Effects of Cadmium and Lead Co-exposure on Sleep Status in Rural Areas Northwestern China.

In this study, we explored how cadmium and lead co-exposure affects sleep status among residents of a polluted area and nature reserve in rural northwestern China. Cadmium and lead levels were measured using blood samples, and sleep status was evaluated using sleep questionnaires, with the main sleep indicators including sleep duration, sleep quality, bedtime, and staying up. Furthermore, cadmium-lead co-exposure levels were divided into three groups: high exposure, medium exposure, and low exposure. Subjects in the contaminated area had significantly higher exposure levels (p < 0.001) and more negative sleep indicators (p < 0.01). Significant differences were found for all four sleep indicators in the high exposure group compared to the low exposure group (p < 0.01). Moreover, the overall evaluation of sleep status with high cadmium-lead co-exposure had a negative impact. Our data suggest that cadmium-lead co-exposure has a negative effect on sleep status and may have a synergistic effect on sleep.

Ecological and health risk assessment of heavy metals in agricultural soils from northern China.

Soil pollution by heavy metals can cause continuing damage to ecosystems and the human body. In this study, we collected nine fresh topsoil samples and 18 maize samples (including nine leaf samples and nine corn samples) from agricultural soils in the Baiyin mining areas. The results showed that the order of heavy metal concentrations (mg/kg) in agricultural soils was as follows: Zn (377.40) > Pb (125.06) > Cu (75.06) > Ni (28.29) > Cd (5.46) > Hg (0.37). Cd, Cu, Zn, and Pb exceeded the Chinese risk limit for agricultural soil pollution. The average the pollution load index (4.39) was greater than 3, indicating a heavy contamination level. The element that contributed the most to contamination and high ecological risk in soil was Cd. Principal component analysis (PCA) and Pearson's correlation analysis indicated that the sources of Ni, Cd, Cu, and Zn in the soil were primarily mixed, involving both industrial and agricultural activities, whereas the sources of Hg and Pb included both industrial and transportation activities. Adults and children are not likely to experience non-carcinogenic impacts from the soil in this region. Nonetheless, it was important to be aware of the elevated cancer risk presented by Cd, Pb, and especially Ni. The exceedance rates of Cd and Pb in corn were 66.67% and 33.3%, respectively. The results of this research provide data to improve soil protection, human health monitoring, and crop management in the Baiyin district.

Effects of cadmium and lead co-exposure on glucocorticoid levels in rural residents of northwest China.

Cadmium (Cd) and lead (Pb) are important environmental endocrine disruptors that are associated with adverse health problems. However, the effects of co-exposure to Cd and Pb on glucocorticoids (GCs) in the body at environmental levels are limited. A total of 468 subjects from the Dongdagou-Xinglong cohort (DDG-XL) were included in this study. We measured the serum levels of two representative endogenous GCs [cortisol (CRL) and cortisone (CRN)], and whole blood levels of Cd and Pb. Multiple linear regression models were constructed to explore the associations of single or combined Cd and Pb exposure with serum CRL and CRN levels. The interactive effects of Cd and Pb on GCs were further assessed using mediation analysis and moderation analysis. Single-heavy metal exposure analysis with adjustment for potential confounders showed that the serum CRL level decreased when the blood Cd or Pb concentration gradually increased (P trend <0.01). Additionally, subjects with high Cd or Pb exposure (Q4) had significantly reduced serum CRN levels compared to those with low Cd or Pb exposure (Q1) (P < 0.05). In Cd and Pb co-exposure analysis, significant negative dose-response relationships were observed between co-exposure to Cd and Pb and serum CRL and CRN levels. Furthermore, mediation analysis showed that Cd completely mediated the relationship between Pb and GCs, and moderation analysis suggested that Pb might weaken the negative relationship between Cd and GCs. These findings suggest that single or combined exposure to Cd and Pb interferes with the homeostasis of serum CRL and CRN levels. Furthermore, we innovatively propose that Cd and Pb may have interactive effects on GCs levels, and Pb can antagonize the negative relationship between Cd and GCs, which may provide clues for further studies on endocrine and metabolic disorders related to these heavy metals.

