Intestinal Calcium Absorption Decreases After Laparoscopic Sleeve Gastrectomy Despite Optimization of Vitamin D Status.

CONTEXT: Laparoscopic sleeve gastrectomy (LSG), now the most commonly performed bariatric operation, is a highly effective treatment for obesity. While Roux-en-Y gastric bypass is known to impair intestinal fractional calcium absorption (FCA) and negatively affect bone metabolism, LSG's effects on calcium homeostasis and bone health have not been well characterized. OBJECTIVE: We determined the effect of LSG on FCA, while maintaining robust 25-hydroxyvitamin D (25OHD) levels and recommended calcium intake. DESIGN, SETTING, PARTICIPANTS: Prospective pre-post observational cohort study of 35 women and men with severe obesity undergoing LSG. MAIN OUTCOMES: FCA was measured preoperatively and 6 months postoperatively with a gold-standard dual stable isotope method. Other measures included calciotropic hormones, bone turnover markers, and bone mineral density (BMD) by dual-energy X-ray absorptiometry and quantitative computed tomography. RESULTS: Mean ± SD FCA decreased from 31.4 ± 15.4% preoperatively to 16.1 ± 12.3% postoperatively (P < 0.01), while median (interquartile range) 25OHD levels were 39 (32-46) ng/mL and 36 (30-46) ng/mL, respectively. Concurrently, median 1,25-dihydroxyvitamin D level increased from 60 (50-82) pg/mL to 86 (72-107) pg/mL (P < 0.01), without significant changes in parathyroid hormone or 24-hour urinary calcium levels. Bone turnover marker levels increased substantially, and areal BMD decreased at the proximal femur. Those with lower postoperative FCA had greater areal BMD loss at the total hip (ρ = 0.45, P < 0.01). CONCLUSIONS: FCA decreases after LSG, with a concurrent rise in bone turnover marker levels and decline in BMD, despite robust 25OHD levels and with recommended calcium intake. Decline in FCA could contribute to negative skeletal effects following LSG.

Prebiotic to Improve Calcium Absorption in Postmenopausal Women After Gastric Bypass: A Randomized Controlled Trial.

CONTEXT: The adverse skeletal effects of Roux-en-Y gastric bypass (RYGB) are partly caused by intestinal calcium absorption decline. Prebiotics, such as soluble corn fiber (SCF), augment colonic calcium absorption in healthy individuals. OBJECTIVE: We tested the effects of SCF on fractional calcium absorption (FCA), biochemical parameters, and the fecal microbiome in a post-RYGB population. METHODS: Randomized, double-blind, placebo-controlled trial of 20 postmenopausal women with history of RYGB a mean 5 years prior; a 2-month course of 20 g/day SCF or maltodextrin placebo was taken orally. The main outcome measure was between-group difference in absolute change in FCA (primary outcome) and was measured with a gold standard dual stable isotope method. Other measures included tolerability, adherence, serum calciotropic hormones and bone turnover markers, and fecal microbial composition via 16S rRNA gene sequencing. RESULTS: Mean FCA ± SD at baseline was low at 5.5 ± 5.1%. Comparing SCF to placebo, there was no between-group difference in mean (95% CI) change in FCA (+3.4 [-6.7, +13.6]%), nor in calciotropic hormones or bone turnover markers. The SCF group had a wider variation in FCA change than placebo (SD 13.4% vs 7.0%). Those with greater change in microbial composition following SCF treatment had greater increase in FCA (r2 = 0.72, P = 0.05). SCF adherence was high, and gastrointestinal symptoms were similar between groups. CONCLUSION: No between-group differences were observed in changes in FCA or calciotropic hormones, but wide CIs suggest a variable impact of SCF that may be due to the degree of gut microbiome alteration. Daily SCF consumption was well tolerated. Larger and longer-term studies are warranted.

Occurrence of estrogens, androgens and progestogens and estrogenic activity in surface water runoff from beef and dairy manure amended crop fields.

