Cobalt Exposure Research Articles

Nonlinearity association of blood cobalt with the risk of anemia among middle-aged and older adults: National Health and Nutrition Examination Survey

ABSTRACT Objective The use of cobalt alloys in medical implants poses a high risk of cobalt exposure, yet there is a lack of evidence regarding the association between blood cobalt levels and anemia. This study aimed to explore the link between blood cobalt levels and the onset of anemia and to identify potential threshold levels of blood cobalt that could affect anemia. Methods The US National Health and Nutrition Examination Survey data from 2017 to 2020 were analyzed for this cross-sectional study. This study primarily employed multivariate logistic regression, stratified interaction analysis, restricted cubic splines (RCS), and threshold effect analysis to explore the relationship between blood cobalt concentration and anemia. Results The study included 5510 participants and among them 12.2% were diagnosed with anemia. Logistic regression model indicates a positive correlation between blood cobalt levels and the risk of anemia. RCS shows that the relationship between ln cobalt concentration and anemia was non-linear (J-shaped). The ln cobalt inflection point was approximately 0.81. The odds ratio of anemia with ln cobalt ≥ 0.81 was 4.00 (95% CI: 2.95–5.43, p < 0.001), the odds ratio of anemia with ln cobalt < 0.81 was 0.73 (95% CI: 0.45–1.18, p = 0.201). Conclusions The analysis unveiled a non-linear relationship, indicating that elevated blood cobalt levels were linked to a heightened likelihood of developing anemia in middle-aged and older adults; the cut-off value of ln cobalt was approximately 0.81. The findings of this study warrant further investigation.

Cobalt exposure and pulmonary function reduction in chronic obstructive pulmonary disease patients: the mediating role of club cell secretory protein

BackgroundCobalt (Co) is a metal which is widely used in the industrial production. The previous studies found the toxic effects of environmental Co exposure on multiple organs. However, the correlation of blood Co concentration with lung function was inconsistent in patients with chronic obstructive pulmonary disease (COPD).MethodsAll 771 stable COPD patients were recruited. Peripheral blood and clinical information were collected. The levels of blood Co and serum CC16 were measured.ResultsCross-sectional study suggested that the level of blood Co was inversely and dose-dependently related to lung function parameters. Each 1 ppm elevation of blood Co was related to 0.598 L decline in FVC, 0.465 L decline in FEV1, 6.540% decline in FEV1/FVC%, and 14.013% decline in FEV1%, respectively. Moreover, higher age, enrolled in winter, current-smoking, higher smoking amount, and inhaled corticosteroids prominently exacerbated the negative correlation between blood Co and lung function. Besides, serum CC16 content was gradually reduced with blood Co elevation in COPD patients. Besides, serum CC16 was positively correlated with lung function, and inversely related to blood Co. Additionally, decreased CC16 substantially mediated 11.45% and 6.37% Co-triggered downregulations in FEV1 and FEV1%, respectively.ConclusionBlood Co elevation is closely related to the reductions of pulmonary function and serum CC16. CC16 exerts a significantly mediating role of Co-related to pulmonary function decrease among COPD patients.

Serum Cobalt Concentration and DNA Methylation Signatures in Women with Obesity

Obesity, a multifactorial disorder, has been associated with alterations in metal metabolismand epigenetic modifications. This pilot case–control study aimed to investigate serum cobalt concentrations and associated DNA methylation patterns in women with obesity. Serum cobalt levels were measured using inductively coupled plasma mass spectrometry (ICP-MS), revealing significantly higher cobalt concentrations in participants with normal weight than in participants with obesity. Additionally, DNA methylation analysis identified differentially methylated positions (DMPs) associated with cobalt exposure, and DMPs between groups highlighted hypomethylation in the top DMPs in individuals with obesity. Functional enrichment analysis of these DMPs unveiled potential pathways implicated in apoptosis, cancer, and metabolic signaling, warranting further investigation into the mechanistic links. This study provides preliminary insights into the interplay between cobalt exposure, DNA methylation, and potential implications for obesity management.