The Effect of Smoking Habits on Blood Cadmium and Lead Levels in Residents Living Near a Mining and Smelting Area in Northwest China: a Cross-Sectional Study.

Few studies have focused on environmental cadmium (Cd) and lead (Pb) exposure while exploring the effect of smoking on blood Cd (BCd) and blood Pb (BPb) levels. Moreover, essential trace elements affect the absorption, accumulation, and toxicity of Cd and Pb. To investigate the effect of smoking on BCd and BPb levels under high Cd and Pb exposure and the influence of essential trace elements on the effect, 301 residents living near a mining and smelting area in Northwest China were included in our study. After collecting health information and measuring BCd, BPb, serum iron, magnesium, and total calcium levels, we analyzed the association between smoking and BCd and BPb levels and the influence of the essential trace elements on the association. The results showed that BCd and BPb levels in smokers were significantly higher than those in non-smokers. There was a dose-response association between pack-years and the odds ratios (ORs) of high BCd and BPb levels in all participants compared with non-smokers. Serum iron, magnesium, and calcium had a negative effect on the elevations of the ORs of high BCd and BPb levels. In addition, smoking-related elevations of BCd and BPb levels vary by sex, age, BMI, and age of smoking initiation. Our findings present evidence for the effect of smoking on BCd and BPb levels under high Cd and Pb exposure and may provide guidance for the prevention and control of BCd and BPb elevations in residents living in Cd- and Pb-polluted areas.

Physical activity reduces the role of blood cadmium on depression: A cross-sectional analysis with NHANES data.

Cadmium (Cd) exposure is recognized as an important risk factor for psychological health, but suitable physical activity may relieve depression. However, it remains unknown whether physical activity (PA) can reduce the effect of cadmium exposure on depression. Therefore, a cross-sectional data from National Health and Nutrition Examination Survey (NHANES) 2015-2018 was used. The Nine-item Patient Health Questionnaire (PHQ-9) was used to assess depression among the participants. PA was calculated according to the metabolic equivalent (MET), weekly frequency, and duration of each activity. Logistic regression and restricted cubic spline models were used to examine the associations of Cd and depression. A total of 5560 adults aged 20 years and above were finally included in this study. The results indicated a positive correlation between blood Cd and depression. The multivariate-adjusted ORs (95% CI) of the highest quartile were 2.290 (1.754-2.990) for depression, which was still significant after controlling other heavy metals (P < 0.05). Under Cd exposure, the high intensity of physical activity group had the lowest risk of depression (OR = 2.226, 95%CI: 1.447-3.425), while the group with no physical activity had the highest risk (OR = 2.443, 95%CI: 1.382-4.318). Our results indicate that inner Cd exposure may be a risk factor for depression, and physical activity can moderate this relationship to some degree.

Effects of lead and cadmium co-exposure on liver function in residents near a mining and smelting area in northwestern China.

Chronic exposure to environmental cadmium (Cd) and lead (Pb) may have adverse effects on the human health. In this study, we aimed to determine the primary and interactive effects of Cd and Pb exposure on liver function in residents near a mining and smelting area in northwestern China. A total of 451 subjects were recruited, from which blood samples were collected to determine the levels of Cd, Pb, and liver function indices. Additionally, the association between the levels of exposure markers and liver function indices was analysed. Cd and Pb levels were significantly higher in subjects living in the polluted area than in those living in the non-polluted reference area. The liver function levels of subjects in the polluted area were poor compared with those in the reference area. In addition, Cd and Pb levels in the blood were positively associated with gamma glutamyl transpeptidase (GGT) levels and negatively associated with direct bilirubin (DBil) levels. Cd and Pb may be risk factors for abnormal liver function. The risk of abnormal liver function was higher in subjects with moderate Cd and Pb levels, high Cd levels, high Pb levels, and high Cd and Pb levels than in those with low Cd and Pb levels. Our data show that exposure to Cd and/or Pb can cause abnormal liver function. Cd and Pb may have an antagonistic effect on liver function, and high Cd exposure alone has a more profound effect on abnormal liver function compared with co-exposure to Pb and Cd.

