Environmental Health Perspectives

Bisphenol A and Peripheral Arterial Disease: Results from the NHANES

2012-05-29T04:00:00Z

Background: Bisphenol A (BPA) is a common chemical used in the manufacture of polycarbonate plastics and epoxy resins, with >93% of US adults having detectable BPA levels in urine. Recent animal studies have suggested that BPA exposure may have a role in several mechanisms involved in the development of cardiovascular disease (CVD), including weight gain, insulin resistance, thyroid dysfunction, endothelial dysfunction, and oxidative stress. However few human studies have examined the association between markers of BPA exposure and CVD. Peripheral arterial disease (PAD) is a subclinical measure of atherosclerotic vascular disease and a strong independent risk factor for CVD and mortality. In this context, we examined the association between urinary BPA levels and PAD in a nationally representative sample of US adults.

Methods: We analyzed data from 745 participants in the National Health and Nutritional Examination Survey 2003-2004. Associations between urinary BPA levels (in tertiles) and PAD (ankle-brachial index <0.9, n=63) were estimated using logistic regression models adjusted for potential confounders (age, gender, race/ethnicity, education, smoking, body mass index (BMI), diabetes mellitus, hypertension, urinary creatinine, estimated glomerular filtration rate, and serum cholesterol levels).

Results: We observed a significant, positive association between increasing levels of urinary BPA and PAD before and after adjustment for confounders. The multivariable-adjusted odds ratio (95% confidence interval) for PAD associated with the highest versus lowest tertile of urinary BPA was 2.69 (1.02-7.09); p-trend=0.01.

Conclusions: Urinary BPA levels were significantly associated with PAD, independent of traditional CVD risk factors.

Birth Weight Following Pregnancy During the 2003 Southern California Wildfires

2012-05-29T04:00:00Z

Background: In late October 2003, a series of wildfires exposed urban populations in southern California to elevated levels of air pollution over a period of several weeks. Previous research suggests that short-term hospital admissions for respiratory outcomes increased specifically as a result of these fires.

Objective: To assess the impact of a wildfire event during pregnancy on birth weight among term infants.

Methods: Using records for singleton term births delivered to mothers residing in California’s South Coast Air Basin (SoCAB) during 2001–2005 (N=886,034), we compared birth weights from pregnancies that took place entirely before or after the wildfire event (N=747,590) to those where wildfire occurred during the first (N=60,270), second (N=39,435), or third (N=38,739) trimester. The trimester-specific effects of wildfire exposure were estimated using a fixed-effects regression model with several maternal characteristics included as covariates.

Results: Compared to pregnancies before and after the wildfires, mean birth weight was estimated to be 7.0g lower (95% CI: -11.8, -2.2) when the wildfire occurred during the third trimester, 9.7g lower when it occurred during the second trimester (95% CI: -14.5, -4.8), and 3.3g lower when it occurred during the first trimester (95% CI: -7.2, 0.6).

Conclusions: Pregnancy during the 2003 southern California wildfires was associated with slightly reduced average birth weight among infants exposed in utero. The extent and increasing frequency of wildfire events may have implications for infant health and development.

Practical Advancement of Multipollutant Scientific and Risk Assessment Approaches for Ambient Air Pollution

2012-05-29T04:00:00Z

OBJECTIVES: The U.S. EPA is working toward gaining a better understanding of the human health impacts of exposure to complex air pollutant mixtures and the key features that drive the toxicity of these mixtures, which can then be used for future scientific and risk assessments.

DATA SOURCES: A public workshop was held in Chapel Hill, NC, February 22-24, 2011, to discuss scientific issues and data gaps related to adopting multipollutant science and risk assessment approaches, with a particular focus on the criteria air pollutants. Expert panelists in the fields of epidemiology, toxicology, and atmospheric and exposure sciences led open discussions to encourage workshop participants to think broadly about available and emerging scientific evidence related to multipollutant approaches to evaluating the health effects of air pollution.

SYNTHESIS: Although there is clearly a need for novel research and analytical approaches to better characterize the health effects of multipollutant exposures, much progress can be made by utilizing existing scientific information and statistical methods to evaluate effects of single pollutants in a multipollutant context. This work will have a direct impact on the development of a multipollutant science assessment and a conceptual framework for conducting multipollutant risk assessments.

CONCLUSIONS: Transitioning to a multipollutant paradigm can be aided through the adoption of a framework for multipollutant science and risk assessment that encompasses well-studied and ubiquitous air pollutants. Successfully advancing methods for conducting these assessments will require collaborative and parallel efforts between the scientific and environmental regulatory/policy communities.

Bisphenol A Diglycidyl Ether Induces Adipogenic Differentiation of Multipotent Stromal Stem Cells Through a Peroxisome Proliferator Activated Receptor Gamma-independent Mechanism

2012-05-25T04:00:00Z

Background: Bisphenol A (BPA) and bisphenol A diglycidyl ether (BADGE) are used for the manufacturing of coating and resins and leach from packaging materials into food. Numerous studies suggested that BPA and BADGE may have adverse consequences on human health, including the possibility that exposure to such chemicals could be superimposed on traditional risk factors to initiate or exacerbate the development of obesity. BPA is a suspected obesogen, whereas BADGE, described as a PPARγ antagonist, could reduce weight gain.