New sensitive tools to characterize meta-metabolome response to short- and long-term cobalt exposure in dynamic river biofilm communities

Untargeted metabolomics is a non-a priori analysis of biomolecules that characterizes the metabolome variations induced by short- and long-term exposures to stressors. Even if the metabolite annotation remains lacunar due to database gaps, the global metabolomic fingerprint allows for trend analyses of dose-response curves for hundreds of cellular metabolites. Analysis of dose/time-response curve trends (biphasic or monotonic) of untargeted metabolomic features would thus allow the use of all the chemical signals obtained in order to determine stress levels (defense or damage) in organisms. To develop this approach in a context of time-dependent microbial community changes, mature river biofilms were exposed for 1 month to four cobalt (Co) concentrations (from background concentration to 1 × 10−6 M) in an open system of artificial streams. The meta-metabolomic response of biofilms was compared against a multitude of biological parameters (including bioaccumulation, biomass, chlorophyll a content, composition and structure of prokaryotic and eukaryotic communities) monitored at set exposure times (from 1 h to 28 d). Cobalt exposure induced extremely rapid responses of the meta-metabolome, with time range inducing defense responses (TRIDeR) of around 10 s, and time range inducing damage responses (TRIDaR) of several hours. Even in biofilms whose structure had been altered by Co bioaccumulation (reduced biomass, chlorophyll a contents and changes in the composition and diversity of prokaryotic and eukaryotic communities), concentration range inducing defense responses (CRIDeR) with similar initiation thresholds (1.41 ± 0.77 × 10−10 M Co2+ added in the exposure medium) were set up at the meta-metabolome level at every time point. In contrast, the concentration range inducing damage responses (CRIDaR) initiation thresholds increased by 10 times in long-term Co exposed biofilms. The present study demonstrates that defense and damage responses of biofilm meta-metabolome exposed to Co are rapidly and sustainably impacted, even within tolerant and resistant microbial communities.

Meta-metabolomic responses of river biofilms to cobalt exposure and use of dose-response model trends as an indicator of effects

The response of the meta-metabolome is rarely used to characterize the effects of contaminants on a whole community. Here, the meta-metabolomic fingerprints of biofilms were examined after 1, 3 and 7 days of exposure to five concentrations of cobalt (from background concentration to 1 × 10−5 M) in aquatic microcosms. The untargeted metabolomic data were processed using the DRomics tool to build dose-response models and to calculate benchmark-doses. This approach made it possible to use 100% of the chemical signal instead of being limited to the very few annotated metabolites (7%). These benchmark-doses were further aggregated into an empirical cumulative density function. A trend analysis of the untargeted meta-metabolomic feature dose-response curves after 7 days of exposure suggested the presence of a concentration range inducing defense responses between 1.7 × 10−9 and 2.7 × 10−6 M, and of a concentration range inducing damage responses from 2.7 × 10−6 M and above. This distinction was in good agreement with changes in the other biological parameters studied (biomass and chlorophyll content). This study demonstrated that the molecular defense and damage responses can be related to contaminant concentrations and represents a promising approach for environmental risk assessment of metals.

Exposure to cobalt metal (without tungsten carbide) and some cobalt compounds: a literature review

Cobalt is a natural metallic element with extensive applications across multiple industries, and a critical metal for lithium-ion battery production. Cobalt's only known biological function is its role as a metal component of vitamin B12. Other cobalt compounds have been described as toxic to the environment and the human body following excessive exposure. The International Agency for Research on Cancer (IARC) has classified cobalt, including cobalt metal and soluble cobalt(II) salts, as Group 2A, meaning it is probably carcinogenic to humans. This review aims to present a comprehensive overview of historical and current sources of cobalt in diverse exposure settings, along with its various intake routes. An extensive literature search was conducted between September 2021 and January 2022, analysing over 300 publications. The primary goal of these studies was to identify cobalt sources, intake routes, and exposure pathways. Workers may be exposed to various cobalt compounds and metal powders primarily through inhalation, but exposure can also occur via skin contact or ingestion. For the general population, food typically arises as the predominant source of cobalt exposure. Furthermore, exposure may occur through ambient air, tobacco smoke, and medical implants.

