rat of 2 compositionally distinct metal-rich welding fume particulates (manual metal arc welding using stainless steel electrodes [MMA-SS] or gas metal arc welding using mild steel electrodes [GMA-MS]) or saline was used to test molecular and functional effects of in vitro cultures of primary cardiac microvascular endothelial cells (PCMEs) or ex vivo organ cultures. The welding fumes elicited significant pulmonary injury and inflammation with only minor changes in measured serum antioxidant and cytokine levels. PCME cells were challenged for 4 h with serum collected from exposed rats, and 84 genes related to endothelial function were analyzed. Changes in relative mRNA patterns indicated that serum from rats exposed to MMA-SS, and not GMA-MS or PBS, could influence several functional aspects related to endothelial cells, including cell migration, angiogenesis, inflammation, and vascular function. The predictions were confirmed using a functional in vitro assay (scratch assay) as well as an ex vivo multicellular environment (aortic ring angiogenesis assay), validating the concept that endothelial cells can be used as an effective screening tool of exposed workers for determining bioactivity of altered circulatory factors. Overall, the results indicate that pulmonary MMA-SS fume exposure can cause altered endothelial function systemically via altered circulating factors.

Effect of a High-Fat Diet and Occupational Exposure in Different Rat Strains on Lung and Systemic Responses: Examination of the Exposome in an Animal Model.

The exposome is the measure of all exposures of an individual in a lifetime and how those exposures relate to health. The goal was to examine an experimental model integrating multiple aspects of the exposome by collecting biological samples during critical life stages of an exposed animal that are applicable to worker populations. Genetic contributions were assessed using strains of male rats with different genetic backgrounds (Fischer-344, Sprague Dawley, and Brown-Norway) maintained on a regular or high-fat diet for 24 weeks. At week 7 during diet maintenance, groups of rats from each strain were exposed to stainless steel welding fume (WF; 20 mg/m3 × 3 h/d × 4 days/week × 5 weeks) or air until week 12, at which time some animals were euthanized. A separate set of rats from each strain were allowed to recover from WF exposure until the end of the 24-week period. Bronchoalveolar lavage fluid and serum were collected at 7, 12, and 24 weeks to assess general health indices. Depending on animal strain, WF exposure and high-fat diet together worsened kidney toxicity as well as altered different serum enzymes and proteins. Diet had minimal interaction with WF exposure for pulmonary toxicity endpoints. Experimental factors of diet, exposure, and strain were all important, depending on the health outcome measured. Exposure had the most significant influence related to pulmonary responses. Strain was the most significant contributor regarding the other health indices examined, indicating that genetic differences possibly drive the exposome effect in each strain.

The Late-Stage Protective Effect of Mito-TEMPO against Acetaminophen-Induced Hepatotoxicity in Mouse and Three-Dimensional Cell Culture Models.

An overdose of acetaminophen (APAP), the most common cause of acute liver injury, induces oxidative stress that subsequently causes mitochondrial impairment and hepatic necroptosis. N-acetyl-L-cysteine (NAC), the only recognized drug against APAP hepatotoxicity, is less effective the later it is administered. This study evaluated the protective effect of mitochondria-specific Mito-TEMPO (Mito-T) on APAP-induced acute liver injury in C57BL/6J male mice, and a three dimensional (3D)-cell culture model containing the human hepatoblastoma cell line HepG2. The administration of Mito-T (20 mg/kg, i.p.) 1 h after APAP (400 mg/kg, i.p.) injection markedly attenuated the APAP-induced elevated serum transaminase activity and hepatic necrosis. However, Mito-T treatment did not affect key factors in the development of APAP liver injury including the activation of c-jun N-terminal kinases (JNK), and expression of the transcription factor C/EBP homologous protein (CHOP) in the liver. However, Mito-T significantly reduced the APAP-induced increase in the hepatic oxidative stress marker, nitrotyrosine, and DNA fragmentation. Mito-T markedly attenuated cytotoxicity induced by APAP in the HepG2 3D-cell culture model. Moreover, liver regeneration after APAP hepatotoxicity was not affected by Mito-T, demonstrated by no changes in proliferating cell nuclear antigen formation. Therefore, Mito-T was hepatoprotective at the late-stage of APAP overdose in mice.

Toward Sustainable Environmental Quality: Priority Research Questions for Asia.

Environmental and human health challenges are pronounced in Asia, an exceptionally diverse and complex region where influences of global megatrends are extensive and numerous stresses to environmental quality exist. Identifying priorities necessary to engage grand challenges can be facilitated through horizon scanning exercises, and to this end we identified and examined 23 priority research questions needed to advance toward more sustainable environmental quality in Asia, as part of the Global Horizon Scanning Project. Advances in environmental toxicology, environmental chemistry, biological monitoring, and risk-assessment methodologies are necessary to address the adverse impacts of environmental stressors on ecosystem services and biodiversity, with Asia being home to numerous biodiversity hotspots. Intersections of the food-energy-water nexus are profound in Asia; innovative and aggressive technologies are necessary to provide clean water, ensure food safety, and stimulate energy efficiency, while improving ecological integrity and addressing legacy and emerging threats to public health and the environment, particularly with increased aquaculture production. Asia is the largest chemical-producing continent globally. Accordingly, sustainable and green chemistry and engineering present decided opportunities to stimulate innovation and realize a number of the United Nations Sustainable Development Goals. Engaging the priority research questions identified herein will require transdisciplinary coordination through existing and nontraditional partnerships within and among countries and sectors. Answering these questions will not be easy but is necessary to achieve more sustainable environmental quality in Asia. Environ Toxicol Chem 2020;39:1485-1505. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Molecular cloning and oxidative modification of human lens ALDH1A1: implication in impaired detoxification of lipid aldehydes.

Earlier studies showed that human lens ALDH1A1 plays a critical role in protection against oxidative stress-induced cytotoxicity in human lens epithelial cells (HLEC), and opacification of rat and mouse lens. The complete coding sequence of ALDH1A1 was cloned from human lens cDNA library by using PCR methods and expressed it in Escherichia coli. The cloned human lens ALDH1A1 cDNA encodes a 501-amino-acid protein (molecular mass = 54.8 kD) that is 100% identical to human liver ALDH1A1 and shares significant identity with the same isozyme from other tissues and species. The purified recombinant human lens ALDH1A1 exhibited optimal catalytic activity at pH 8 and preferred NAD(+) as cofactor and specifically catalyzed the oxidation of toxic lipid aldehydes such as 4-hydroxynonenal (HNE; K(m) = 4.8 microM) and malonaldehyde (K(m) MDA = 3.5 microM). Citral, disulfiram, and cyanamide were found to inhibit human lens ALDH1A1 at IC50 values of 55, 101, and 22610 microM, respectively, whereas diethylstilbestrol (DES) was found to be an activator (EC(50), 1.3 microM). Further, modification of recombinant human lens ALDH1A1 with nitric oxide donors such as S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) significantly inhibited the enzyme activity. It therefore appears that activation of ALDH1A1, which efficiently catalyzes the detoxification of lipid-derived toxic aldehydes, and/or prevention of its oxidative modification may be novel therapeutic interventions against oxidative stress-induced lens pathologies.