Objectives: We sought to test the adipogenic effects of BADGE in a biologically-relevant cell culture model.

Methods: We used multipotent mesenchymal stromal stem cells (MSCs) to study the adipogenic capacity of BADGE and BPA and evaluated their effects on adipogenesis, osteogenesis, gene expression and nuclear receptor activation.

Discussion: BADGE induced adipogenesis in mouse and human MSCs, as well as in mouse 3T3-L1 preadipocytes. In contrast, BPA failed to promote adipogenesis in MSCs, but induced adipogenesis in 3T3-L1 cells. BADGE exposure elicited an adipogenic gene expression profile and its ability to induce adipogenesis and expression of adipogenic genes was not blocked by known PPARγ antagonists. Neither BADGE nor BPA activated or antagonized RXR or PPARγ in transient transfection assays.

Conclusions: We conclude that BADGE can induce adipogenic differentiation in both MSCs and in preadipocytes at low nM concentrations, comparable to those that have been observed in limited human biomonitoring. BADGE probably acts through a mechanism that is downstream of, or parallel to PPARγ.

Placental Mitochondrial DNA Content and Particulate Air Pollution During in Utero Life

2012-05-24T04:00:00Z

BACKGROUND: Studies emphasize the importance of particulate matter (PM) in the formation of reactive oxygen species and inflammation. We hypothesized that these processes can influence mitochondrial function of the placenta and fetus.

OBJECTIVES: We investigated the influence of PM₁₀ exposure during pregnancy on the mitochondrial DNA-content (mtDNA content) of the placenta and umbilical cord blood.

METHODS: DNA was extracted from placental tissue (n = 174) and umbilical cord leukocytes (n = 176). Relative mtDNA copy numbers (i.e. mtDNA content) were determined by real-time PCR. Multiple regression models were used to link mtDNA content and in utero exposure to PM10 over various time windows during pregnancy.

RESULTS: In multivariate-adjusted analysis, a 10-µg/m³ increase in PM10 exposure during the last month of pregnancy was associated with a 16.1% decrease (95% CI: -25.2, -6.0%, p = 0.003) in placental mtDNA content. The corresponding effect-size for average PM10 exposure during the third trimester was 17.4% (95% CI: -31.8, -0.1%, p = 0.05). Furthermore, we found that each doubling in residential distance to major roads was associated with an increase in placental mtDNA content of 4.0% (95% CI: 0.4, 7.8%, p = 0.03). No association was found between cord blood mtDNA content and PM₁₀ exposure.

CONCLUSIONS: Prenatal PM₁₀ exposure was associated with placental mitochondrial alterations, which may both reflect and intensify oxidative stress production. The potential health consequences of decreased placental mtDNA content in early life must be further elucidated.

Chronic Cadmium Exposure In Vitro Causes Acquisition of Multiple Tumor Cell Characteristics in Human Pancreatic Epithelial Cells

2012-05-24T04:00:00Z

BACKGROUND: Studies link cadmium to human pancreatic cancer. Evidence suggests that cancer is a stem cell (SC)-based disease involving formation of cancer SCs (CSCs) potentially arising from transformation of normal SCs.

OBJECTIVE: We studied cadmium-exposure of human pancreatic ductal epithelial (HPDE) cells and whether SCs may be targeted in this process.

METHODS: We chronically exposed HPDE cells to low level cadmium (1 μM) for up to 29 weeks. We assessed tumor cell characteristics including secretion of matrix metalloproteinase-9 (MMP-9), invasion, and colony formation, fortified by gene expression of relevant genes by RT-PCR and Western blot. Non-adherent spheroid formation was used to indicate CSC-like cell production and we assessed tumor cell characteristics in such spheres.

RESULTS: In chronic cadmium exposed (CCE) cells (29 weeks of exposure) increased MMP-9 secretion and over-expression of the pancreatic cancer marker S100P occurred. CCE cells also showed markedly higher colony formation and invasion, typical of cancer cells. Floating “spheres” of viable cells, known to contain an abundance of normal SCs or CSCs, will form in vitro with many cell types. CCE cells produced 3-fold more spheres than control cells and were more invasive, secreted more MMP-9 and over-expressed markers for pancreatic SCs/CSCs (CXCR4, OCT4, CD44) and S100P, a marker for pancreatic cancer. CCE-derived spheres rapidly produced aggressive, highly branched and poorly differentiated glandular-like structures in Matrigel.

CONCLUSIONS: Chronic cadmium exposure produced multiple tumor cell characteristics in HPDE cells and derived spheres. These data support the plausibility of cadmium as a human pancreatic carcinogen.

Serum PBDEs in a North Carolina Toddler Cohort: Associations with Hand Wipes, House Dust and Socioeconomic Variables

2012-05-23T04:00:00Z

Background: Polybrominated diphenyl ethers (PBDEs) are persistent, bioaccumulative and endocrine disrupting chemicals.

Objectives: We used handwipes to estimate exposure to PBDEs in house dust among toddlers, and examined sex, age, breastfeeding, race and parents’ education as predictors of serum PBDEs.

Methods: Eighty-three children from 12 to 36 months of age were enrolled in North Carolina between May 2009 and November 2010. Blood, hand wipe, and house dust samples were collected and analyzed for PBDEs. A questionnaire was administered to collect demographic data.