Association between urinary cobalt exposure and kidney stones in U.S. adult population: results from the National Health and Nutrition Examination Survey

Purpose Heavy metal exposure can cause impaired or reduced pathology in the kidneys, lungs, liver, and other vital organs. However, the relationship between heavy metal exposure and kidney stones has not been determined. The goal of this research was to determine the association between heavy metal exposure and kidney stones in a population of American adults in general. Materials and methods We evaluated 29,201 individuals (≥20 years) from the National Health and Nutrition Examination Survey (NHANES). The association between heavy metal exposure and kidney stones was verified by multiple logistic regression and restricted cubic spline (RCS) regression. Dose–response curves were generated to analyze the relationship between heavy metal concentrations and the occurrence of kidney stones. Moreover, we used propensity score matching (PSM) to exclude the effect of confounding variables. Results After a rigorous enrollment screening process, we included 8518 participants. Logistic regression showed that urinary cadmium (U-Cd) and urinary cobalt (U-Co) concentrations were significantly different in the kidney stone group before PSM (p < 0.001). Dose–response curves revealed that the occurrence of kidney stones increased significantly with increasing U-Cd and U-Co concentrations. After adjustment for covariates, only biomarkers of U-Co were linked to the occurrence of kidney stones. When the lowest quartile was used as a reference, the 95% confidence intervals (95% CIs) for kidney stones across the other quartiles were 1.015 (0.767–1.344), 1.409 (1.059–1.875), and 2.013 (1.505–2.693) for U-Cos (p < 0.001). Conclusion In the U.S. population, high U-Co levels are positively correlated with the potential risk of kidney stones.

Investigating the association between blood cobalt and gallstones: a cross-sectional study utilizing NHANES data.

With the use of cobalt alloys in medical prosthetics, the risk of cobalt exposure has increased. The objective of this study was to investigate the correlation between blood cobalt levels and the occurrence of gallstones utilizing data from the National Health and Nutrition Examination Survey (NHANES). Data collected between 2017 and 2020 were analyzed, encompassing a total of 5,610 participants. Cobalt concentrations in whole blood specimens were directly measured using inductively coupled plasma mass spectrometry (ICP-MS). The presence of gallstones was ascertained through a standardized questionnaire. To assess the association between blood cobalt levels and the presence of gallstones, logistic regression analysis, restricted cubic spline analysis, and subgroup analysis were utilized. The results of logistic regression analysis revealed a heightened risk of developing gallstones in the Quartiles 2 and Quartiles 4 groups based on blood cobalt levels when compared to the Quartiles 1 group (OR = 1.54, 95% CI: 1.15-2.07; OR = 1.35, 95% CI: 1.03-1.77). The restricted cubic spline analysis exhibited a positive linear correlation between blood cobalt levels and the occurrence of gallstones. Subgroup analyses further demonstrated a statistically significant correlation between the Quartiles 4 category of blood cobalt levels and an elevated risk of gallstones, particularly among individuals aged 60 years or older, females, those with a body mass index (BMI) equal to or exceeding 25, serum total cholesterol levels below 200 mg/dL, as well as individuals diagnosed with hypertension or diabetes. Our study findings indicate a notable association between elevated blood cobalt levels and an increased risk of gallstones. To establish a causal relationship between blood cobalt levels and the elevated risk of developing gallstones, further prospective cohort studies are warranted.