The Effects of Lead and Cadmium Co-exposure on Serum Ions in Residents Living Near a Mining and Smelting Area in Northwest China.

In this study, we investigated the associations between cadmium (Cd) and lead (Pb) co-exposure, and serum ion levels in two populations living near a mining/smelting area and a nature reserve (control area), respectively. A total of 445 participants were included in this study. Their blood cadmium (BCd), blood lead (BPb), and serum ion levels were determined, and the association between exposure levels and serum ion levels was analyzed. The exposure levels of subjects living in the polluted area were significantly higher (p < 0.001). Lower levels of potassium, inorganic phosphorus, and iron were observed in subjects from the polluted area, whereas their sodium and chloride levels were higher (p < 0.01). The anion gap in their serum was also significantly lower. We observed positive dose-effect relationships between Cd and/or Pb exposure and serum sodium and chloride, and negative dose-effect relationships between Cd and/or Pb exposure and serum inorganic phosphorus, iron, as well as the anion gap. High Cd-Pb, high Cd, and high Pb exposure led to modification effects in potassium, calcium, inorganic phosphorus, and iron levels, and the anion gap. No synergistic effects were observed in our results. In conclusion, our data demonstrate that Cd and Pb exposure, alone or in combination, can lead to serum ion imbalances.

Association between lead and cadmium co-exposure and systemic immune inflammation in residents living near a mining and smelting area in NW China.

Exposure to both cadmium (Cd) and lead (Pb) can promote systemic inflammation. However, the effects of combined exposure to environmental levels of Cd and Pb on systemic immune inflammation have not been fully clarified. A total of 486 subjects (313 women and 173 men) living in either a control area or heavy metal-polluted area were included. Blood Cd and Pb and immune inflammation biomarkers were determined, including the eosinophil-lymphocyte ratio (ELR), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and systemic immune-inflammation index (SII); moreover, the associations between exposure markers and systemic inflammation markers were analysed. The exposure levels in the polluted area were significantly higher than those in the control area. The NLR, PLR, and SII of subjects in the polluted area were higher and the LMR was lower than in the control area. Blood Pb and Cd levels are associated with elevated or decreased immune inflammation biomarkers in subjects from the exposed and control areas. Furthermore, co-exposure to both Cd and Pb was divided into high, middle, and low exposure groups. The subjects in the high co-exposure group displayed higher levels of ELR, NLR, and SII compared with the middle and low co-exposure group, and LMR levels displayed the opposite trend. Our data demonstrate that Cd and Pb co-exposure is associated with systemic immune inflammation, and the immune inflammatory response is aggravated with an increased co-exposure to Cd and Pb.

Airborne particulate matter (PM2.5) triggers ocular hypertension and glaucoma through pyroptosis.

BACKGROUND: Particulate matter (PM) is strongly linked to human health and has detrimental effects on the eye. Studies have, however, focused on the ocular surface, with limited research on the impact of PM2.5 on intraocular pressure (IOP). METHODS: To investigate the impact of PM2.5 on IOP and the associated mechanism, C57BL/6 mouse eyes were topically exposed to a PM2.5 suspension for 3 months, and human trabecular meshwork (HTM) cells were subjected to various PM2.5 concentrations in vitro. Cell viability, NLRP3/caspase-1, IL-1ß, and GSDMD expression, reactive oxygen species (ROS) production and cell contractility were measured by western blot, ELISA, cell counting kit-8, ROS assay kit or a cell contractility assay. ROS scavenger N-acetyl-L-cysteine (NAC) and caspase-1 inhibitor VX-765 were used to intervene in PM2.5-induced damages. RESULTS: The results revealed that the IOP increased gradually after PM2.5 exposure, and upregulations of the NLRP3 inflammasome, caspase-1, IL-1ß, and GSDMD protein levels were observed in outflow tissues. PM2.5 exposure decreased HTM cell viability and affected contraction. Furthermore, elevated ROS levels were observed as well as an activation of the NLRP3 inflammasome and downstream inflammatory factors caspase-1 and IL-1ß. NAC improved HTM cell viability, inhibited the activation of the NLRP3 inflammasome axis, and HTM cell contraction by scavenging ROS. VX-765 showed similar protection against the PM2.5 induced adverse effects. CONCLUSION: This study provides novel evidence that PM2.5 has a direct toxic effect on intraocular tissues and may contribute to the initiation and development of ocular hypertension and glaucoma. This occurs as a result of increased oxidative stress and the subsequent induction of NLRP3 inflammasome mediated pyroptosis in trabecular meshwork cells.