Hormone contamination of aquatic systems has been shown to cause reproductive impairment of aquatic organisms. To assess to what extent beef and dairy farms represent a source of hormones to the aquatic environment, surface water runoff samples from three beef and dairy farms that utilize best manure management practices were evaluated for hormone concentrations (estrogens, androgens, progestogens) and estrogenic activity. Runoff was collected from weirs at the edge of each of six study fields from March 2008 to March 2010 and was analyzed for hormone concentrations using liquid chromatography with tandem mass spectrometry and for estrogenic activity using the E-screen bioassay. The majority of runoff events occurred in February and March when the soil was frozen. Progesterone and 4-androstenedione were the most frequently detected hormones (63% and 50%, respectively) and occurred at event loads up to 49,000 µg/ha and 26,000 µg/ha, respectively. Progesterone, 4-androstenedione, 17α-estradiol had the highest event load concentrations and were found at the field that sustained dairy cattle grazing during the winter and were likely due to application of excreta on frozen soil. The high progesterone event loads could lead to concentrations in receiving streams that exceed the lowest observable effects concentrations for fish. There was a consistent association with the elevated zearalenone presence and corn production. The synthetic hormones, 17α-trenbolone and 17ß-trenbolone, were not detected in runoff from the beef farm that utilized trenbolone acetate implants, which is likely due to their short half lives. Estrogenic activity in runoff samples ranged from 0.09 to 133 ng/L estradiol equivalents, with 39% of runoff events exceeding the 2 ng/L predicted-no-effect-concentration for fish. These results indicate that grazing cattle and application of manure to frozen fields present the greatest risk to elevated hormones in runoff and that progesterone is the primary hormone of concern from beef and dairy operations.

Cd isotope fractionation during tobacco combustion produces isotopic variation outside the range measured in dietary sources.

Cadmium production has risen 1000-fold in the past 100 years, from under 20 to over 20,000 tons per year, causing anthropogenically-mobilized Cd to overwhelm natural sources in global cycling. Cadmium has no known biological function in humans, yet has biochemical behaviors similar to zinc and manganese, making exposure detrimental to human health. Identifying and quantifying the sources of Cd for human sub-populations is key to reducing exposures. Cadmium stable isotopes may provide a method for tracing Cd sources throughout the environment and the human body, but at present the limited database for high precision Cd isotopic compositions is inadequate to support such an analysis. Here, we provide new Cd isotope data on dietary sources, cigarette smoking components, and environmentally relevant standard reference materials. Results indicated that minor but significant variations are observed in food products (e.g., peanuts, sunflower seeds, spinach, kale, lettuce, cocoa powder; ~0.9‰ at 4 amu) that may be useful for tracing contamination in agricultural soils. In contrast, Cd isotope fractionation during smoking is larger (~6‰ at 4 amu) and has implications for tracing cadmium sources from tobacco combustion in the environment and throughout the human body. The primary inhaled component of cigarette smoke contains highest delta values (δ116/112Cd or δ114/110Cd ~5.2‰), while the second-hand smoke and cigarette ash have the lowest delta values (δ116/112Cd or δ114/110Cd ~-0.9‰). Used cigarette butts have δ114/110Cd ~2.4‰, in between the values measured in ash/s hand smoke and the inhaled smoke components. The high delta values of the inhaled smoke indicate that Cd isotopes may be used to determine the extent of Cd exposure due to smoking in human biological samples. This study provides new data for previously uncharacterized isotopic reservoirs that can be included in future studies of Cd source-exposure tracing.

Chemical composition and health risk indices associated with size-resolved particulate matter in Pearl River Delta (PRD) region, China.