Developmental exposure to cobalt chloride affected mouse testis via altered iron metabolism in adulthood

InroductionCobalt (Co) is known to interfere with iron (Fe) metabolism that is essential for differentiating male germ cells. Our aim was to study the effect of developmental chronic cobalt exposure on mouse testis through changes in iron homeostasis in adulthood. MethodsPregnant ICR mice were exposed to 75 mg (low dose) or 125 mg (high dose)/kg b.w. cobalt chloride (CoCl2) with drinking water for 3 days before delivery and treatment continued until postnatal day 90 of the pups. Age-matched control animals obtained regular tap water. Testes of control and Co-treated mice were processed for immunohistochemistry and inductively coupled plasma mass spectrometry. Sperm count was performed. ResultsChronic CoCl2 administration resulted in significant dose-dependent Co accumulation in sera and testes of the exposed mice. Fe content also showed a significant increase in sera and testes compared to the untreated controls. Surprisingly, testes of low dose-treated mice had ∼ 2.7-fold higher Fe content compared to those exposed to the high dose. A significant dose-dependent reduction in relative testis weight by 18.8% and by 37.7% was found after treatment with low and high dose CoCl2, respectively was found. Our study demonstrated that developmental chronic exposure to CoCl2 affected cellular composition of the testis manifested by germ cell loss and low sperm count, accompanied by altered androgen response in Sertoli cells (loss of stage-specific expression of androgen receptor). A possible mechanism involved is iron accumulation in the testis that was associated with altered ferroportin-hepcidin localization in seminiferous tubules depleted in germ cells. As a protective mechanism for germ cells in condition of iron excess, ferroportin was distributed in Sertoli cells around elongating spermatids. Similar changes in expression of transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) implied that both factors of testicular Fe homeostasis are closely related. Outside the seminiferous tubules, Leydig cells localized ferroportin, hepcidin, DMT1 and TfR1 thus they could be considered as a main site for iron metabolism. ConclusionOur data suggest that Co exerts its effects on the testis by indirect mechanism possibly through alteration in Fe homeostasis.

The association of cobalturia with cobaltism symptoms a prospective blinded study of 229 post-arthroplasty patients.

Cobalt is a mitochondrial toxin, clinical cobaltism manifests with constitutional, neurologic, and cardiovascular symptomatology. Cobalt's severe toxidrome is known through case reports from extreme wear or corrosion of cobalt-chromium arthroplasty components. However, the spectrum and epidemiology of orthopedic-implant cobaltism and its relationship to duration and degree of cobalt exposure are not well defined. The relationship of urine-cobalt concentration and duration of exposure to cobalt-chromium joint implants and cobaltism symptomatology were prospectively studied in 229 patients. Subjects received a Cobaltism-Symptom-Inventory-Score (CSIS) based on a protocolized interview and examination followed by a spot urine-cobalt measurement. 129 (56%) subjects were cobalturic (urine-cobalt ≥1.0 ppb). 122 (53%) subjects had a CSIS of >2, this status significantly associates with cobalturia. Median [IQR] urine-cobalt in the subjects with a CSIS >2 was 4.1[1.1-17.0] ppb compared to 0.5[0.5-1.4] ppb in subjects with CSIS ≤ 2. Cobalturia has a sensitivity of 0.69, a specificity of 0.77, and a positive predictive value of 0.74 for a CSIS of >2. The product of years-exposed to a cobalt-chromium implant and urine-cobalt by quartiles significantly positively associates with the Cobaltism-Symptom-Inventory-Score. A urine-cobalt of ≥1 ppb likely indicates adverse systemic exposure to orthopedic-implant generated cobalt. Cobaltism severity as quantified by the CSIS significantly correlates with the product of spot urine-cobalt concentration and years-exposed to a cobalt-chromium orthopedic-implant indicating a dose-response relationship. Medical provider and public awareness of orthopedic-implant cobaltism is vital because tens-of-millions are at-risk and early cobaltism is reversible. Further use of cobalt-chromium orthopedic-implants should be questioned given cobaltism becomes clinically apparent at a spot urine-cobalt of 1 ppb or greater. Monitoring of patients with high-risk cobalt-chromium orthopedic-implants appears to be indicated.

