Abstract  This study investigated nickel and cobalt ion release from the metals and several alloys in synthetic gastric, as well as interstitial and lysosomal lung fluids. Results were used to calculate the relative bioaccessible concentrations (RBCs) of the metals. Nickel release from SS 316L powder in gastric fluid was >300-fold lower than from a simple mixture of powders of the same bulk composition. Gastric bioaccessibility data showed 50-fold higher metal releases per gram of sample from powder than massive forms. RBCs of nickel and cobalt in the alloy powders were lower, equal, or higher in all fluids tested than their bulk concentrations. This illustrates the fact that matrix effects can increase or decrease the metal ion release, depending on the metal ingredients, alloy type, and fluid, consistent with research by others. Acute inhalation toxicity studies with cobalt-containing alloy powders showed that the RBC of cobalt in interstitial lung fluid predicted acute toxicity better than bulk concentration. This example indicates that the RBC of a metal in an alloy may estimate the concentration of bioavailable metals better than the bulk concentration, and the approach may provide a means to refine the classification of alloys for several human health endpoints.

Abstract  BACKGROUND: Disturbances in the homeostasis of essential trace elements (ETEs) may interfere with embryonic organogenesis. However, the effect of ETEs on the development of orofacial clefts (OFCs) remains unclear.

OBJECTIVES: This study examined associations between concentrations of iron (Fe), zinc (Zn), selenium (Se), cuprum (Cu), cobalt (Co), and molybdenum (Mo) in maternal serum and risk for OFCs in offspring.

METHODS: A total of 130 cases of OFCs and 260 nonmalformed controls were included in this study. Concentrations of Fe, Zn, Se, Cu, Co, and Mo in maternal serum were detected by inductively coupled plasma mass spectrometry. We examined associations between levels of the six ETEs in maternal serum and risk for OFCs for each element separately using multilevel mixed-effects logistic regression and for all elements collectively using Bayesian kernel machine regression (BKMR).

RESULTS: Higher concentrations of Mo and Co in maternal serum were associated with a decreased risk for OFCs in a dose-dependent manner, with odds ratios and 95% confidence intervals of 0.37 (0.20-0.66) for the second tertile of Mo, 0.28 (0.15-0.54) for the third tertile of Mo, 0.54 (0.29-1.00) for the second tertile of Co, and 0.47 (0.25-0.87) for the third tertile of Co, with the lowest tertile as the referent. When all six ETEs were considered together, increased levels of ETEs were associated with a decreased risk for OFCs. In addition, Mo showed a protective effect against risk for OFCs when the other ETEs were fixed at their 25th, 50th, or 75th percentile, whereas the protective effect of Co turned to a null effect in the BKMR model. No association was observed between levels of Fe, Zn, Se, or Cu and risk for OFCs in either statistical model.

CONCLUSION: Elevated concentrations of Mo in maternal serum were associated with a reduced risk for OFCs.

Abstract  Adipose tissue (AT) expansion induces local hypoxia, a key contributor to the chronic low-grade inflammation that drives obesity-associated disease. Apple flavonols phloretin (PT) and phlorizin (PZ) are suggested anti-inflammatory molecules but their effectiveness in obese AT is inadequately understood. Using in vitro models designed to reproduce the obese AT microenvironment, 3T3-L1 adipocytes were cultured for 24 h with PT or PZ (100 μM) concurrent with the inflammatory stimulus lipopolysaccharide (LPS; 10 ng/mL) and/or the hypoxia mimetic cobalt chloride (CoCl2; 100 μM). Within each condition, PT was more potent than PZ and its effects were partially mediated by peroxisome proliferator-activated receptor (PPAR)-γ (p < 0.05), as tested using the PPAR-γ antagonist bisphenol A diglycidyl ether (BADGE). In LPS-, CoCl2-, or LPS + CoCl2-stimulated adipocytes, PT reduced mRNA expression and/or secreted protein levels of inflammatory and macrophage chemotactic adipokines, and increased that of anti-inflammatory and angiogenic adipokines, which was consistent with reduced mRNA expression of M1 polarization markers and increased M2 markers in RAW 264.7 macrophages cultured in media collected from LPS + CoCl2-simulated adipocytes (p < 0.05). Further, within LPS + CoCl2-stimulated adipocytes, PT reduced reactive oxygen species accumulation, nuclear factor-κB activation, and apoptotic protein expression (p < 0.05). Overall, apple flavonols attenuate critical aspects of the obese AT phenotype.