Size-resolved particulate matter (PM) was collected at the Heshan Super-Station in the Pearl River Delta (PRD) region, China, to evaluate their chemical characteristics and potential health risks. The chemical mass closures illustrate that the dominant fraction in coarse (2.5 µm < Dp < 10 µm) PM was dust, while organic matter made up a substantial portion of both fine (0.1 < Dp < 2.5 µm) and ultra-fine (Dp < 0.10 µm) PM fractions. The size distribution of most PM components varied substantially. PM, NO3-, K+, Cl-, Na+ and most of the transition/redox metals displayed bimodal size distributions with the dominant peak at 0.32-0.56 µm plus a small peak at 1.8-3.2 µm. In contrast, unimodal size distributions were found for the rest of the species, such as water-soluble organic carbon (WSOC), NH4+, and SO42- and the majority of oxyanion metals with a single peak at 0.32-0.56 µm, and Mg2+, Ca2+, and dust tracer elements which mainly accumulated in coarse particles. Based on the crustal enrichment factor (CEF) analysis, Cd, Zn, Sb, Sn, As, Pb, Mo, Cu, and Cr primarily originated from anthropogenic activities, while Ti in all size fractions and Sr, Mg, Na, and Fe in fine and ultra-fine particles were mainly emitted from natural sources. The potential health risk assessment of trace metals was performed using the hazard quotient (HQ) and excess lifetime cancer risk (ELCR) indices. Although the adverse health effects of most metals were limited, significant potential carcinogenic risks were found for As and Cr in both fine and coarse particle size fractions, which contributed more than 95% of total ELCR. Therefore, considering that these two elements were mainly emitted from industrial processes, improvements in air quality and health risks in the PRD region can be largely achieved by reducing the emissions of local industrial sources.

Seasonal variations in the oxidative stress and inflammatory potential of PM2.5 in Tehran using an alveolar macrophage model; The role of chemical composition and sources.

The current study was designed to assess the association between temporal variations in urban PM2.5 chemical composition, sources, and the oxidative stress and inflammatory response in an alveolar macrophage (AM) model. A year-long sampling campaign collected PM2.5 samples at the Sharif University in Tehran, Iran. PM-induced reactive oxygen species (ROS) production was measured both with an acellular dithiothreitol consumption assay (DTT-ROS; ranged from 2.1 to 9.3 nmoles min-1 m-3) and an in vitro macrophage-mediated ROS production assay (AM-ROS; ranged from 125 to 1213 µg Zymosan equivalents m-3). The production of tumor necrosis factor alpha (TNF-α; ranged from ~60 to 518 pg TNF-α m-3) was quantified as a marker of the inflammatory potential of the PM. PM-induced DTT-ROS and AM-ROS were substantially higher for the colder months' PM (1.5-fold & 3-fold, respectively) compared with warm season. Vehicular emission tracers, aliphatic diacids, and hopanes exhibited moderate correlation with ROS measures. TNF-α secretion exhibited a markedly different pattern than ROS activity with a 2-fold increase in the warm months compared to the rest of the year. Gasoline vehicles and residual oil combustion were moderately associated with both ROS measures (R ≥ 0.67, p < 0.05), while diesel vehicles exhibited a strong correlation with secreted TNF-α in the cold season (R = 0.89, p < 0.05). mRNA expression of fourteen genes including antioxidant response and pro-inflammatory markers were found to be differentially modulated in our AM model. HMOX1, an antioxidant response gene, was up-regulated throughout the year. Pro-inflammatory genes (e.g. TNF-α and IL1ß) were down-regulated in the cold season and displayed moderate to weak correlation with crustal elements (R > 0.5, p < 0.05). AM-ROS activity showed an inverse relationship with genes including SOD2, TNF, IL1ß and IL6 (R ≥ -0.66, p < 0.01). Our findings indicate that Tehran's PM2.5 has the potential to induce oxidative stress and inflammation responses in vitro. In the current study, these responses included NRF2, NF-κB and MAPK pathways.

Application of the direct peptide reactivity assay (DPRA) to inorganic compounds: a case study of platinum species.