Cobalt exposure triggers impairments in cognitive and anxiety‐like behaviors, brain oxidative stress and inflammation, and hippocampo‐amygdala histomorphological alterations: Protective role of aqueous Prosopis africana seed extract

AbstractBackgroundCobalt toxicity has become a health concern in recent years, due to overexposure resulting in neurological impairments like dementia. With a growing interest in the therapeutic roles of herbs, in toxicity research, it’s worth looking into the curative effects of aqueous Prosopis africana seed extract, a plant rich in flavonoids on cobalt‐induced dementia‐like and anxiogenic behaviour.MethodWe treated rats with Cobalt (CoCl2) or CoCl2 in combination with aqueous Prosopis africana seed extract (PAE) orally for 14 days. Control rats received distilled water for the same period. Following treatments, behavioral experiments for cognition and anxiety, analysis for oxidative stress, inflammation, histological and immunohistochemical analysis were performed.ResultResults revealed that CoCl2 reduced the exploration time, recognition index in the novel object recognition test, percentage spontaneous alternation in the Y‐maze tests, and reduced open arm entry and duration in elevated plus‐maze. However, treatment with PAE improved these parameters to levels comparable with those of the control group. Furthermore, PAE therapy reduced CoCl2‐induced surge in hydrogen peroxide, malondialdehyde, TNF‐α and IL‐1β levels in brain homogenate, while also increasing superoxide dismutase and reduced reduced‐glutathione activities. CoCl2 exposure resulted in obvious features of neurodegeneration like nuclear disintegration, nuclear shrinkage, and cytoplasmic vacuolations of the cells of the hippocampus and amygdala, with an increased expression of GFAP. The hippocampal and amygdala histology improved after PAE administration, while exacerbated GFAP expressions were attenuated.ConclusionThese findings imply that PAE may be anxiolytic and can help reduce cognitive impairments and hippocampal damage caused by CoCl2 neurotoxicity, via mechanisms that involve attenuation of oxidative stress and neuroinflammation.

The Role of Cobalt Exposure in the Incidence of Cancer: A Systematic Review and Meta-Analysis Protocol

Background: Cobalt, a versatile transition metal, has widespread industrial applications, but its potential link to cancer has raised concerns. This systematic review and meta-analysis protocol aims to investigate the relationship between cobalt exposure and cancer incidence, addressing its implications for public health and occupational safety. Methods: A comprehensive literature search will be conducted in PubMed, Scopus, and Web of Science databases up to August 2023. Eligible studies will include human participants exposed to cobalt, with cancer incidence as an outcome. Both observational and analytical study designs will be considered. Results: Quantitative meta-analysis will be performed using random-effects models to calculate pooled Incidence Rate Ratios (IRRs). Subgroup and sensitivity analyses will explore heterogeneity and potential bias. Findings will be compared with prior research to assess consistency and support. Conclusion: This systematic review and meta-analysis protocol aims to provide a comprehensive assessment of the potential association between cobalt exposure and cancer incidence. The outcomes could have significant implications for occupational health, public safety, and policy decisions.

The deficiency of N6-methyladenosine demethylase ALKBH5 enhances the neurodegenerative damage induced by cobalt

Cobalt exposure, even at low concentrations, induces neurodegenerative damage, such as Alzheimer's disease (AD). The specific underlying mechanisms remain unclear. Our previous study demonstrated that m6A methylation alteration is involved in cobalt-induced neurodegenerative damage, such as in AD. However, the role of m6A RNA methylation and its underlying mechanisms are poorly understood. In this study, both epidemiological and laboratory studies showed that cobalt exposure could downregulate the expression of the m6A demethylase ALKBH5, suggesting a key role for ALKBH5. Moreover, Methylated RNA immunoprecipitation and sequencing (MeRIP-seq) analysis revealed that ALKBH5 deficiency is associated with neurodegenerative diseases. KEGG pathway and Gene ontology analyses further revealed that the differentially m6A-modified genes resulting from ALKBH5 downregulation and cobalt exposure were aggregated in the pathways of proliferation, apoptosis, and autophagy. Subsequently, ALKBH5 deficiency was shown to exacerbate cell viability decline, motivate cell apoptosis and attenuate cell autophagy induced by cobalt with experimental techniques of gene overexpression/inhibition. In addition, morphological changes in neurons and the expression of AD-related proteins, such as APP, P-Tau, and Tau, in the cerebral hippocampus of wild-type and ALKBH5 knockout mice after chronic cobalt exposure were also investigated. Both in vitro and in vivo results showed that lower expression of ALKBH5 aggravated cobalt-induced neurodegenerative damage. These results suggest that ALKBH5, as an epigenetic regulator, could be a potential target for alleviating cobalt-induced neurodegenerative damage. In addition, we propose a novel strategy for the prevention and treatment of environmental toxicant-related neurodegeneration from an epigenetic perspective.