Abstract  Cobalt has been known for its neurotoxicity in numerous studies. However, the molecular mechanism underlying cobalt-induced neurotoxicity remains largely unknown. In this study, two neuroblastoma (SHSY5Y and N2a) cell lines and a phaeochromocytoma (PC12) line were used as in vitro models. Cells were treated for 24 h with 50, 100, 200, 300, 400 µM cobalt chloride (CoCl2) or cultured with 300 μM CoCl2 for 4, 8, 12 and 24 h to investigate the effects of histone acetylation on CoCl2-induced neurodegenerative damages. Our findings demonstrate that CoCl2 suppresses the acetylation of histone H3 and H4 in a time-dependent and dosage-dependent manner. Furthermore, CoCl2 selectively decreases the expression and activity of histone acetyltransferase (HAT) but has no effects on histone deacetylase (HDAC) in SHSY5Y cells. More importantly, we show that 100 ng/mL HDAC inhibitor trichostatin (TSA) pre-treatment partly attenuates 300 μM CoCl2-induced neurodegenerative damages in SHSY5Y cells. Mechanistic analyses show that CoCl2-induced neurodegenerative damages are associated with the dysfunction of APP, BACE1, PSEN1, NEP and HIF-1α genes, whose expression are partly mediated by histone modification. In summary, we demonstrate that histone acetylation is involved in CoCl2-induced neurodegenerative damages. Our study indicates an important connection between histone modification and the pathological process of neurodegenerative damages and provides a mechanism for cobalt-mediated epigenetic regulation.

Abstract  The present research evaluated the course of cobalt and chromium in the blood and urine after the revision of metal-on-metal with a ceramic-on-polyethylene total hip arthroplasty. Seven patients were enrolled for hip prosthesis revision owing to ascertained damage of the implant. Metals in the blood and urine were evaluated before and after the hip revision. The double measurement before the total hip revision revealed high levels of metal ions (on average, 88.1 µg/L of cobalt in the blood, 399.0 µg/g of creatinine cobalt in the urine, 46.8 µg/L of chromium in the blood, and 129.6 µg/g of creatinine chromium in the urine at the first measurements), with an increasing trend between the first and second dosage. Within a week after the hip revision, the levels of metal ions significantly decreased by approximately half. Four to six months after the operation, the cobalt levels were found near to the reference values, whereas the chromium levels reached 25% of the values measured before the revision. The revision of malfunctioning metal-on-metal implants produced a dramatic decrease of metal ions in biological fluids, although it did not completely rescue the chromium level.

Abstract  Ischemic brain injury is a dynamic process that involves oxidative stress, inflammation, and cell death, as well as activation of endogenous adaptive and regenerative mechanisms depending on activation of transcription factors such as hypoxia inducible factor 1-alpha (HIF-1alpha). Because CoCl2 activates HIF-1alpha, we described a new focal-hypoxia model by direct intracerebral CoCl2 injection. Adult male Wistar rats were intracerebrally injected with CoCl2 (2 microl-50 mM), in frontoparietal cortex of right hemisphere, and saline (2 microl) in the contralateral hemisphere. In slides of fixed brains at 1, 6, 9, 24 h or 5 day after treatment, TTC, histochemistry (toluidine blue, Hoescht-33342, TUNEL), immunostaining (HIF-1alpha, GFAP), Lycopersicon esculentum lectin staining, and electron microscopy (EM) were performed. Immediately after 1 h post CoCl2 injection, HIF-1alpha stabilization and neuronal nuclear shrinkage and cromathin condensation were observed by immunostaining and EM, respectively. Neuronal apoptotic nuclear morphology and GFAP immunoreactivity and lectin maximal reactivity were detected during 6-9 h. Ultrastructural alterations of morphology included edematous perinuclear cytoplasm, organelles and endoplasmic reticulum (RE) enlargement, mitochondrial swelling with increased matrix density, and deposits of electron-dense material. Neurons showed particular nuclear indentations. Astrocytes and oligodendrocytes presented alterations in both nuclei and RE with dilated lumen and altered mitochondrias, and all these ultrastructural changes became detectable at day 5. CoCl2 cortical injection mimics focal brain ischemia, inducing neuronal death and glial activation. This model brings the opportunity to develop focal ischemia in selected brain areas to study their functional consequences and potential pharmacological therapies for in vivo models of stroke.