The in chemico Direct Peptide Reactivity Assay (DPRA) was developed as a non-animal, relatively high throughput, screening tool for skin sensitization potential. Although the Adverse Outcome Pathway (AOP) for respiratory sensitization remains to be fully elucidated, it is recognized that the molecular initiation event for both skin and respiratory sensitization to low molecular weight chemicals involves haptenation with proteins. The DPRA examines the reactivity of a test compound to two model peptides (containing either cysteine or lysine) and consequently is able to screen for both skin and respiratory sensitization potential. The DPRA was primarily developed for and validated with organic compounds and assessment of the applicability of the assay to metal compounds has received only limited attention. This paper reports the successful application of the DPRA to a series of platinum compounds, including hexachloroplatinate and tetrachloroplatinate salts, which are some of the most potent chemical respiratory sensitizers known. Eleven platinum compounds were evaluated using the DPRA protocol as detailed by Lalko et al., with only minor modification. Two palladium compounds with structures similar to that of the platinum species studied and cobalt chloride were additionally tested for comparison. The hexachloroplatinate and tetrachloroplatinate salts showed exceptionally high reactivity with the cysteine peptide (EC15 values of 1.4 and 14 µM, respectively). However, for platinum compounds (e.g. hydrogen hexahydroxyplatinate and tetraammineplatinum) where clinical and epidemiological evidence indicates limited sensitization potential, the cysteine DPRA showed only minor or no reactivity (EC15 values of 24 600 and >30 000 µM, respectively). The outcomes of the lysine peptide assays were less robust and where EC15 was measurable, values were substantially higher than the corresponding results from the cysteine assay. This work supports the value of in chemico peptide reactivity as a metric for assessment of platinum sensitization potential and therefore in screening of new platinum compounds for low or absent sensitization potential. Additional studies are required to determine whether the DPRA may be successfully applied to other metals. We provide details on method modifications and precautions important to the success of the DPRA in the assessment of metal reactivity.

Physical, chemical, and toxicological characteristics of particulate emissions from current technology gasoline direct injection vehicles.

We assessed the physical, chemical and toxicological characteristics of particulate emissions from four light-duty gasoline direct injection vehicles when operated over the LA92 driving cycle. Our results showed that particle mass and number emissions increased markedly during accelerations. For three of the four vehicles tested, particulate matter (PM) mass and particle number emissions were markedly higher during cold-start and the first few accelerations following the cold-start period than during the hot running and hot-start segments of the LA92 cycle. For one vehicle (which had the highest emissions overall) the hot-start and cold-start PM emissions were similar. Black carbon emissions were also much higher during the cold-start conditions, indicating severe fuel wetting leading to slow evaporation and pool burning, and subsequent soot formation. Particle number concentrations and black carbon emissions showed large reductions during the urban and hot-start phases of the test cycle. The oxidative potential of PM was quantified with both a chemical and a biological assay, and the gene expression impacts of the PM in a macrophage model with PCR (polymerase chain reaction) and ELISA (enzyme-linked immunosorbent assay) analyses. Inter- and intra-vehicle variability in oxidative potential per milligram of PM emitted was relatively low for both oxidative assays, suggesting that real-world emissions and exposure can be estimated with distance-normalized emission factors. The PCR response from signaling markers for oxidative stress (e.g., NOX1) was greater than from inflammatory, AhR (aryl hydrocarbon receptor), or MAPK (mitogen-activated protein kinase) signaling. Protein production associated with inflammation (tumor necrosis factor alpha-TNFα) and oxidative stress (HMOX-1) were quantified and displayed relatively high inter-vehicle variability, suggesting that these pathways may be activated by different PM components. Correlation of trace metal concentrations and oxidative potential suggests a role for small, insoluble particles in inducing oxidative stress.

Urinary Magnesium and Other Elements in Relation to Mammographic Breast Density, a Measure of Breast Cancer Risk.