Airborne particulate matter (PM2.5) triggers cornea inflammation and pyroptosis via NLRP3 activation.

Although studies have demonstrated that fine particulate matter (PM2.5) induces ocular surface damage, PM2.5 exposure causes cornea toxicity is not entirely clear. The aim of this study is to investigate the role of the nod-like receptor family pyrin domain containing three (NLRP3) inflammasome-mediated pyroptosis in PM2.5-related corneal toxicity. Human corneal epithelial cells (HCECs) were exposed to different concentrations of PM2.5, and the cell viability, expressions of NLRP3 inflammasome mediated pyroptosis axis molecules and intracellular reactive oxygen species (ROS) formation were measured in HCECs. Animal experiments were undertaken to topically apply PM2.5 suspension to mouse eyes for three months and the pyroptosis related molecules in the mouse corneas were measured. RESULTS: Our results showed a dose-dependent decrease of HCEC viability in the PM2.5-treated cells. NLRP3 inflammasome-mediated pyroptosis axis (NLRP3, ASC, GSDMD, caspase-1, IL-1ß, and IL-18) were activated in the PM2.5-treated HCECs, accompanied by increased ROS formation. Further in vivo study confirmed the activation of this pathway in the mouse corneas exposed to PM2.5. In conclusion, this study provids novel evidence that PM2.5 induces corneal toxicity by triggering cell pyroptosis.

Indoor air pollution from solid fuels and hypertension: A systematic review and meta-analysis.

Cardiovascular diseases (CVD) are leading global health issue. More studies have linked indoor air pollution from solid fuel usage to hypertension risk, a leading risk factor for CVD. We conducted a systematic review and meta-analysis of observational studies assessing the relationship of indoor air pollution from solid fuel with hypertension risk. Using a protocol standardized a priori, two independent reviewers searched PubMed, the Cochrane Library, Ovid MEDLINE, Web of Science and EMBASE for available studies published before Dec.1, 2019. A random effects model was used to analyse the pooled results. Out of 3740 articles, 47 were reviewed in depth and 11 contributing to this meta-analysis. The use of household solid fuel was significantly associated with an increased risk of hypertension (OR = 1.52, 95% CI = 1.26 to 1.85). The smoking-controlled group (OR = 2.38, 95% CI = 1.58 to 3.60) had greater effect size of hypertension than the uncontrolled group (OR = 1.11, 95% CI = 1.10 to 1.11). These findings implicate that indoor air pollution from solid fuel may be an important risk factor for hypertension.

Cold stress provokes lung injury in rats co-exposed to fine particulate matter and lipopolysaccharide.

Cold exposure aggravates respiratory diseases, which are also influenced by the exposures to particulate matter and endotoxin in the air. The aim of this study was to investigate the potential interactions among cold stress, fine particulate matter (PM2.5, particles with aerodynamic diameter of 2.5 µm or less) and lipopolysaccharide (LPS, pure chemical form of endotoxin) on rat lung and to explore the related possible mechanisms of the interactions. Wistar rats were randomly grouped to be exposed to, 1) normal saline (0.9% NaCl), 2) PM2.5, 3) LPS, and 4) PM2.5 and LPS (PM2.5 + LPS) through intratracheal instillation under cold stress (0 °C) and normal temperature (20 °C). Lung function, lung tissue histology, inflammatory response and oxidative stress levels were measured to examine the lung injury and to investigate the potential mechanisms. Exposure to PM2.5 or LPS substantially changed pulmonary function [indicated by peak inspiratory flow (PIF) and peak expiratory flow (PEF)], inflammatory cytokine levels [indicated by interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)] and lung histology, compared to the non-exposed groups. Exposure to PM2.5 + LPS under cold stress induced the most significant changes, including the increases of IL-6, TNF-α and thiobarbituric acid-reactive substances (TBARS), the decreases of PIF and PEF and more severe lung injury, among all exposure scenarios. Glutathione peroxidase activity and, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were found to be suppressed under cold stress, whereas Nrf2 and HO-1 levels were observed to be upregulated by exposure to PM2.5 or LPS under normal temperature. In conclusion, cold stress may aggravate the lung injury in rats induced by simultaneous exposure to PM2.5 and LPS. The progress may involve the suppressing of Nrf2/HO-1 signal pathway.