Abstract  To examine sex-specific associations of neonatal and childhood exposure to eight trace elements with cognitive abilities of school-age children. The association between exposure and effects was assessed among 296 school-age children from a population-based birth cohort study, who had manganese (Mn), cadmium (Cd), and lead (Pb) exposure measured in cord blood and chromium (Cr), manganese, cobalt (Co), copper (Cu), arsenic (As), selenium (Se), cadmium, and lead exposure quantified in spot urine. Cognitive abilities were assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models were performed to analyze associations of intelligence quotient (IQ) with trace element concentrations in cord blood and urinary trace element levels. General linear models were used to evaluate association between exposure fluctuation and children's IQ. Urinary Cd concentrations were negatively associated with full-scale IQ (β = - 3.469, 95% confidence interval (CI) - 6.291, - 0.647; p = 0.016) and performance IQ (β = - 4.012, 95% CI - 7.088, - 0.936; p = 0.011) in girls; however, neonatal Cd exposure expressed as Cd concentrations in cord blood was in inverse associations with verbal IQ (β = - 2.590, 95% CI - 4.570, - 0.609; p = 0.010) only in boys. Positive association between urinary Mn concentrations and performance IQ (β = 1.305, 95% CI 0.035, 2.575; p = 0.044) of children was observed, especially in girls. In addition, inverse association of urinary Cu concentrations with verbal IQ (β = - 2.200, 95% CI - 4.360, - 0.039; p = 0.046) was only found in boys. Childhood Cd exposure may adversely affect cognitive abilities, while Mn exposure may beneficially modify cognitive abilities of school-age children, particularly in girls.

Abstract  BACKROUND: This study aimed to investigate the impact of changes in the levels of trace elements and heavy metals in threatened abortion. Threatened abortion is a common complication in early pregnancy. Previous studies have shown that changes in the levels of some trace elements and increased serum concentrations of heavy metals are associated with spontaneous abortion; however, this relationship has not been fully clarified.

METHODS: The patient group consisted of 45 pregnant women diagnosed with threatened abortion. There were 40 healthy nonpregnant women in the control group. Blood samples were obtained from the patients and the healthy controls, and the concentrations of serum trace elements and heavy metals were measured using atomic absorption spectrophotometry (AAS).

RESULTS: Statistically significant decreases were found in the serum zinc (Zn), iron (Fe), magnesium (Mg) and manganese (Mn) levels, and significant increases were found in the serum copper (Cu), cadmium (Cd) and lead (Pb) levels in cases of threatened abortion in comparison to the controls (p < 0.001). However, there was no difference between the groups in terms of the serum cobalt (Co) levels (p > 0.001).