Results: PBDEs were detected in all serum samples (geometric mean for ∑PentaBDE in serum was 43.3 ng/g lipid), 98% of the handwipe samples, and 100% of the dust samples. Serum ∑PentaBDEs were significantly correlated with both handwipe and house dust ∑PentaBDE levels, but were more strongly associated with handwipe levels (r = 0.57; p<0.001 versus r = 0.35; p<0.01). Multivariate model estimates revealed that handwipe levels, child’s sex, child’s age, and father’s education accounted for 39% of the variation in serum ∑BDE₃ levels (sum of BDE47, 99 and 100). In contrast, age, handwipe levels and breast feeding duration explained 39% of the variation in serum BDE 153.

Conclusions: Our study suggests that hand to mouth activity may be a significant source of exposure to PBDEs. Furthermore, age, socioeconomic status and breast feeding were significant predictors of exposure, but associations varied by congener. Specifically, serum ∑BDE₃ was inversely associated with socioeconomic status, while serum BDE153 was positively associated with duration of breastfeeding and mother’s education.

The Organochlorine o,p’-DDT Plays a Role in Coactivator-Mediated MAPK Crosstalk in MCF-7 Breast Cancer Cells

2012-05-18T04:00:00Z

Background: The organochlorine dichlorodiphenyltrichloroethane (DDT), a known estrogen mimic and endocrine disruptor, has been linked to animal and human disorders. However, the detailed mechanism(s) by which DDT affects cellular physiology remains incompletely defined.

Objectives: We and others have shown DDT activates cell signaling cascades, culminating in the activation of estrogen receptor-dependent and independent gene expression. Here, we identify a mechanism by which DDT alters cellular signaling and gene expression, independent of the estrogen receptor.

Methods: We performed a qPCR array analysis of gene expression in MCF-7 breast cancer cells using either estradiol or o,p’-DDT to identify distinct cellular gene expression responses. To elucidate the mechanisms by which DDT regulates cell signaling, molecular and pharmacological techniques were utilized.

Results: Estradiol and DDT treatment both altered the expression of many of the genes assayed, but upregulation of vascular endothelial growth factor A (VEGF-A) was observed following DDT treatment only and this increase was not affected by the pure ERα antagonist ICI. Furthermore, DDT increased the activation of the HIF-1 response element (HRE), a known enhancer of the VEGF-A gene. This DDT-mediated increase in HRE activity was augmented by the coactivator CBP and was dependent on the p38 pathway.

Conclusions: DDT upregulated the expression of several genes in MCF-7 breast cancer cells that were not altered by treatment with estradiol, including VEGF-A. We propose that this DDT-initiated, ER-independent stimulation of gene expression is due to DDT’s ability to initiate a crosstalk between MAPK signaling pathways and transcriptional coactivators.

The Temporal Lag Structure of Short-term Associations of Fine Particulate Matter Chemical Constituents and Cardiovascular and Respiratory Hospitalizations

2012-05-18T04:00:00Z

Background: In air pollution time-series studies, the temporal pattern of the association of fine particulate matter (PM_2.5) and health endpoints has been observed to vary by disease category. The lag pattern of PM_2.5 chemical constituents has not been well investigated, largely because daily data have not been available.

Objectives: Using daily PM_2.5 chemical constituent data for five years in the Denver Aerosol Sources and Health (DASH) study, we explored the lag structure for hospital admissions.

Methods: PM_2.5 constituents, including elemental and organic carbon, sulfate, and nitrate, were measured daily at a central residential site from 2003 through 2007 and linked to daily hospital admission counts in the five-county Denver metropolitan area. Total hospital admissions and subcategories of respiratory and cardiovascular admissions were examined. We assessed the lag structure of relative risks of hospital admissions for PM_2.5 and four constituents on the same day and one to fourteen previous days from a constrained distributed lag model, adjusting for temperature, humidity, longer term temporal trends, and day of week using a generalized additive model.

Results: Relative risks were generally larger at shorter lags for total cardiovascular admissions but at longer lags for total respiratory admissions. The delayed lag pattern was particularly prominent for asthma. Elemental and organic carbon generally showed more immediate patterns, while sulfate and nitrate showed delayed patterns.

Conclusion: In general, PM_2.5 chemical constituents were found to have more immediate estimated effects on cardiovascular diseases and more delayed estimated effects on respiratory diseases, depending somewhat on the constituent.

Obesity Is Mediated by Differential Aryl Hydrocarbon Receptor Signaling in Mice Fed A Western Diet

2012-05-18T04:00:00Z

Background. Obesity is a growing worldwide problem with genetic and environmental causes and an underlying basis for many diseases. Studies have shown that the toxicant-activated aryl hydrocarbon receptor (AHR) may disrupt fat metabolism and contribute to obesity. The AHR is a nuclear receptor/transcription factor that is best known for responding to environmental toxicant exposures to induce a battery of xenobiotic metabolizing genes.

Objectives. The intent of the work reported here was to test more directly the role of the AHR in obesity and fat metabolism in lieu of exogenous toxicants.

Methods. We used two congenic mouse models that differ at the Ahr gene and which encode AHRs with a 10-fold difference in signaling activity.

Results. The two Ahr mouse strains were fed a Western diet, which differentially affected body size, body fat:body mass ratios, liver size and liver metabolism, and liver mRNA and miRNA profiles. A low-fat regular diet had no significant differential effects.