PURPOSE: Heavy metals and other elements may act as breast carcinogens due to estrogenic activity. We investigated associations between urine concentrations of a panel of elements and breast density. METHODS: Mammographic density categories were abstracted from radiology reports of 725 women aged 40-65 yr in the Avon Army of Women. A panel of 27 elements was quantified in urine using high resolution magnetic sector inductively coupled plasma mass spectrometry. We applied LASSO (least absolute shrinkage and selection operator) logistic regression to the 27 elements and calculated odds ratios (OR) and 95% confidence intervals (CI) for dense vs. nondense breasts, adjusting for potential confounders. RESULTS: Of the 27 elements, only magnesium (Mg) was selected into the optimal regression model. The odds ratio for dense breasts associated with doubling the Mg concentration was 1.24 (95% CI 1.03-1.49). Doubling the calcium-to-magnesium ratio was inversely associated with dense breasts (OR 0.83, 95% CI 0.70-0.98). CONCLUSIONS: Our cross-sectional study found that higher levels of urinary magnesium were associated with greater breast density. Prospective studies are needed to confirm whether magnesium as evaluated in urine is prospectively associated with breast density and, more importantly, breast cancer.

Associations between microvascular function and short-term exposure to traffic-related air pollution and particulate matter oxidative potential.

BACKGROUND: Short-term exposure to ambient air pollution has been associated with acute increases in cardiovascular hospitalization and mortality. However, causative chemical components and underlying pathophysiological mechanisms remain to be clarified. We hypothesized that endothelial dysfunction would be associated with mobile-source (traffic) air pollution and that pollutant components with higher oxidative potential to generate reactive oxygen species (ROS) would have stronger associations. METHODS: We carried out a cohort panel study in 93 elderly non-smoking adults living in the Los Angeles metropolitan area, during July 2012-February 2014. Microvascular function, represented by reactive hyperemia index (RHI), was measured weekly for up to 12 weeks (N = 845). Air pollutant data included daily data from regional air-monitoring stations, five-day average PM chemical components and oxidative potential in three PM size-fractions, and weekly personal nitrogen oxides (NOx). Linear mixed-effect models estimated adjusted changes in microvascular function with exposure. RESULTS: RHI was inversely associated with traffic-related pollutants such as ambient PM2.5 black carbon (BC), NOx, and carbon monoxide (CO). An interquartile range change increase (1.06 µg/m(3)) in 5-day average BC was associated with decreased RHI, -0.093 (95 % CI: -0.151, -0.035). RHI was inversely associated with other mobile-source components/tracers (polycyclic aromatic hydrocarbons, elemental carbon, and hopanes), and PM oxidative potential as quantified in two independent assays (dithiothreitol and in vitro macrophage ROS) in accumulation and ultrafine PM, and transition metals. CONCLUSIONS: Our findings suggest that short-term exposures to traffic-related air pollutants with high oxidative potential are major components contributing to microvascular dysfunction.

Development and evaluation of a novel monitor for online measurement of iron, manganese, and chromium in ambient particulate matter (PM).

A prototype atmospheric aerosol monitor was developed for online measurement of three toxicologically relevant redox-active metals (Fe, Mn, and Cr) in ambient fine particulate matter (PM2.5). The monitor has the unique ability to quantify these metals in specific chemical oxidation states in addition to both their total and water-soluble fractions in the ambient PM2.5. This information is critical for advancing our understanding of mechanisms of PM-induced toxicity as well as chemical processing of aerosol in the atmosphere. The metal monitor utilizes a high flow rate aerosol-into-liquid collector to collect ambient PM2.5 directly as concentrated aqueous slurry samples. The concentrations of target metals in the collected slurries are subsequently measured in a aerosol-into-liquid collector, micro volume flow cell (MVFC) using spectrophotometry to quantify the light absorption of colored complexes resulting from the reaction between the target metals and added analytical reagents. Our experimental evaluation indicated that, overall, this novel monitor can achieve accurate and reliable measurements over long sampling periods (i.e. at least several weeks). The online measurements for all three target elements were in good agreement (i.e., with slopes of the linear regression lines ranging between 0.90 and 1.07, and R(2) values between 0.76 and 0.95) with time-integrated filter samples collected in parallel and analyzed by magnetic sector inductively coupled plasma mass spectrometry (SF-ICPMS). Moreover, this metal monitor can provide semi-continuous measurements (i.e., every 2h) for at least 5 consecutive days without obvious shortcomings in its field operation. The online monitor measured total concentrations of Fe that ranged between 4.8 and 65.6ng/m(3), for Mn from below detection limit to 10.0ng/m(3), and for Cr from below detection limit to 6.6ng/m(3), respectively. Our results indicate that the developed metal monitor is a promising technology for online measurement and chemical speciation of important redox-active metals in ambient PM2.5.