CONCLUSION: Changes in the balance of some essential trace elements (especially decreases in Fe and Zn) and elevated concentrations of some toxic heavy metals in the blood may be important diagnostic and prognostic parameters for threatened abortionThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract  Background: Li-ion batteries (LIB) are increasingly used worldwide. They are made of low solubility micrometric particles, implying a potential for inhalation toxicity in occupational settings and possibly for consumers. LiCoO2 (LCO), one of the most used cathode material, induces inflammatory and fibrotic lung responses in mice. LCO also stabilizes hypoxia-inducible factor (HIF) -1 alpha, a factor implicated in inflammation, fibrosis and carcinogenicity. Here, we investigated the role of cobalt, nickel and HIF-1 alpha as determinants of toxicity, and evaluated their predictive value for the lung toxicity of LIB particles in in vitro assays.Results: By testing a set of 5 selected LIB particles (LCO, LiNiMnCoO2, LiNiCoAlO2) with different cobalt and nickel contents, we found a positive correlation between their in vivo lung inflammatory activity, and (i) Co and Ni particle content and their bioaccessibility and (ii) the stabilization of HIF-1 alpha in the lung. Inhibition of HIF-1 alpha with chetomin or PX-478 blunted the lung inflammatory response to LCO in mice. In IL-1 beta deficient mice, HIF-1 alpha was the upstream signal of the inflammatory lung response to LCO. In vitro, the level of HIF-1 alpha stabilization induced by LIB particles in BEAS-2B cells correlated with the intensity of lung inflammation induced by the same particles in vivo.Conclusions: We conclude that HIF-1 alpha, stabilized in lung cells by released Co and Ni ions, is a mechanism-based biomarker of lung inflammatory responses induced by LIB particles containing Co/Ni. Documenting the Co/Ni content of LIB particles, their bioaccessibility and their capacity to stabilize HIF-1 alpha in vitro can be used to predict the lung inflammatory potential of LIB particles.

Abstract  In low-income and middle-income countries such as Iran, smoking is becoming increasingly popular, especially among young people. This has led to additional exposure to a variety of substances, including metals which may exert a toxic influence and lead to severe diseases. In order to evaluate the influence of smoking on metal concentrations, a case-control study of levels of metal in urine was carried out in smokers (n = 64) and non-smokers (n = 35) from the city of Birjand (Iran). They were divided according to their age and socioeconomic status. Concentrations of cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), nickel (Ni), lead (Pb), and zinc (Zn) were measured using ET-AAS. We found higher concentrations of Cd (0.03 vs. 0.12 μg/L), Co (0.6 vs. 1.22 μg/L), and Cr (14.00 vs. 18.17 μg/L) in the urine of smokers. Age and occupation are factors that also influence the levels of metals. Young smokers demonstrate higher Cd and Pb levels than other age groups. It would also appear that public sector workers and self-employed are the sectors most susceptible to high levels of metals.

Abstract  OBJECTIVES: There is an epidemic of Mesoamerican nephropathy (MeN) in Central America, where sugarcane production is prominent. Numerous causes are proposed, but to date limited evidence supports any one hypothesis. A nested case-control study using biosamples from a rural, community-based follow-up study of 350 young adults from Northwest Nicaragua at risk of MeN was conducted with the aim of characterising the associations between urinary concentrations of metals, pesticides and mycotoxins from samples collected in the first 6 months and decline in kidney function over 2 years.

METHODS: Urine samples collected at baseline (pre-sugarcane harvest) and the first 6 month follow-up (post-sugarcane harvest) visit were tested. Twelve metals and metalloids (aluminium, total arsenic, cadmium, chromium, cobalt, copper, lead, manganese, mercury, selenium, silicon and strontium) were analysed by inductively coupled plasma-mass spectrometry. Twelve pesticides or their metabolites (2,4-dichlorophenoxyacetic acid, 3-phenoxybenzoic acid, 4-fluoro-3-phenoxybenzoic acid, chloro-3,3,3-trifluoro-1-propen-1-yl-2,2-dimethylcyclopropanecarboxylic acid, cis/trans 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid, ethylenethiourea, glyphosate, 4-chloro-2-methylphenoxy acetic acid, 3-hydroxy-pyrimetanil, 5-hydroxytiabendazole, hydroxy-tebuconazole and 3,5,6-trichloro-2-pyridinol) and two mycotoxins (ochratoxin A (OTA) and citrinin (CIT)) were analysed by liquid chromatography coupled-mass spectrometry. Differences in the creatinine-corrected urinary concentrations of the measured exposures between outcome groups (participants with stable vs declining kidney function) were examined.

RESULTS: Elevated levels of aluminium and total arsenic as well as metabolites of several pesticides were detected across the population. No differences were identified between the declining and stable groups in the levels of metals or pesticides tested. OTA and CIT were below the limit of detection.