COPD rat model is more susceptible to cold stress and PM2.5 exposure and the underlying mechanism.

The purpose of this study is to verify the hypothesis that chronic obstructive pulmonary disease (COPD) model rat is more susceptible to cold stress and fine particulate matter (PM2.5) exposure than the healthy rat, and explore the related mechanism. COPD rat model, established with cigarette smoke and lipopolysaccharide intratracheal instillation, were exposed to cold stress (0 °C) and PM2.5 (0, 3.2, 12.8 mg/ml). After that, the levels of superoxide dismutase, inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1) and angiotensin Ⅱ (Ang-Ⅱ) in lung were measured, as well as the expression levels of lung 8-hydroxy-2-deoxyguanosine (8-OHdG), nuclear factor kappa B (NF-κB), heme-oxygenase-1 (HO-1) and nuclear factor erythroid-2-related factor 2 (Nrf2). There were significant positive relationships between PM2.5 and lung level of iNOS, TNF-α, MCP-1 and Ang-Ⅱ, lung function and pathologic damage in COPD rats. The HO-1, NF-κB and 8-OHdG were found highly expressed in COPD rat lung, particularly at the higher PM2.5 dose of cold stress groups, while Nrf2 was found declined. Thus, COPD rats may be more susceptible to cold stress and PM2.5 exposure. Cold stress may aggravate PM2.5-induced toxic effects in the lung of COPD rats through increasing Ang-Ⅱ/NF-κB signaling pathway and suppressing Nrf2 signaling pathway.

The probable roles of valsartan in alleviating chronic obstructive pulmonary disease following co-exposure to cold stress and fine particulate matter.

Angiotensin II (ANG II) might play an important role in the co-effects of cold stress and fine particulate matter (PM2.5) on chronic obstructive pulmonary disease (COPD). The purpose of this study is to evaluate the roles of valsartan in alleviating COPD following co-exposure to cold stress and PM2.5. Both the two intervention factors are carried out upon COPD rats with the intervention of valsartan. Blockade of angiotensin receptor by valsartan decreases the levels of malondialdehyde in the normal temperature and tumor necrosis factor-α under cold stress significantly. When treated with valsartan and PM2.5 simultaneously, the expression of 8-hydroxy-2-deoxyguanosine, nuclear factor kappa B and heme oxygenase-1 decrease significantly in the group of cold stress. In conclusion, these results indicate that valsartan might relieve the co-effects of cold stress and PM2.5 on COPD rat lung to some degree.

Impact of probable interaction of low temperature and ambient fine particulate matter on the function of rats alveolar macrophages.

The present study aimed to explore the probable interaction of low temperature and ambient fine particulate matter (PM2.5) on rat alveolar macrophages (AMs). AMs were separated from rat BALF and exposed to PM2.5 (0, 25, 50, 100µg/ml) under different temperature (18, 24, 30, 37°C) for 8h. Results indicated that viability and phagocytosis function of AMs decreased with the decline of temperature and the rise of PM2.5 dose, and the strongest toxicity was shown in the highest PM2.5 (100µg/ml) exposure group at 18°C. Both PM2.5 and lower temperature increased the releasing of tumor necrosis factor alpha (TNF-α), macrophage inflammatory protein 1α (MIP-1α) and interleukin-6 (IL-6), while significant interaction was only found in MIP-1α production. No obvious change was found in granulocyte-macrophage colony-stimulating factor (GM-CSF) detection. These results indicated that both the two factors are harmful to rat AMs and lower temperature could increase the toxicity of PM2.5 on the AMs.