Cobalt induces neurodegeneration through FTO-triggered autophagy impairment by targeting TSC1 in an m6A-YTHDF2-dependent manner

Cobalt is the most widely used heavy metal pollutant in medicine and industry. Excessive cobalt exposure can adversely affect human health. Neurodegenerative symptoms have been observed in cobalt-exposed populations; however, the underlying mechanisms remain largely unknown. In this study, we demonstrate that the N6-methyladenosine (m6A) demethylase fat mass and obesity-associated gene (FTO) mediates cobalt-induced neurodegeneration by impairing autophagic flux. Cobalt-induced neurodegeneration was exacerbated through FTO genetic knockdown or repression of demethylase activity, but was alleviated by FTO overexpression. Mechanistically, we showed that FTO regulates TSC1/2-mTOR signaling pathway by targeting TSC1 mRNA stability in an m6A-YTHDF2 manner, which resulted in autophagosome accumulation. Furthermore, FTO decreases lysosome-associated membrane protein-2 (LAMP2) to inhibit the integration of autophagosomes and lysosomes, leading to autophagic flux damage. In vivo experiments further identified that central nervous system (CNS)-Fto-specific knockout resulted in serious neurobehavioral and pathological damage as well as TSC1-related autophagy impairment in cobalt-exposed mice. Interestingly, FTO-regulated autophagy impairment has been confirmed in patients with hip replacement. Collectively, our results provide novel insights into m6A-modulated autophagy through FTO-YTHDF2 targeted TSC1 mRNA stability, revealing cobalt is a novel epigenetic hazard that induces neurodegeneration. These findings suggest the potential therapeutic targets for hip replacement in patients with neurodegenerative damage.

Cobalt exposure and dyslipidemia in elderly population: the mediating role of systemic inflammation and lipid peroxidation.

Heavy metal exposure has been reported to be correlated with lipid profile alteration and dyslipidemia. While the associations between serum cobalt (Co) with lipid profile levels and risk of dyslipidemia have not been explored in elderly population, and the underlying mechanisms remain unclear. All eligible 420 elderly people were recruited in three communities of Hefei City in this cross-sectional study. Peripheral blood samples and clinical information were collected. The level of serum Co was detected through ICP-MS. The biomarkers for systemic inflammation (TNF-α) and lipid peroxidation (8-iso-PGF2α) were measured with ELISA. Each 1-unit increase of serum Co was related with 0.513mmol/L, 0.196mmol/L, 0.571mmol/L, and 0.303g/L in TC, TG, LDL-C, and ApoB, respectively. Multivariate linear and logistic regression analyses indicated that the prevalence of elevated TC, elevated LDL-C, and elevated ApoB were gradually increased according to tertiles of serum Co concentration (all P trend < 0.001). The risk of dyslipidemia was positively correlated with serum Co (OR = 3.500; 95% CI 1.630 ~ 7.517). Moreover, the levels of TNF-α and 8-iso-PGF2α were gradually risen in parallel with elevating serum Co. The elevation of TNF-α and 8-iso-PGF2α partially mediated Co-caused elevation of TC and LDL-C. Environmental Co exposure is associated with elevated lipid profile levels and dyslipidemia risk among elderly population. Systemic inflammation and lipid peroxidation partially mediate the associations of serum Co with dyslipidemia.

Cobalt exposure triggers impairments in cognitive and anxiety-like behaviors, brain oxidative stress and inflammation, and hippocampo-amygdala histomorphological alterations: Protective role of aqueous Prosopis africana seed extract.