Conclusions. The results suggest that the AHR plays a large and broad role in obesity and associated complications, and importantly, may provide a simple and effective therapeutic strategy to combat obesity, heart disease, and other obesity-associated illnesses.

Particulate Matter, DNA Methylation in Nitric Oxide Synthase, and Childhood Respiratory Disease

2012-05-16T04:00:00Z

Background: Air pollutants have been associated with childhood asthma and wheeze. Epigenetic regulation of nitric oxide synthase, the gene responsible for nitric oxide production, may be affected by air pollutants and contribute to the pathogenesis of asthma and wheeze.

Objectives: To investigate the association between air pollutants, DNA methylation, and respiratory outcomes in children.

Methods: Based on residential address and buccal sample collection date, 7 day, 1 month, 6 month and 1 year cumulative average PM_2.5 and PM₁₀ exposures were estimated for 940 participants in the Children’s Health Study. Methylation of 12 CpG sites in 3 NOS genes was measured using a bisulfite-polymerase chain reaction Pyrosequencing assay. Beta regression models were used to estimate associations between air pollutants, % DNA methylation, and respiratory outcomes.

Results: A 5 µg/m³ increase in PM_2.5 was associated with a 0.20% (95% CI -0.32, -0.07) to 1.0% (95% CI -1.61, -0.56) lower DNA methylation at NOS2A Position 1, 0.06% (95% CI -0.18, 0.06) to 0.58% (95% CI -1.13, -0.02) lower methylation at Position 2, and 0.34% (95% CI -0.57, -0.11) to 0.89% (95% CI -1.57, -0.21) lower methylation at Position 3, depending on the length of exposure and CpG locus. One year PM_2.5 exposure was associated with 0.33% (95% CI 0.01, 0.65) higher in average DNA methylation of 4 loci in the NOS2A CpG island. A 5 µg/m³ increase in 7 day and 1 year PM_2.5 was associated with 0.6% (95% CI 0.13, 0.99) and 2.8% (95% CI 1.77, 3.75) higher NOS3 DNA methylation. No associations were observed for NOS1. PM₁₀ showed similar but weaker associations with DNA methylation in these genes.

Conclusions: PM_2.5 exposure was associated with % DNA methylation of several CpG loci in NOS genes, suggesting an epigenetic mechanism through which these pollutants may alter production of nitric oxide.

Mercury, Cadmium and Lead Levels in Human Placenta: A Systematic Review

2012-05-16T04:00:00Z

Background: Placental tissue may furnish information on the exposure of both mother and fetus. Mercury, cadmium and lead are toxicants of interest in pregnancy, associated with alterations in child development.

Objectives: To summarize the available information regarding total mercury, cadmium and lead levels in human placenta and possible related factors.

Methods: Systematic search of PubMed, Medline, EMBASE, Lilacs, OSH and Web of Science for original papers on total mercury, cadmium or lead levels in human placenta, published in English or Spanish (1976-2011). Data on study design, population characteristics, collection and analysis of placenta specimens and main results were extracted using a standardized form.

Results: A total of 79 papers (73 different studies) were found. Mercury, cadmium and lead levels were reported in 24, 46 and 46 studies, respectively. Most studies included small convenience samples of healthy pregnant women. Studies were heterogeneous as to populations selected, processing of specimens and presentation of results. Mercury concentrations of over 50 ng/g were found in China (Shanghai), Japan and the Faroe Islands. Cadmium levels ranged from 1.2 ng/g to 53 ng/g, and were highest in USA, Japan and Eastern Europe. Lead showed the greatest variability, with levels ranging from 1.18 ng/g in China (Shanghai) to 500 ng/g in a polluted area of Poland.

Conclusion: The use of the placenta to assess heavy metals exposure is underdeveloped. International standardized protocols are needed to enhance comparability and increase the usefulness of this promising tissue in biomonitoring studies.

Di(2-ethylhexyl) Phthalate (DEHP) Impairs Female Fertility and Promotes Adipogenesis in C3H/N Mice

2012-05-15T04:00:00Z

Background: Di(2-ethylhexyl) phthalate (DEHP) and its metabolites are known to affect lipid metabolism and adipogenesis, mainly by activation of PPARs. Exposure to DEHP has been linked with testicular impairment and male subfertility. However, the effects of DEHP on female reproductive health and metabolism remain to be studied in detail.

Objectives: Analysis of dietary DEHP exposure on metabolism and fertility in female mice.

Methods: In two independent approaches, female C3H/N mice were exposed via their diet to DEHP [0.05, 5, 500 mg/kg bw/day] for 8 weeks. Food intake, weight gain and litter size were recorded. After exposure, liver, visceral fat, and plasma were analyzed by qRTPCR and ELISA in F0 females (Study I) and F0 dams and their F1 offspring (Study II).

Results: In Study I, F0 females had a significant increase in body weight, food intake, and visceral adipose tissue in all exposure groups compared with controls. In liver tissue, PPARα and PPARγ transcripts were significantly changed in the 500mg group. In the same group, PPARγ mRNA was significantly reduced in liver but not in fat tissue. Leptin and FABP4 mRNA were increased in adipose tissue, while adiponectin was decreased. In Study II, we detected a 100% abortion rate in F0 dams in the 500mg group. F1 offspring exposed in utero and during lactation had an increase in visceral fat tissue and body weight.