CONCLUSIONS: The tested metals, metalloids, pesticides and mycotoxins were not associated with loss of kidney function in participants at-risk of MeN.

Abstract  There is limited evidence on the relationships between plasma levels of multiple metals and risk of incident cancer in patients with type 2 diabetes mellitus (T2DM). We examined the associations between plasma levels of 12 metals (iron, copper, zinc, selenium, chromium, manganese, molybdenum, cobalt, nickel, arsenic, cadmium, and lead) and cancer risk in 4573 T2DM patients using Cox proportional hazards models. With a median follow-up of 10.2 years, 541 incident cancers were identified. The multiple-metals model revealed that each 1-SD increase in ln-transformed plasma copper (HR: 1.14; 95%CI: 1.02, 1.27) and lead (HR:1.20; 95%CI:1.03, 1.39) were significantly associated with increased cancer incidence while each 1-SD increase in ln-transformed plasma zinc (HR: 0.82; 95%CI: 0.71, 0.96) and chromium (HR: 0.88; 95%CI: 0.82, 0.94) were significantly associated with decreased cancer incidence. When all participants were further stratified into four subgroups by the quartile levels (Q1-4) of plasma metals, manganese showed significant positive associations with cancer incidence in the upper two quartiles (P trend = 0.003) while nickel showed significant negative associations with cancer incidence in Q2 and 4 groups (P trend = 0.033) compared with participants in Q1 group. Collectively, monitoring of metal levels in diabetic patients needs to be strengthened, which is of great significance for the prevention of incident cancer.

Abstract  Hypoxia microenvironment plays a crucial role during tumor progression and it tends to exhibit poor prognosis and make resistant to various conventional therapies. HIF-1α acts as an important transcriptional regulator directly or indirectly associated with genes involved in cell proliferation, angiogenesis, apoptosis and energy metabolism during tumor progression in hypoxic microenvironment. This study was aimed to investigate the expression pattern of the hypoxia associated genes and their association during breast cancer progression under hypoxic microenvironment in breast cancer cells.

Abstract  BACKGROUND: Kathon CG, a combination of methylchloroisothiazolinone and methylisothiazolinone, is widely used as preservative in cosmetics, as well in household cleaning products, industrial products such as paints and glues. It has emerged as an important sensitizing agent in allergic contact dermatitis.

OBJECTIVES: This study evaluated the reactivity to this substance in patients subjected to patch tests at the Dermatology Institute in Bauru, São Paulo from 2015 to 2017 and its correlation with other preservatives, the professional activity and location of the lesions.

METHODS: The patients were submitted to standard series of epicutaneous tests, standardized by the Brazilian Group Studies on Contact Dermatitis.

RESULTS: Out the 267 patients tested, 192 presented positivity to at least one substance and 29 of the patients (15.10%) presented reaction to Kathon CG, with predominance of the female gender (n=27); main professional activity associated with Kathon CG sensibilization was cleaning (17.24%), followed by aesthetic areas (13.79%) and health care (10.34%). The most prevalent sensitizations among the substances tested were nickel sulphate (56.3%), followed by cobalt chloride (23.4%), neomycin (18.2%), potassium dichromate (17.7%), thimerosal (14.5%), formaldehyde (13.2%), paraphenylenediamine (9.3%), and fragrance mix (8.3%).

STUDY LIMITATIONS: We do not have data from patients that were submitted to patch test a decade ago in order to confront to current data and establish whether or no sensitization to Kathon CG has increased.

CONCLUSION: High positivity to Kathon CG corroborates the recent findings in the literature, suggesting more attention to concentration of this substance, used in cosmetics and products for domestic use.

Abstract  BACKGROUND: Dermatological services in Laos, South East Asia are limited mainly to the capital and patch testing is currently not available, so no data exists regarding the common cutaneous allergens in this population.

OBJECTIVES: The aim of this study was to document common allergens in paediatric patients with atopic dermatitis attending the allergy clinic in the capital, Vientiane.