Urinary Cadmium and Risk of Invasive Breast Cancer in the Women's Health Initiative.

Cadmium is a widespread heavy metal pollutant that may act as an exogenous estrogenic hormone. Environmental cadmium exposure has been associated with risk of breast cancer in retrospective studies. We prospectively assessed the relationship between cadmium exposure, evaluated by creatinine-normalized urinary cadmium concentration, and invasive breast cancer among 12,701 postmenopausal women aged ≥50 years in a Women's Health Initiative study of bone mineral density. After a median of 13.2 years of follow-up (1993-2010), 508 cases of invasive breast cancer and 1,050 comparison women were identified for a case-cohort analysis. Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals. Risk of breast cancer was not associated with urinary cadmium parameterized either in quartiles (comparing highest quartile with lowest, hazard ratio = 0.80, 95% confidence interval: 0.56, 1.14; P for trend = 0.20) or as a log-transformed continuous variable (per 2-fold higher urinary cadmium concentration, hazard ratio = 0.94, 95% confidence interval: 0.86, 1.03). We did not observe an association between urinary cadmium and breast cancer risk in any subgroup examined, including never smokers and women with body mass index (weight (kg)/height (m)(2)) less than 25. Results were consistent in both estrogen receptor-positive and estrogen receptor-negative tumors. Our results do not support the hypothesis that environmental cadmium exposure is associated with risk of postmenopausal breast cancer.

Oxidative potential of size-fractionated atmospheric aerosol in urban and rural sites across Europe.

In this study we applied several assays, an in vitro rat alveolar macrophage model, a chemical ROS probe (DTT, dithiothreitol), and cytokine induction (TNFα) to examine relationships between PM-induced generation of reactive oxygen species (ROS) and PM composition, using a unique set of size-resolved PM samples obtained from urban and rural environments across Europe. From April-July 2012, we collected PM from roadside canyon, roadside motorway, and background urban sites in each of six European cities and from three rural sites spanning the continent. A Hi-Vol sampler was used to collect PM in three size classes (PM>7, PM7-3, PM3) and PM was characterized for total elements, and oxidative activity quantified in unfiltered and filtered PM extracts. We measured a remarkable uniformity in air concentrations of ROS and especially DTT activity across the continent. Only a 4-fold difference was documented for DTT across the urban sites and a similar variance was documented for ROS, implying that chemical drivers of oxidative activity are relatively similar between sites. The ROS and DTT specific activity was greater at urban background sites (and also rural sites) than at urban canyon locations. PM3 dominated the size distribution of both ROS activity (86% of total) and DTT activity (76% of total), reflecting both the large contribution of PM3 to total PM mass levels and importantly the higher specific oxidative activity of the PM3 in comparison with the larger particles. The soluble fraction of total activity was very high for DTT (94%) as well as for ROS (64%) in the PM3. However in the larger PM size fractions the contributions of the insoluble components became increasingly significant. The dominance of the insoluble PM drivers of activity was particularly evident in the TNFα data, where the insoluble contribution to cytokine production could be 100-fold greater than that from soluble components. ROS and DTT activity were strongly correlated in the PM3 (r = 0.93), however oxidative activity was not correlated with any measured inorganic element in this size cut. In contrast, significant correlations of both ROS and DTT oxidative activity with specific groups of chemical elements were documented in the larger PM size fractions.

Urinary heavy metals in Hispanics 40-85 years old in Doña Ana County, New Mexico.

Exposure to As, Cd, Pb, and U among older Hispanic adults residing in underserved communities in southern New Mexico was investigated. Personal information was obtained by standardized interview from 188 adults aged 40-85 years. Urinary metal concentrations were measured and compared to results from the National Health and Nutritional Examination Survey (NHANES). Urinary As and U in study participants significantly (p < .05) exceeded NHANES reference values. Elevated urinary As concentration was significantly associated with older age, Latin American birthplace, clinic site, private-well drinking water, higher self-rated health, and diabetes. Higher urinary Cd was significantly associated with older age, clinic site, female sex, agricultural work, and current cigarette smoking. No personal characteristics were significantly associated with urinary Pb or U. Our results suggest elevated levels of As and U in this population.