Conclusion: DEHP impaired fertility in high concentrations and increased body weight and visceral fat depots in female C3H/N mice in environmentally relevant dosages. Although DEHP exposure was only in utero and during lactation, metabolic changes induced by DEHP did also occur in the offspring of diet-exposed females.

Ambient Temperature and Biomarkers of Heart Failure: A Repeated Measures Analysis

2012-05-15T04:00:00Z

Background: Extreme temperatures have been associated with hospitalization and death among individuals with heart failure, but few studies have explored the underlying mechanisms. Objectives: We hypothesized that outdoor temperature in the Boston area (one to four day moving averages) would be associated with higher levels of biomarkers of inflammation and myocyte injury in a repeated-measures study of individuals with stable heart failure.

Methods: We analyzed data from a completed clinical trial that randomized 100 patients to 12 weeks of tai chi classes or time-matched education control. B-natriuretic peptide (BNP), C-reactive protein (CRP) and tumor necrosis factor were measured at baseline, 6 and 12 weeks. Endothelin-1 was measured at baseline and 12 weeks. We used fixed effects models to evaluate associations with temperature measures and adjusted for time-varying covariates.

Results: Higher apparent temperature was associated with higher levels of BNP beginning with two day moving averages and reached statistical significance for three and four day moving averages. CRP results followed a similar pattern, but were delayed by one day. A 5° C change in three and four day moving averages of apparent temperature was associated with 11.3% (95%CI: 1.1, 22.5, p=.03) and 11.4% (95%CI: 1.2, 22.5, p=.03) higher BNP. A 5° C change in the four day moving average of apparent temperature was associated with 21.6% (95%CI: 2.5, 44.2, p=.03) higher CRP. No clear associations with tumor necrosis factor or endothelin-1 were observed.

Conclusions: Among patients undergoing treatment for heart failure, we observed positive associations between temperature and both BNP and CRP, predictors of heart failure prognosis and severity.

A Three-Stage Algorithm to Make Toxicologically Relevant Activity Calls from Quantitative High Throughput Screening Data

2012-05-10T04:00:00Z

Background: The ability of a substance to induce a toxicological response is better understood by analyzing the response profile over a broad range of concentrations than at a single concentration. In vitro quantitative high throughput screening (qHTS) assays are multiple-concentration experiments with an important role in the National Toxicology Program’s (NTP) efforts to advance toxicology from a predominantly observational science at the level of disease-specific models to a more predictive science based on broad inclusion of biological observations.

Objective: To develop a systematic approach to classify substances from large scale concentration-response data into statistically supported and toxicologically relevant activity categories.

Methods: The first stage of the approach finds active substances with robust concentration-response profiles within the tested concentration range. The second stage finds substances with activity at the lowest tested concentration not captured in the first stage. The third and final stage separates statistically significant (but not robustly statistically significant) profiles from responses that lack statistically compelling support, or “inactives”. The performance of the proposed algorithm was evaluated with simulated qHTS data sets.

Results: The proposed approach performed well for 14 point concentration-response curves with typical levels of residual error (σ ≤ 25%) or when maximal response (|RMAX|) was greater than 25% of the positive control response. The approach also worked well in most cases for smaller sample sizes when |RMAX| ≥ 50%, even with as few as 4 data points.

Conclusions: The three-stage classification algorithm performed better than one-stage classification approaches based on overall F-tests, t-tests or linear regression.

Evaluation of Developmental Toxicants and Signaling Pathways in a Functional Test Based on the Migration of Human Neural Crest Cells

2012-05-09T04:00:00Z

BACKGROUND: Information on the potential developmental toxicity (DT) of the majority of chemicals is scarce, and test capacities for further animal-based testing are limited. Therefore, new approaches with higher throughput are required. A screening strategy based on the use of relevant human cell types has been proposed by the EPA and others. As impaired neural crest (NC) function is one of the known causes for teratologic effects, testing of toxicant effects on NC is desirable for a DT test battery.

OBJECTIVE: To develop a robust and widely applicable human-relevant NC function assay, allowing sensitive screening of environmental toxicants, and a definition of toxicity pathways.

METHODS: We generated NC cells from human embryonic stem cells, and after establishing a migration assay of NC (MINC), we tested environmental toxicants as well as inhibitors of physiological signal transduction pathways.

RESULTS: Methylmercury (50 nM), valproic acid (> 10 µM) and Lead-acetate (1 µM) affected migration of NC more potently than migration of other cell types. The MINC assay correctly identified the neural crest toxicants triadimefon and triadimenol, additionally it showed different sensitivities to various organic and inorganic mercury compounds. Applying classic pharmacologic inhibitors and large-scale microarray gene expression profiling, we found several signaling pathways that are relevant for the migration of NC in the MINC.

CONCLUSIONS: The MINC assay faithfully models human NC migration, and reveals impairment of this function by developmental toxicants with good sensitivity and specificity.

Selective Pressure of Antibiotic Pollution on Bacteria of Importance to Public Health

2012-05-08T04:00:00Z

BACKGROUND: Many bacteria of clinical importance survive and may grow in different environments. Antibiotic pollution may exert on them a selective pressure leading to an increase in the prevalence of resistance.

OBJECTIVES: Determine whether environmental concentrations of antibiotics and concentrations representing action limits used in environmental risk assessment may exert a selective pressure on clinically relevant bacteria in the environment.