Cobalt toxicity has become a health concern in recent years, due to overexposure resulting in neurological impairments. With a growing interest in the therapeutic roles of herbs, in toxicity research, it's worth looking into the curative effects of aqueous Prosopis africana seed extract, a plant rich in flavonoids on cobalt-induced neurotoxicity. We treated rats with CoCl2 or CoCl2 in combination with aqueous PA seed extract (PAE) orally for 14 days. Control rats received distilled water for the same period. Following treatments, behavioral experiments, analysis for oxidative stress, inflammation, and histological and immunohistochemical analysis were performed. Results revealed that CoCl2 reduced the exploration time, recognition index in the novel object recognition test, percentage spontaneous alternation in the Y-maze tests, and reduced open arm entry and duration in elevated plus-maze. However, treatment with PAE improved these parameters to levels comparable with those of the control group. Furthermore, PAE therapy reduced CoCl2-induced surge in hydrogen peroxide, malondialdehyde, TNF-α and IL-1β levels in brain homogenate, while also increasing superoxide dismutase and reduced reduced-glutathione activities. CoCl2 exposure resulted in obvious features of neurodegeneration like nuclear disintegration, nuclear shrinkage, and cytoplasmic vacuolations of the cells of the hippocampus and amygdala, with an increased expression of GFAP. The hippocampal and amygdala histology improved after PAE administration, while exacerbated GFAP expressions were attenuated. These findings imply that PAE may be anxiolytic and can help reduce cognitive impairments and hippocampal damage caused by CoCl2 neurotoxicity, via mechanisms that involve attenuation of oxidative stress and inflammation.

Environmental pathways affecting gene expression (E.PAGE) as an R package to predict gene–environment associations

The purpose of this study is to manually and semi-automatically curate a database and develop an R package that will act as a comprehensive resource to understand how biological processes are dysregulated due to interactions with environmental factors. The initial database search run on the Gene Expression Omnibus and the Molecular Signature Database retrieved a total of 90,018 articles. After title and abstract screening against pre-set criteria, a total of 237 datasets were selected and 522 gene modules were manually annotated. We then curated a database containing four environmental factors, cigarette smoking, diet, infections and toxic chemicals, along with a total of 25,789 genes that had an association with one or more of gene modules. The database and statistical analysis package was then tested with the differentially expressed genes obtained from the published literature related to type 1 diabetes, rheumatoid arthritis, small cell lung cancer, COVID-19, cobalt exposure and smoking. On testing, we uncovered statistically enriched biological processes, which revealed pathways associated with environmental factors and the genes. The curated database and enrichment tool are available as R packages at https://github.com/AhmedMehdiLab/E.PATH and https://github.com/AhmedMehdiLab/E.PAGE respectively.

Cobalt induces neurodegenerative damages through impairing autophagic flux by activating hypoxia-inducible factor-1α triggered ROS overproduction

Cobalt is an environmental toxicant, and excessive bodily exposure can damage the nervous system. Particularly, our previous study reported that low-dose cobalt (significantly less than the safety threshold) is still able to induce neurodegenerative changes. However, the underlying molecular mechanism is still insufficient revealed. Herein, we further investigate the molecular mechanism between cobalt-induced neurodegeneration and autophagy, as well as explore the interplay between hypoxia-inducible factor-1α (HIF-1α), reactive oxygen species (ROS), and autophagy in cobalt-exposed mice and human neuroglioma cells. We first reveal cobalt as an environmental toxicant to severely induce β amyloid (Aβ) deposition, tau hyperphosphorylation, and dysregulated autophagy in the hippocampus and cortex of mice. In particular, we further identify that cobalt-induced neurotoxicity is triggered by the impairment of autophagic flux in vitro experiments. Moreover, the mechanistic study reveals that cobalt exposure extremely activates HIF-1α expression to facilitate the overproduction of ROS. Then, elevated ROS can target the amino-threonine kinase (AKT)-mammalian target of rapamycin (mTOR)-Unc-51 like autophagy activating kinase 1 (ULK1) signaling pathway to participate in cobalt-induced impairment of autophagic flux. Subsequently, defected autophagy further exacerbates cobalt-induced neurotoxicity for its unable to eliminate the deposition of pathological protein. Therefore, our data provide scientific evidence for cobalt safety evaluation and risk assessment and propose a breakthrough for understanding the regulatory relationship between HIF-1α, ROS, and autophagy in cobalt-induced neurodegeneration.