Nrf2-related gene expression and exposure to traffic-related air pollution in elderly subjects with cardiovascular disease: An exploratory panel study.

Gene expression changes are linked to air pollutant exposures in in vitro and animal experiments. However, limited data are available on how these outcomes relate to ambient air pollutant exposures in humans. We performed an exploratory analysis testing whether gene expression levels were associated with air pollution exposures in a Los Angeles area cohort of elderly subjects with coronary artery disease. Candidate genes (35) were selected from published studies of gene expression-pollutant associations. Expression levels were measured weekly in 43 subjects (≤ 12 weeks) using quantitative PCR. Exposures included gaseous pollutants O3, nitrogen oxides (NOx), and CO; particulate matter (PM) pollutants elemental and black carbon (EC, BC); and size-fractionated PM mass. We measured organic compounds from PM filter extracts, including polycyclic aromatic hydrocarbons (PAHs), and determined the in vitro oxidative potential of particle extracts. Associations between exposures and gene expression levels were analyzed using mixed-effects regression models. We found positive associations of traffic-related pollutants (EC, BC, primary organic carbon, PM 0.25-2.5 PAH and/or PM 0.25 PAH, and NOx) with NFE2L2, Nrf2-mediated genes (HMOX1, NQO1, and SOD2), CYP1B1, IL1B, and SELP. Findings suggest that NFE2L2 gene expression links associations of traffic-related air pollution with phase I and II enzyme genes at the promoter transcription level.

Genetic variation in metallothionein and metal-regulatory transcription factor 1 in relation to urinary cadmium, copper, and zinc.

BACKGROUND: Metallothionein (MT) proteins play critical roles in the physiological handling of both essential (Cu and Zn) and toxic (Cd) metals. MT expression is regulated by metal-regulatory transcription factor 1 (MTF1). Hence, genetic variation in the MT gene family and MTF1 might influence excretion of these metals. METHODS: 321 women were recruited in Seattle, WA and Las Cruces, NM and provided demographic information, urine samples for measurement of metal concentrations by mass spectrometry and creatinine, and blood or saliva for extraction of DNA. Forty-one single nucleotide polymorphisms (SNPs) within the MTF1 gene region and the region of chromosome 16 encoding the MT gene family were selected for genotyping in addition to an ancestry informative marker panel. Linear regression was used to estimate the association of SNPs with urinary Cd, Cu, and Zn, adjusted for age, urinary creatinine, smoking history, study site, and ancestry. RESULTS: Minor alleles of rs28366003 and rs10636 near the MT2A gene were associated with lower urinary Cd, Cu, and Zn. Minor alleles of rs8044719 and rs1599823, near MT1A and MT1B, were associated with lower urinary Cd and Zn, respectively. Minor alleles of rs4653329 in MTF1 were associated with lower urinary Cd. CONCLUSIONS: These results suggest that genetic variation in the MT gene region and MTF1 influences urinary Cd, Cu, and Zn excretion.

Single Exposure to near Roadway Particulate Matter Leads to Confined Inflammatory and Defense Responses: Possible Role of Metals.

Inhalation of traffic-associated atmospheric particulate matter (PM2.5) is recognized as a significant health risk. In this study, we focused on a single ("subclinical response") exposure to water-soluble extracts from PM collected at a roadside site in a major European city to elucidate potential components that drive pulmonary inflammatory, oxidative, and defense mechanisms and their systemic impacts. Intratracheal instillation (IT) of the aqueous extracts induced a 24 h inflammatory response characterized by increased broncho-alveolar lavage fluid (BALF) cells and cytokines (IL-6 and TNF-α), increased reactive oxygen species production, but insignificant lipids and proteins oxidation adducts in mouse lungs. This local response was largely self-resolved by 48 h, suggesting that it could represent a subclinical response to everyday-level exposure. Removal of soluble metals by chelation markedly diminished the pulmonary PM-mediated response. An artificial metal solution (MS) recapitulated the PM extract response. The self-resolving nature of the response is associated with activating defense mechanisms (increased levels of catalase and glutathione peroxidase expression), observed with both PM extract and MS. In conclusion, metals present in PM collected near roadways are largely responsible for the observed transient local pulmonary inflammation and oxidative stress. Simultaneous activation of the antioxidant defense response may protect against oxidative damage.