Rat lung response to PM2.5 exposure under different cold stresses.

Ambient particulate matters and temperature were reported to have additive effects over the respiratory disease hospital admissions and deaths. The purpose of this study is to discuss the interactive pulmonary toxicities of cold stress and fine particulate matter (PM2.5) exposure by estimating inflammation and oxidative stress responses. 48 Wistar male rats, matched by weight and age, were randomly assigned to six groups, which were treated with cold stress alone (0 °C, 10 °C, and 20 °C (Normal control)) and cold stresses plus PM2.5 exposures respectively. Cold stress alone groups were intratracheal instillation of 0.25 mL normal saline, while cold stress plus PM2.5 exposure groups were intratracheal instillation of 8 mg/0.25 mL PM2.5. These procedures were carried out for three times with an interval of 48 hours for each treatment. All rats were sacrificed after 48 hours of the third treatment. The bronchoalveolar lavage fluid (BALF) was collected for analyzing inflammatory cells and cytokines, and lung homogenate MDA was determined for oxidative stress estimation. Results showed higher level of total cell and neutrophil in the BALF of PM2.5 exposed groups (p < 0.05). Negative relationships between cold stress intensity and the level of tumor necrosis factor alpha (TNF-a), C-reactive protein (CRP) interleukin-6 (IL-6) and interleukin-8 (IL-8) in BALF were indicated in PM2.5 exposure groups. Exposure to cold stress alone caused significant increase of inflammatory cytokines and methane dicarboxylic aldehyde (MDA) and decline of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity only in 0 °C exposure group (p < 0.05). The two-way ANOVA found significant interactive effects between PM2.5 exposure and cold stress in the level of neutrophil, IL-6 and IL-8 and SOD activity (p < 0.05). These data demonstrated that inflammation and oxidative stress involved in the additive effect of PM2.5 exposure and cold stress on pulmonary toxicity, providing explanation for epidemiological studies on the health effect of ambient PM2.5 and cold stress.

The Association between Leptin Level and Breast Cancer: A Meta-Analysis.

BACKGROUND: Contradictory results have been reported regarding the association between leptin level and breast cancer. Therefore, a meta-analysis was performed to investigate this issue. METHODS: Published literature from PubMed and the Chinese National Knowledge Infrastructure (CNKI) Database was retrieved. This study was performed based on different cases and control groups. The combined effect ([Formula: see text]) with 95% confidence interval (CI) was calculated using fixed-effects or random-effects model analysis. RESULTS: Overall, the mean serum leptin level of case groups was significantly higher than that of control groups. A) For 9 studies comparing breast cancer cases and healthy controls the combined effect [Formula: see text] was 0.58 with 95% CI (0.48, 0.68). B) For 4 studies comparing premenopausal breast cancer cases and healthy controls the [Formula: see text] was 0.32 (0.12, 0.52). C) For 5 studies comparing postmenopausal cases and healthy controls the [Formula: see text] was 0.65 (0.46, 0.84). D) For 4 studies comparing breast cancer cases and breast benign controls the [Formula: see text] was 0.38 (0.17, 0.59). E) For 2 studies comparing premenopausal breast cancer cases and breast benign controls the [Formula: see text] was 0.33 (-0.25, 0.91). F) For 6 studies comparing postmenopausal breast cancer cases and breast benign controls the [Formula: see text] was 0.39 (0.19, 0.60). G) For 4 studies comparing lymph node metastasis positive cases and negative controls the [Formula: see text] was 0.72 (0.45, 1.00). H) For 3 studies comparing breast benign cases and healthy controls the [Formula: see text] was 0.71 (0.41, 1.01). CONCLUSION: This meta-analysis suggests that leptin level plays a role in breast cancer and has potential for development as a diagnostic tool.