METHODS: We used bacterial inhibition as an assessment endpoint to link antibiotic selective pressures to the prevalence of resistance in bacterial populations. Species sensitivity distributions were derived for three antibiotics by fitting log-logistic models to endpoints calculated from minimum inhibitory concentration (MIC) distributions based on worldwide data collated by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Bacteria represented in these distributions were placed in a broader context by performing a brief phylogenetic analysis. The potentially affected fraction of bacterial genera at measured environmental concentrations of antibiotics and environmental risk assessment action limits was used as a proxy for antibiotic selective pressure. Measured environmental concentrations and environmental risk assessment action limits were also directly compared to wild-type cut-off values.

RESULTS: The potentially affected fraction of bacterial genera at antibiotic concentrations measured in water environments is estimated not to exceed 7%. Measured environmental concentrations in river sediments, swine feces lagoons, liquid manure and farmed soil are estimated to inhibit wild-type populations in up to 60%, 92%, 100% and 30% of bacterial genera, respectively. At concentrations used as action limits in environmental risk assessment, erythromycin and ciprofloxacin are estimated to inhibit wild-type populations in up to 25% and 76% of bacterial genera.

CONCLUSIONS: Measured environmental concentrations of antibiotics and concentrations representing environmental risk assessment action limits are high enough to exert a selective pressure on clinically relevant bacteria that may lead to an increase in the prevalence of resistance.

Plasmid-Mediated Quinolone Resistance Genes and Antibiotic Residues in Wastewater and Soil Adjacent to Swine Feedlots: Potential Transfer to Agricultural Lands

2012-05-08T04:00:00Z

BACKGROUND: Inappropriate use of antibiotics in swine feed could cause accelerated emergence of antibiotic resistance genes, and agricultural application of swine waste could spread antibiotic resistance genes to the surrounding environment.

OBJECTIVES: This study was conducted to investigate the distribution of plasmid-mediated quinolone resistance (PMQR) genes from swine feedlots and their surrounding environment

METHODS: We used a culture-independent method to identify PMQR genes and estimate their levels in wastewater from seven swine feedlot operations and corresponding wastewater-irrigated farm fields. Concentrations of (fluoro)quinolones in wastewater and soil samples were determined by ultra-performance liquid chromatography-electrospray tandem mass spectrometry

RESULTS: The predominant PMQR genes in the samples were qnrD, qepA and oqxB, whereas qnrS and oqxA were present only in wastewater samples. Absolute concentrations of all PMQR genes combined ranged from 1.66×10⁷ to 4.06×10⁸ copies/mL in wastewater and 4.06×10⁶ to 9.52×10⁷ copies/g in soil. Concentrations of (fluoro)quinolones ranged from 4.57 to 321 ng/mL in wastewater and below detection limit to 23.4 ng/g in soil. Significant correlations were found between the relative abundance of PMQR genes and (fluoro)quinolone concentrations (r =0.71, p=0.005) and the relative abundance of PMQR genes in paired wastewater and agricultural soil samples (r =0.91, p =0.005)

CONCLUSIONS: Swine feedlot wastewater may be a source of PMQR genes that could facilitate the spread of antibiotic resistance. To our knowledge, this is the first study to examine the occurrence of PMQR genes in animal husbandry environments using a culture-independent method.

Maternal Exposure to Polycyclic Aromatic Hydrocarbons and 5’-CpG Methylation of Interferon-γ in Cord White Blood Cells

2012-05-04T04:00:00Z

Background: Maternal factors are implicated in the onset of childhood asthma. Differentiation of naïve CD4+ T lymphocytes into pro-allergic T helper 2 cells induces interleukin (IL)4 expression and inhibits interferon (IFN)γ expression accompanied by concordant methylation changes in the promoters of these genes. However, it has yet to be established if maternal exposure to polycyclic aromatic hydrocarbons (PAHs) can alter these gene promoters epigenetically during fetal development.

Objectives: This study sought to elucidate the relationship between maternal PAH exposure and promoter methylation status of IFNγ and IL4.

Methods: We assessed the effects of benzo[a]pyrene (BaP), a representative airborne PAH, on the methylation status of the IFNγ and IL4 promoters in Jurkat cells and two lung adenocarcinoma cell lines, and on gene expression. In addition we evaluated methylation status of the IFNγ promoter in cord white blood cells from 53 participants in the Columbia Center for Children's Environmental Health cohort. Maternal PAH exposure was estimated by personal air monitoring during pregnancy.

Results: In vitro exposure of the cell models to low, non-cytotoxic doses (0.1 and 1 nM) of BaP elicited increased promoter hypermethylation and reduced expression of IFNγ, but not IL4. IFNγ promoter methylation in cord white blood cells was associated with maternal PAH exposure in the cohort study subsample.

Conclusion: Consistent with the results for the cell lines, maternal exposure to PAHs was associated with hypermethylation of IFNγ in cord blood DNA from cohort children. These findings support a potential role of epigenetics in fetal reprogramming by PAH-induced environmental diseases.

Controlled Exposure Study of Air Pollution and T Wave Alternans in Volunteers without Cardiovascular Disease

2012-05-02T04:00:00Z

Background: Epidemiological studies have assessed T wave alternans (TWA) as a possible mechanism of cardiac arrhythmias related to air pollution in high risk subjects and have reported associations with increased TWA magnitude.