Assessing the role of chemical components in cellular responses to atmospheric particle matter (PM) through chemical fractionation of PM extracts.

In order to further our understanding of the influence of chemical components and ultimately specific sources of atmospheric particulate matter (PM) on pro-inflammatory and other adverse cellular responses, we promulgate and apply a suite of chemical fractionation tools to aqueous aerosol extracts of PM samples for analysis in toxicity assays. We illustrate the approach with a study that used water extracts of quasi-ultrafine PM (PM0.25) collected in the Los Angeles Basin. Filtered PM extracts were fractionated using Chelex, a weak anion exchanger diethylaminoethyl (DEAE), a strong anion exchanger (SAX), and a hydrophobic C18 resin, as well as by desferrioxamine (DFO) complexation that binds iron. The fractionated extracts were then analyzed using high-resolution sector field inductively coupled plasma mass spectrometry (SF-ICPMS) to determine elemental composition. Cellular responses to the fractionated extracts were probed in an in vitro rat alveolar macrophages model with measurement of reactive oxygen species (ROS) production and the cytokine tumor necrosis factor-α (TNF-α). The DFO treatment that chelates iron was very effective at reducing the cellular ROS activity but had only a small impact on the TNF-α production. In contrast, the hydrophobic C18 resin treatment had a small impact on the cellular ROS activity but significantly reduced the TNF-α production. The use of statistical methods to integrate the results across all treatments led to the conclusion that sufficient iron must be present to participate in the chemistry needed for ROS activity, but the amount of ROS activity is not proportional to the iron solution concentration. ROS activity was found to be most related to cationic mono- and divalent metals (i.e., Mn and Ni) and oxyanions (i.e., Mo and V). Although the TNF-α production was not significantly affected by the chelexation of iron, it was greatly impacted by the removal of organics with the C18 resin and all other metal removal methods, suggesting that iron is not a critical pathway leading to TNF-α production, but a wide range of soluble metals and organic compounds in particulate matter play a role. Although the results are specific to the Los Angeles Basin, where the samples used in the study were collected, the method employed in the study can be widely employed to study the role of components of particulate matter in in vitro or in vivo assays.

Particulate metals and organic compounds from electronic and tobacco-containing cigarettes: comparison of emission rates and secondhand exposure.

In recent years, electronic cigarettes have gained increasing popularity as alternatives to normal (tobacco-containing) cigarettes. In the present study, particles generated by e-cigarettes and normal cigarettes have been analyzed and the degree of exposure to different chemical agents and their emission rates were quantified. Despite the 10-fold decrease in the total exposure to particulate elements in e-cigarettes compared to normal cigarettes, specific metals (e.g. Ni and Ag) still displayed a higher emission rate from e-cigarettes. Further analysis indicated that the contribution of e-liquid to the emission of these metals is rather minimal, implying that they likely originate from other components of the e-cigarette device or other indoor sources. Organic species had lower emission rates during e-cigarette consumption compared to normal cigarettes. Of particular note was the non-detectable emission of polycyclic aromatic hydrocarbons (PAHs) from e-cigarettes, while substantial emission of these species was observed from normal cigarettes. Overall, with the exception of Ni, Zn, and Ag, the consumption of e-cigarettes resulted in a remarkable decrease in secondhand exposure to all metals and organic compounds. Implementing quality control protocols on the manufacture of e-cigarettes would further minimize the emission of metals from these devices and improve their safety and associated health effects.