PATIENTS/MATERIALS/METHODS: Fifty paediatric patients with atopic dermatitis were patch tested using TRUE Test® panels 1 to 3 (35 allergens). Readings were taken at Days 2 and 4.

RESULTS: Twenty-six positive patch tests were recorded on Day 4 in 15 children (30%). The most common allergens were: gold (18%), nickel (10%), formaldehyde (6%) and p-Phenylenediamine (6%). Other positive allergens were potassium dichromate (2%), cobalt dichloride (2%), Bronopol (2%), paraben mix (2%), fragrance mix 1 (2%) and neomycin (2%). The majority of the patients with positive reactions were female.

CONCLUSIONS: This study represents the first documented patch test results in the Lao population. It is hoped that these findings will help clinicians to advise the families of children with atopic dermatitis on common allergens to avoid and inform future work on contact dermatitis in this population.

Abstract  BACKGROUND: Metal(loid)s have been associated to adverse birth outcomes in experimental and epidemiological studies, but the underlying mechanism(s) are not well understood. Endocrine disruption may be a mechanism by which the metal(loid)s impact birth outcomes.

METHODS: Pregnant women were recruited through the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT). Urine, blood, demographic and pregnancy-related data were collected at recruitment and subsequent visits. Sixteen metal(loid)s were analyzed in urine and blood samples, while nine maternal hormones (corticotropin-releasing hormone (CRH), sex-hormone binding globulin (SHBG), estriol (E3), progesterone, testosterone, thyroid-stimulating hormone (TSH), total triiodothyronine (T3), total thyroxine (T4), and free thyroxine (fT4)) were measured in serum samples from 815 singleton pregnancies. Linear mixed models with random intercepts were used to examine associations between metal(loid)s in blood and urine with hormone concentrations.

RESULTS: Arsenic blood concentrations were significantly associated with increased levels in CRH (%Δ: 23.0, 95%CI: 8.4-39.6) and decreased levels in testosterone (%Δ: -16.3, 95%CI: -26.2--5.1). Cobalt, manganese, and lead blood concentrations were associated with small increases in SHBG (%Δ range: 3.3-4.2), E3 (%Δ range: 3.9-8.7) and progesterone (%Δ range: 4.1-6.3) levels, respectively. Nickel blood concentration was inversely associated with testosterone levels (%Δ -13.3, 95%CI: -18.7--7.6). Significant interactions were detected for the association between nickel and study visit in relation to CRH (p < 0.02) and testosterone levels (p < 0.01).

CONCLUSION: Our analysis suggests that metal(loid)s may act as endocrine disruptors by altering prenatal hormone levels. This disruption may depend on specific windows of exposure during pregnancy. Additionally, some essential metal(loid)s such as managense and cobalt may be contributors to adverse maternal and fetal outcomes. The study of metal(loid)s as endocrine disruptors is in the early stages of epidemiological research and future studies are needed to further investigate these associations.

Abstract  Our objective was to evaluate the relationship of blood metal levels including strontium, cadmium, lead, vanadium, aluminum, cobalt, and manganese with dyslipidemia in the elderly Chinese population. In this study, stratified cluster sampling was adopted in the elderly in two communities of Lu'an City from June to September 2016, and 1013 participants were finally included. The inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the metals' concentrations in whole blood. After multivariable adjustment, the odds ratios (95% confidence interval [CI]) of dyslipidemia associated with the highest quartile of metal concentrations were 1.32 (0.89 similar to 1.96), 1.28 (0.83 similar to 1.97), 1.86 (1.23 similar to 2.80), 0.80 (0.55 similar to 1.16), 0.76 (0.51 similar to 1.13), 0.76 (0.53 similar to 1.11), and 1.14 (0.78 similar to 1.67) for strontium, cadmium, lead, vanadium, aluminum, cobalt, and manganese, respectively, compared with the lowest quartile. After reducing the dimensionality of metal elements by principal component analysis, we found that the combined exposure of aluminum, cobalt, and vanadium was the protective factor of non-dyslipidemia, while the combined exposure of cadmium, strontium, and lead was the risk factor of dyslipidemia.