Objective: In this controlled human exposure study we assessed the impact of exposure to concentrated ambient particulate matter (CAP) and ozone (O₃) on T wave alternans in resting volunteers without pre-existing cardiovascular disease.

Methods: 17 participants without pre-existing cardiac disease were randomized to filtered air (FA), CAP (150 μg/m³), O₃ (120 ppb), or combined CAP+O₃ exposures for 2 hours. Continuous electrocardiograms (ECGs) were recorded at rest and T wave alternans (TWA) was computed by modified moving average analysis with QRS alignment for the artifact free intervals of 20 beats along the V2 andV5 leads. Exposure-induced changes in the highest TWA magnitude (TWA_Max) were estimated for the first and last 5 minutes of each exposure (TWA_{Max_}Early and TWA_{Max_}Late respectively). ∆TWA_Max (Late - Early) were compared among exposure groups using analysis of variance (ANOVA).

Results: Mean values for ∆TWAMax were -2.1 ± 0.4, -2.7 ± 1.1, -1.9 ± 1.5 and -1.2 ± 1.5 in FA, CAP, O₃ and CAP+O₃ exposure groups respectively; with no significant difference between pollutant exposures and FA.

Conclusion: In our study of 17 volunteers without pre-existing cardiovascular disease, we did not observe significant changes in T wave alternans after 2-hour exposures to CAP, O₃, or combined CAP+O₃. This finding, however, does not preclude the possibility of pollution-related effects on TWA at elevated heart rates, such as during exercise, or the possibility of delayed responses.

Respiratory Health Effects of Airborne Particulate Matter: The Role of Particle Size, Composition and Oxidative Potential - The RAPTES Project

2012-05-02T04:00:00Z

Background. Specific characteristics of particulate matter (PM) responsible for associations with respiratory health observed in epidemiological studies are not well established. High correlations among and differential measurement errors of individual components contribute to this uncertainty.

Objectives. Investigate which PM characteristics have the most consistent associations with acute changes in respiratory function in healthy volunteers.

Methods. We used a semi-experimental design to accurately assess exposure. We increased exposure contrast and reduced correlations among PM characteristics by exposing volunteers at 5 different locations- an underground train station, two traffic sites, a farm and an urban background site. Each of the 31 volunteers was exposed for 5 hours, while exercising intermittently, 3-7 times at different locations from March-October 2009. We measured PM₁₀, PM_2.5, particle number concentrations (PNC), absorbance, elemental/organic carbon, trace metals, secondary inorganic components, endotoxin content, gaseous pollutants, and PM oxidative potential (OP). Lung function (FEV₁, FVC, FEF_25-75, PEF) and fractional exhaled nitric oxide (FE_NO) were measured before and at three time points after exposure. Data were analyzed with mixed linear regression.

Results. An interquartile increase in PNC (33,000 particles/cm³) was associated with an 11% (95% confidence interval (CI): 5% to 17%) and 12% (95% CI: 6% to 17%) FENO increase over baseline immediately and two hours post-exposure, respectively. A 7% (95% CI: 0.5% to 14%) increase persisted until the following morning. These associations were robust and insensitive to adjustment for other pollutants. Similarly consistent associations were seen between FVC and FEV₁ with PNC, NO₂ and NO_X.

Conclusions. Changes in PNC, NO₂ and NO_X were associated with evidence of acute airway inflammation (FE_NO) and impaired lung function. PM mass concentration and PM₁₀ OP were not predictive of the observed acute responses.

Bisphenol A Induces Gene Expression Changes and Proliferative Effects through GPER in Breast Cancer Cells and Cancer-Associated Fibroblasts

2012-05-02T04:00:00Z

BACKGROUND: Bisphenol-A (BPA) is the principal constituent of baby bottles, reusable water bottles, metal cans and plastic food containers. BPA exerts estrogen-like activity interacting with the classical estrogen receptors (ERα and ERβ) and through the G protein-coupled receptor named Gpr30/Gper. In this regard, recent studies have shown that Gper was involved in the proliferative effects induced by BPA in both normal and tumor cells.

OBJECTIVES: We studied the transduction signaling pathways through which BPA influences cell proliferation and migration in breast cancer cells and cancer-associated fibroblasts (CAFs).

METHODS AND RESULTS: We used as a model system the SKBR3 breast cancer cells and CAFs that lack the classical ERs. Specific pharmacological inhibitors and gene-silencing procedures were used to show that BPA induces the expression of the Gper target genes c-FOS, EGR-1 and CTGF through the Gper/egfr/erk transduction pathway in SKBR3 breast cancer cells and CAFs. Moreover, we demonstrate that Gper is required for the growth effects and migration stimulated by BPA in both cell types.

CONCLUSIONS: Our results indicate that Gper is involved in the biological action elicited by BPA in breast cancer cells and CAFs. Hence, Gper-mediated signaling should be included among the transduction mechanisms through which BPA may stimulate cancer progression.