Gene expression profiles in peripheral blood mononuclear cells of Chinese nickel refinery workers with high exposures to nickel and control subjects.

BACKGROUND: Occupational exposure to nickel (Ni) is associated with an increased risk of lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, alter the cell's epigenetic homeostasis, and activate signaling pathways. However, changes in gene expression associated with Ni exposure have only been investigated in vitro. This study was conducted in a Chinese population to determine whether occupational exposure to Ni was associated with differential gene expression profiles in the peripheral blood mononuclear cells (PBMC) of Ni-refinery workers when compared with referents. METHODS: Eight Ni-refinery workers and ten referents were selected. PBMC RNA was extracted and gene expression profiling was conducted using Affymetrix exon arrays. Differentially expressed genes (DEG) between both groups were identified in a global analysis. RESULTS: There were a total of 2,756 DEGs in the Ni-refinery workers relative to the referents [false discovery rate (FDR) adjusted P < 0.05] with 770 upregulated genes and 1,986 downregulated genes. DNA repair and epigenetic genes were significantly overrepresented (P < 0.0002) among the DEGs. Of 31 DNA repair genes, 29 were repressed in the Ni-refinery workers and 2 were overexpressed. Of the 16 epigenetic genes, 12 were repressed in the Ni-refinery workers and 4 were overexpressed. CONCLUSIONS: The results of this study indicate that occupational exposure to Ni is associated with alterations in gene expression profiles in PBMCs of subjects. IMPACT: Gene expression may be useful in identifying patterns of deregulation that precede clinical identification of Ni-induced cancers.

Plasma Anti-Glycan Antibody Profiles Associated with Nickel level in Urine.

Nickel (Ni) compounds are widely used in industrial and commercial products including household and cooking utensils, jewelry, dental appliances and implants. Occupational exposure to nickel is associated with an increased risk for lung and nasal cancers, is the most common cause of contact dermatitis and has an extensive effect on the immune system. The purpose of this study was two-fold: (i) to evaluate immune response to the occupational exposure to nickel measured by the presence of anti-glycan antibodies (AGA) using a new biomarker-discovery platform based on printed glycan arrays (PGA), and (ii) to evaluate and compile a sequence of bioinformatics and statistical methods which are specifically relevant to PGA-derived information and to identification of putative "Ni toxicity signature". The PGAs are similar to DNA microarrays, but contain deposits of various carbohydrates (glycans) instead of spotted DNAs. The study uses data derived from a set of 89 plasma specimens and their corresponding demographic information. The study population includes three subgroups: subjects directly exposed to Nickel that work in a refinery, subjects environmentally exposed to Nickel that live in a city where the refinery is located and subjects that live in a remote location. The paper describes the following sequence of nine data processing and analysis steps: (1) Analysis of inter-array reproducibility based on benchmark sera; (2) Analysis of intra-array reproducibility; (3) Screening of data - rejecting glycans which result in low intra-class correlation coefficient (ICC), high coefficient of variation and low fluorescent intensity; (4) Analysis of inter-slide bias and choice of data normalization technique; (5) Determination of discriminatory subsamples based on multiple bootstrap tests; (6) Determination of the optimal signature size (cardinality of selected feature set) based on multiple cross-validation tests; (7) Identification of the top discriminatory glycans and their individual performance based on nonparametric univariate feature selection; (8) Determination of multivariate performance of combined glycans; (9) Establishing the statistical significance of multivariate performance of combined glycan signature. The above analysis steps have delivered the following results: inter-array reproducibility ρ=0.920 ± 0.030; intra-array reproducibility ρ=0.929 ± 0.025; 249 out of 380 glycans passed the screening at ICC>80%, glycans in selected signature have ICC ≥ 88.7%; optimal signature size (after quantile normalization)=3; individual significance for the signature glycans p=0.00015 to 0.00164, individual AUC values 0.870 to 0.815; observed combined performance for three glycans AUC=0.966, p=0.005, CI=[0.757, 0947]; specifity=94.4%, sensitivity=88.9%; predictive (cross-validated) AUC value 0.836.