The effect of taxifolin on oxidative sciatic nerve damage induced by cobalt chloride in rats: a biochemical and histopathological evaluation.

Cobalt is a trace element that increases lipid peroxidation and malondialdehyde levels and reduces the antioxidant defense mechanisms of nerve cells. High levels of cobalt exposure may cause peripheral neuropathy, but the mechanism behind this has not yet been elucidated. Taxifolin is a flavonoid whose antioxidant and anti‑inflammatory properties are well‑known. We aimed to investigate the effect of taxifolin on cobalt‑induced oxidative sciatic nerve damage. Eighteen albino male Wistar rats were assigned to three groups: Control, Cobalt, and Taxifolin + Cobalt groups. Total oxidant and total antioxidant status and levels of malondialdehyde, total glutathione, and superoxide dismutase were measured to determine the effect of taxifolin on cobalt‑induced sciatic nerve injury. The following statistically significant effect of taxifolin was observed: It prevented cobalt‑induced oxidative sciatic nerve damage by reducing malondialdehyde levels and total oxidant status and increasing total antioxidant status, total glutathione levels, and superoxide dismutase levels. In a histopathological analysis, we observed similar findings in Control and Taxifolin + Cobalt groups. We determined that taxifolin is effective in preventing cobalt‑induced oxidative damage in sciatic nerve injury.

Autophagy promotes GSDME-mediated pyroptosis via intrinsic and extrinsic apoptotic pathways in cobalt chloride-induced hypoxia reoxygenation-acute kidney injury

Cobalt is a transition element that abundantly exists in the environment. Besides direct hypoxia stress, cobalt ions indirectly induce hypoxia-reoxygenation injury (HRI), the main cause of acute kidney injury (AKI), a life-threatening clinical syndrome characterized by the necrosis of the proximal tubular epithelial cells (PTECs) and inflammation. Pyroptosis, a type of inflammatory programmed cell death, might play an essential role in HRI-AKI. However, whether pyroptosis is involved in cobalt chloride (CoCl2)-induced HRI-AKI remains unknown. Autophagy is a cellular biological process maintaining cell homeostasis that is involved in cell damage in AKI, yet the underlying regulatory mechanism of autophagy on pyroptosis has not been fully understood. In this study, the in vitro and in vivo models of CoCl2-induced HRI-AKI were established with HK-2 cell line and C57BL/6J mouse. Pyroptosis-related markers were detected with western blotting and immunofluorescence assays, and results showed that gasdermin E (GSDME)-mediated pyroptosis was involved in the cell damage in HRI-AKI. Specific chemical inhibitors of caspase 3, caspase 8, and caspase 9 significantly inhibited GSDME-mediated pyroptosis, verifying that GSDME-mediated pyroptosis was induced via the activation of caspase 3/8/9. The western blotting and immunofluorescence assays were adopted to detect the accumulation of the autophagosomes, and results suggested that HRI increased the autophagic level. The effects of autophagy on apoptosis and pyroptosis were evaluated using lentivirus transfection assays to knock down autophagy-specific genes atg5 and fip200, and results demonstrated that autophagy induced GSDME-mediated pyroptosis via apoptotic pathways in HRI-AKI. Our results revealed the involvement of GSDME-mediated pyroptosis in CoCl2-induced HRI-AKI and promoted the understanding of the regulatory mechanism of GSDME cleavage. Our study might provide a potential therapeutic target for HRI-AKI, and will be helpful for the risk evaluation of cobalt exposure.