Current Status of the Epidemiologic Evidence Linking Polychlorinated Biphenyls and Non-Hodgkin Lymphoma, and the Role of Immune Dysregulation

2012-05-02T04:00:00Z

Background: While case-control studies conducted to date have largely affirmed the relationship between polychlorinated biphenyls (PCBs) and non-Hodgkin lymphoma (NHL), occupational cohort studies of PCB-exposed workers have been generally interpreted as negative, thereby raising doubts about a potential causal association. A common theme of immune dysregulation unifies many of NHL’s strongest risk factors, and several authors have posited that sub-clinical immune dysregulation may increase NHL risk by decreasing host resistance, reducing control of cellular proliferation and differentiation, and diminishing tumor surveillance mechanisms.

Objectives: The goals of this review are: I) to evaluate the epidemiological research examining the association between PCB exposure and NHL and discuss the contribution to the weight of evidence of case-control studies and occupational cohort studies; and II) to summarize the evidence for immune dysregulation as a means by which PCBs may cause NHL.

Methods: We performed a literature search using PubMed and 7 additional online biomedical and toxicological referencing libraries to identify literature published through August 2011.

Discussion and Conclusions: Overall, we conclude that the weight of evidence supports a causal role of PCBs in lymphomagenesis. The strongest epidemiological evidence for the relationship between PCBs and NHL comes from case-control studies conducted among the general population. Epidemiological and toxicological data demonstrating immunosuppressive and inflammatory effects of PCBs further contribute to the weight of evidence by providing a plausible explanation for how PCBs can cause NHL through immune dysregulation.

Profiling Environmental Chemicals for Activity in the Antioxidant Response Element Signaling Pathway Using a High-Throughput Screening Approach

2012-05-02T04:00:00Z

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of a variety of diseases ranging from cancer to neurodegeneration, highlighting the need to identify chemicals that can induce this effect. The antioxidant response element (ARE) signaling pathway plays an important role in the amelioration of oxidative stress. Thus, assays that detect the up-regulation of this pathway could be useful for identifying chemicals that induce oxidative stress.

OBJECTIVES: To utilize cell-based reporter methods and informatics tools to efficiently screen a large collection of environmental chemicals and identify compounds that induce oxidative stress.

METHODS: We utilized two cell-based ARE assay reporters, ß-lactamase and luciferase, to screen a U.S. National Toxicology Program 1408 (1340 unique) compound library for their ability to induce oxidative stress in HepG2 cells using quantitative high throughput screening (qHTS).

RESULTS: Roughly 3% (34 of 1340 unique) of compounds demonstrated activity across both cell-based assays. Based on biological activity and structure-activity relationship profiles, we selected 50 compounds for re-testing in the two ARE assays and in an additional follow-up assay that employed a mutated ARE linked to ß-lactamase. Based on this strategy, we identified 30 compounds that demonstrated activity in the ARE-bla and ARE-luc assays and were able to determine structural features conferring compound activity across assays.

CONCLUSIONS: Our results support the robustness of utilizing two different cell-based approaches for identifying compounds that induce ARE signaling. These methods are useful for prioritizing chemicals for further in-depth mechanism-based toxicity testing.

Satellite-based Estimates of Ambient Air Pollution and Global Variations in Childhood Asthma Prevalence

2012-05-01T04:00:00Z

Background: The effect of ambient air pollution on global variations and trends in asthma prevalence is unclear.

Objectives: To investigate community-level associations between asthma prevalence data from the International Study of Asthma and Allergies in Childhood (ISAAC) and satellite-based estimates of particulate matter with aerodynamic diameter <2.5 µm (PM_2.5) and nitrogen dioxide (NO₂), and modelled estimates of ozone.

Methods: We assigned satellite-based estimates of PM_2.5 and NO₂ at a spatial resolution of 0.1˚ x 0.1˚ and modelled estimates of ozone at a resolution of 1˚ x 1˚ to 183 ISAAC centres. We used centre-level prevalence of severe asthma as the outcome and multilevel models to adjust for gross national income (GNI) and centre- and country-level sex, climate and population density. We examined associations (adjusting for GNI) between air pollution and asthma prevalence over time in centres with data from ISAAC Phase One (mid-1900’s) and Phase Three (2001 – 2003).

Results: For the 13-14 year age group (128 centres in 28 countries) the estimated average within-country change in centre-level asthma prevalence per 100 children per 10% increase in centre-level PM_2.5 and NO₂ was -0.043 (-0.139, 0.053) and 0.017 (-0.030, 0.064) respectively. For ozone the estimated change in prevalence per ppbV was -0.116 (-0.234, 0.001). Equivalent results for the 6-7 year age-group (83 centres in 20 countries) though slightly different were not significantly positive.

For the 13-14 year age-group, change in centre-level asthma prevalence over time per 100 children per 10% increase in PM2.5 from Phase One to Phase Three was -0.139 (-0.347, 0.068). The corresponding association with ozone (per ppbV) was -0.171 (-0.275, -0.067).

Conclusion: In contrast to reports from within-community studies of individuals exposed to traffic pollution we did not find evidence of a positive association between ambient air pollution and asthma prevalence as measured at the community level.

Environmental Lead after Hurricane Katrina

2012-05-01T04:00:00Z

Environmental Lead: Rabito et al. Respond

2012-05-01T04:00:00Z

Stephen M. Levin: 1941–2012

2012-05-01T04:00:00Z

Common Bacterium Induces Histamine Production in Neutrophils

2012-05-01T04:00:00Z

Shark Fin Consumption May Expose People to Neurotoxic BMAA

2012-05-01T04:00:00Z